Korte 2005

Neuroscience and Biobehavioral Reviews 29 (2005) 338
www.elsevier.com/locate/neubiorev
The Darwinian concept of stress:

benefits of allostasis and costs of allostatic load
and the trade-offs in health and disease
S. Mechiel Kortea,*, Jaap M. Koolhaasb, John C. Wingfieldc, Bruce S. McEwend
a
Animal Sciences Group, Wageningen University and Research Centre, Box 65, Edelhertweg 15, 8200 AB Lelystad, The Netherlands
b
Department of Animal Physiology, University of Groningen, Box 14, 9750 AA Haren, The Netherlands
c
Department of Zoology, Box 351800, University of Washington, Seattle, WA 98195, USA
d
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
Abstract
Why do we get the stress-related diseases we do? Why do some people have flare ups of autoimmune disease, whereas others suffer from
melancholic depression during a stressful period in their life? In the present review possible explanations will be given by using different
levels of analysis.
First, we explain in evolutionary terms why different organisms adopt different behavioral strategies to cope with stress. It has become
clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves)
within a population. The existence of these personality types (HawksDoves) is widespread in the animal kingdom, not only between males
and females but also within the same gender across species.
Second, proximate (causal) explanations are given for the different stress responses and how they work. Hawks and Doves differ in
underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks
preferentially adopt the fightflight response when establishing a new territory or defending an existing territory, while cautious Doves show
the freezehide response to adapt to threats in their environment. Thus, adaptive processes that actively maintain stability through change
(allostasis) depend on the personality type and the associated stress responses.
Third, we describe how the expression of the various stress responses can result in specific benefits to the organism.
Fourth, we discuss how the benefits of allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and
disease, thereby reinforcing a Darwinian concept of stress. Collectively, this provides some explanation of why individuals may differ in their
vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and nonaggressive Doves in a population.
A conceptual framework is presented showing that Hawks, due to inefficient management of mediators of allostasis, are more likely to be
violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and
inflammation. In contrast, Doves, due to the greater release of mediators of allostasis (surplus), are more susceptible to anxiety disorders,
metabolic syndromes, melancholic depression, psychotic states and infection.
q 2004 Elsevier Ltd. All rights reserved.
Keywords: Stress; Allostasis; Allostatic state; Allostatic load; Coping; Evolutionary stable strategy; Hawks; Doves; Fightflight; Freezehide; Darwin;
Evolution; Natural selection; Brain; Amygdala; Hippocampus; Locus coeruleus; Prefrontal cortex; Atypical depression; Melancholic depression; Chronic
fatigue; Psychosis; Rat; Birds; Human
* Corresponding author.
E-mail address: mechiel.korte@wur.nl (S.M. Korte).
0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2004.08.009
S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338
Contents
1. General introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Evolutionary explanations for individual variation in behavior . . . . . . . . . . . . . . . . . .

2.1. Theoretical considerations: evolutionary stable strategies . . . . . . . . . . . . . . . . . .
2.2. Variation in behavioral strategies in birds (Parus major) . . . . . . . . . . . . . . . . . . .
2.3. Variation in behavioral strategies in rodents (Mus musculus; Rattus norvegicus) .
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3. Proximate explanations for individual differences in physiology . . . . . .

3.1. Neuroendocrine differences between Hawks and Doves . . . . . . . .
3.2. Structural differences in neurobiology in Hawks and Doves . . . . .
3.3. The inverted U-shape curve of allostasis . . . . . . . . . . . . . . . . . . .
3.4. The benefits of allostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.1. Allostasis in relation to the animals natural environment
3.4.2. Allostasis and the emotional brain . . . . . . . . . . . . . . . . .
3.4.3. Allostasis and energy metabolism . . . . . . . . . . . . . . . . . .
3.4.4. Allostasis and the cardiovascular system . . . . . . . . . . . . .
3.4.5. Allostasis and the immune system . . . . . . . . . . . . . . . . .
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4. The costs of allostatic load . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4.1. Allostatic state, allostatic load and the emotional brain . . . . . . . . . . . . . . . . . . . . . .
4.1.1. Aggression, anti-social behavior and violence . . . . . . . . . . . . . . . . . . . . . .
4.1.2. Psychosocial challenge in mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.3. Psychosocial defeat in isolated rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.4. Psychosocial challenge in the visible burrow system with rats . . . . . . . . . .
4.1.5. Psychosocial conflict in tree shrews . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.6. Temporal dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.7. Altered MRGR balance in the limbic system . . . . . . . . . . . . . . . . . . . . . .
4.1.8. Increased CRF mRNA expression in the amygdala . . . . . . . . . . . . . . . . . .
4.1.9. Increased noradrenergic feed-forward . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.10. Altered 5-HT2A receptor, 5-HT1A receptor and 5-HT transporter expression
4.1.11. Decreased neurogenesis in the hippocampus . . . . . . . . . . . . . . . . . . . . . . .
4.1.12. Increased dendritic remodeling in the hippocampus . . . . . . . . . . . . . . . . . .
4.2. Allostatic load and energy metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Allostatic load and the cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Allostatic load and the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27
1. General introduction
Due to the pioneering work of Hans Selye [1], the use of
the word Stress has become popular all over the world.
However, despite the vast amount of scientific research
generated in this field the term stress has been a stumbling
block right from its first use. The term has so many different
meanings [2] that it becomes counterproductive by inhibiting a proper application and critical interpretation of
experimental results. Stress has mostly been associated
with negative events and consequences, i.e. it can take its
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toll on physical and mental health. There is, however, no

justification for the assumption that the expression of stress
responses always compromise health and/or welfare.
Indeed, the functional aspects of stress have been neglected
too often. The paradox of stress lies in the simultaneity of its
adaptive nature and its possible maladaptive consequences.
A somewhat modified version of Marius Tausks metaphor
[3] of water used by firemen can illuminate this paradox.
Firemen may use water to extinguish certain fires or to
prevent them. But if much water is used it can cause more
damage than the flames. Another risk is that increased water
usage can lead to a loss of water pressure, thereby making

efficient fire fighting impossible and contributing to the
spread of the fire. Just like the firemans water stress
responses are ideally beneficial but they can impose a cost to
the body, particularly when they are either elicited too often
or are inefficiently managed [4]. Recently, a new stress
concept has been developed. The concept of Allostasis [5
7] introduces new terminology that avoids the ambiguity of
the word Stress. In this concept, allostasis is defined as the
adaptive process for actively maintaining stability through
change [8]. The brain plays a central role in allostasis. By
controlling all the mechanisms simultaneously, the brain
can enforce its command and incorporate influential factors
such as experience, memories, anticipation, and re-evaluation of needs in anticipation of physiological requirements
[9]. Allostasis is important during both unpredictable
events, e.g. conflict in social hierarchies, competition for
resources, storms and natural disasters, and predictable
events, e.g. seasonal changes that trigger migration and
hibernation. The central idea is that cost to the body arises if
mediators of allostasis: adrenal hormones, neurotransmitters, or immuno-cytokines, etc. are released too often or if
they are inefficiently managed [4,7]. That cost is referred to
as Allostatic Load which can be described as the
cumulative wear and tear.
It is well known that, dependent on the environment,
some individuals are more vulnerable to stress-related
disease than others. This implies that a certain environmental condition may differentially affect allostatic loads in
different individuals. Charles Darwin [10] was the first to
understand that animal populations consist of individuals
that differ from one another in their adaptive qualities and
limitations. Those individuals possessing a variation that
confers some survival advantage in their natural habitat and
allows them to live long enough to successfully reproduce
are the ones that pass on their traits more frequently to the
next generation. This process has come to be known as
natural selection [10]. It is important to realize that natural
selection exerts genetic benefits by maximizing reproductive success of the adapted organisms even at the expense of
individual happiness, health and longevity [1113]. Thus,
individual health is not necessarily the primary goal.
Without doubt, the balance between allostasis and allostatic
load has been shaped in the course of evolution by trade-offs
on the basis of costs and benefits that occur at different
stages of the life cycle or that are affected by season, social
status, sex, or environmental change.
In building a new conceptual framework it is important to
consider different levels of analysis that can lead to
complementary explanations [14,15].
First, we provide evolutionary explanations for the fact
that different organisms adopt different behavioral strategies
in order to cope with stressful events. We discuss the
evolutionary significance of the stress response and the
variation of responsiveness among individuals in their
natural or ancestral environment.
Second, we give proximate (causal) explanations for the

different stress responses and we describe how they work.
Third and fourth, we emphasise that stress research
should consider a cost benefit analysis of the different
behavioral and physiological stress responses. Such an
analysis forms the basis of The Darwinian concept of
stress since the benefits of allostasis and the costs of
allostatic load produce trade-offs in health and disease. We
discuss how different personalities, each with associated
differences in underlying physiology and behavior, vary in
their vulnerability to stress-related diseases.
2. Evolutionary explanations for individual

variation in behavior
2.1. Theoretical considerations: evolutionary stable
strategies
Why do organisms adopt different behavioral strategies
for coping with stress? The question arises why variation is
maintained in a population or why a population does not
simply drift towards a homogeneous group of the most
successful phenotypes. There is some theoretical support for
the maintenance of individual variation within a population.
For instance, Maynard Smith [16] applied Game Theory to
animal behavior and found that natural selection tends to
maintain a balance between different behavioral traits and
strategies. The best example of such an evolutionary stable
strategy is the HawkDove game in which the aggressive
individuals are the so-called Hawks and cooperative,
relatively passive ones are the so-called Doves (see
Table 1), even though they may be members of the same
species. In a competitive situation the Hawk shows
aggressive behavior, stopping only when injured or when
the opponent submits. The Hawk generally wins the entire
resource. A successful Hawk produces more and larger
offspring than a hungry Dove but an unsuccessful Hawk
may have lower fitness because of energy loss, wounds,
blood loss and infection (Table 1).
When a Dove is faced by a Hawk that is likely to attack,
the Dove retreats and thereby avoids incurring any cost.
This strategy rests on the assumption that Doves are able to
recognize Hawks. Different types of information gathering
that may aid such discrimination have been described. Thus,
eavesdropping may allow the assessment of the aggressiveness and fighting ability of potential opponents before any
direct contest occurs [17,18]. Perception of visual (e.g. size,
breast stripes or colors), acoustic (e.g. song or vibration) or
chemical signals (pheromones) can also underlie discrimination [19]. When two Doves meet, they will equally share
the resource without a fight and hence at low cost. Thus,
from the perspective of controlling resources, both strategies may be successful. The existence of different
behavioral strategies is a widespread phenomenon in the
animal kingdom, not only between males and females, but
Table 1
The different geneenvironment interactions in Hawks and Doves and the consequences for fitness depend heavily on their biological role in a population, the
adopted behavioral strategy, the environmental context, food availability, and population cycle (see Sections 2.12.3)
Hawk
Dove
Behavioral strategy
Coping style
Emotional state
Biological role
Fightflight
Proactive
Aggressive and bold
Establish territory or defend existing territory
Exploration
Behavioral flexibility
Energy metabolism
Body damage (e.g. wounds, blood loss)
Advantage according to food availability
Advantage according to population cycle
Fast and superficial

Rigid and routine-like
High energy consumption
High risk
When stable and abundant
When density is high
Freezehide
Reactive
Non-aggressive and cautious
Adopt strategy to avoid danger within territory,
e.g. immobility
Cautious and thorough
Flexible
Energy conservation
Low risk
During food scarcity
When density is low
also within the same gender across species. In the following

paragraphs we provide (field) data of the Hawk and Dove
strategy in birds and rodents showing that both strategies
can be successful but under different environmental
conditions.
2.2. Variation in behavioral strategies in birds
(Parus major)
Field data, particularly in the great tit (Parus major)
suggests that the HawkDove strategy can be observed in
birds, e.g. [2023]. More specifically, juvenile males that
quickly visit all trees and explore the environment in a
superficial way are very aggressive (fast superficial
explorers). In contrast, juvenile males that explore an
environment more thoroughly (slow-explorers) are nonaggressive [20,21]. The fast-superficial explorers take
greater risks in fighting (Hawks) and they approach novel
objects faster than the slow-explorers (Doves) ([21,24];
Table 1). Recent field studies support the view that the two
coping strategies have differential evolutionary fitness,
measured in terms of survival, in years that vary according
to food availability (Dingemanse et al. in press). The
aggressive fast-superficial explorers are more likely to
become founders of new populations because natal dispersal
distance correlated positively with aggression and because
immigrants were faster than residents [25]. Interestingly, the
different traits underpinning these strategies (e.g. high
versus low aggression, fightflight versus freezing, superficial versus thorough exploration, rigid and routine-like
versus flexible behavior) may not have evolved in isolation,
but rather as a package due to pleiotropy, gene-linkage or
co-selection [26].
Superficial fast-explorers (aggressive Hawks) may have
an advantage in areas with high food availability and stable
food distribution because they search for food in a routine
way, concentrating their search mostly on usual and known
items ([27]; Table 1). In contrast, when food is scarce, the
non-aggressive slow-explorers have an advantage because
they spend more time exploring the surroundings
thoroughly. This difference was elegantly demonstrated
when slow-explorers extended their search to many feeders

whereas superficial fast-explorers kept going to a food bowl
that has formerly contained food but that was now empty
[21,24]. The slow-explorers (non-aggressive Doves) pay
more attention to changes in their environment and thereby
probably gain more detailed knowledge of it [21]. By
thorough exploration, they learn where they can find water,
food, shelter and opponents. Interestingly, superficial
aggressive fast-explorers (Hawks) may profit from viewing
the behavior of slow-explorers because they copied a trained
tutor or even stole its food [27]. HawkDove strategies also
exist in mammals, like rodents, pigs and humans, as well as
in birds [2832].
2.3. Variation in behavioral strategies in rodents (Mus
musculus; Rattus norvegicus)
Rodents are probably the best-studied species with
respect to HawkDove strategies [33,34]. When exposed
to a large dominant conspecific, aggressive rats and mice
(Hawks) show flight behavior while the non-aggressive ones
(Doves) show freezing ([34]; Table 1). In addition, nonaggressive rats and mice show more freezing in response to
sudden silence and in the defensive burying test, whereas
the aggressive ones show more active behavior [34,35].
Further support for this dichotomy came from observations
of the aggressive and non-aggressive mice in the forced
swim test [36]. The aggressive mice continued to display
escape behavior, more climbing and swimming, even when
no escape was possible whereas the non-aggressive mice
showed relatively passive floating behavior, which can be
interpreted as very adaptive because it saves energy [37].
Surprisingly, wild-type rats showed no differences in
learning tests, such as the 8-arm radial maze or the Morris
water maze, nor in acute fear measured in the elevated plusmaze [34]. However, when tested for the second time in the
elevated plus-maze, the non-aggressive individuals spent
less time than aggressive ones in the open arms, suggesting
they had higher anxiety levels [36,38].
Interestingly, the non-aggressive mice showed active
defensive burying behavior when given sawdust from
their own home cages but they froze if fresh sawdust was
used, i.e. reactive coping. The aggressive mice always
showed burying behavior, i.e. proactive coping, regardless
of the type of bedding material [35]. In line with these
results, it has been suggested that aggressive individuals
(Hawks) easily develop routines relatively independently of
environmental stimuli (rigid behavior) whereas non-aggressive ones (Doves) are more perceptive of changes in their
environment and consequently show more flexibility in their
behavior [30,39,40].
Although female mice do not usually show territorial
aggression, those of a high aggression selection line showed
much more defensive burying than the females of the nonaggressive line, supporting the view that aggression is only
one of a larger set of behavioral characteristics that make up
the Hawk phenotype [30].
Field observations in wild house mice support the view
that fitness varies between the different behavioral phenotypes according to environmental conditions. Thus, low
aggressive male mice seem to be adapted to variable
conditions such as those encountered during migration,
whereas high aggressive male mice function better in stable
environments [41].
Clearly, the above-mentioned benefits of being a Hawk
or a Dove depend heavily on their biological role in a
population, the adopted behavioral strategy, the environmental context, food availability, and population cycle.
Hawks and Doves differ in emotional state, exploration
rates and energy metabolism that make them more or less
able to adapt to different environmental changes (Table 1).
Therefore, it is not surprising that the different behavioral
strategies require different underlying physiological mechanisms (see below). In the literature there is some
confusion about the dichotomy of behavioral phenotypes
[30] but clear bimodal distributions have been observed in
feral rodent and bird populations [24,42]. Recently, three
peaks in the frequency distribution of attack latency
emerged above a certain age in a population of 2500
laboratory-bred adult male wild-type rats [30,34]. The
existence of an intermediate group was explained by the
fact that there is little or no natural selection pressure in the
laboratory. In contrast, aggressive Hawk type individuals
appear to be missing from Wistar rat populations, probably
because these rats have been genetically selected for easy
handling [34].
3. Proximate explanations for individual

differences in physiology
3.1. Neuroendocrine differences between Hawks
and Doves
In order to adapt to a changing environment Hawks and
Doves not only differ in the type of behavioral responses
shown, i.e. fightflight versus freezehide, but also in their
Table 2
Differences between the neuroendocrine responses of Hawks and Doves to
acute threat
HPG-output (testosterone)
HPA-output
(cortisol or corticosterone)
Hypothalamus (CRF mRNA)
Hippocampus (MR mRNA)
Hippocampus (GR mRNA)
Pituitary (ACTH as % of
basal)
Adrenal cortex sensitivity
Neurosympathetic (NE)
Adrenomedullary (ECNE)
Parasympathetic (heart rate
variability)
Hawk
Dove
High
Low
Low
High
No response
No response, except
CA1[
No response
High
High
Low
No
response
High
Low
High
High
Low
High
Low
Medium
High
Definitions of acronyms: HPG, hypothalamicpituitarygonadal; HPA,

hypothalamicpituitaryadrenal; CRF, corticotropin-releasing factor;
mRNA, messenger ribonucleic acid; GR, glucocorticoid receptor; MR,
mineralocorticoid receptor; ACTH, adrenocorticotropic hormone; NE,
norepinephrine; E, epinephrine.
underlying physiology, neuroendocrinology (Table 2) and

neurobiology (Table 3). We provide proximate (causal)
explanations for the requirement for different stress
responses and for how they exert their actions. First though,
we list the differences in the physiological responses of
Hawks and Doves (Sections 3.1 and 3.2). Much of our
current thinking on variation in physiological responsivity is
derived from the work of Jim Henry [43]. He suggested, on
the basis of social conflict in mice, that two physiological
response patterns may be distinguished. This model was
further developed by Bela Bohus, Jaap Koolhaas and their
colleagues [30,44].
Hawks show a fightflight response originally described
by Cannon [45]. This behavioral response is characterized
by high activation of the sympathetic adrenalmedullar
system. Sympathetic activation of the adrenal medulla
results in high levels of epinephrine (E) in the blood, while
nerve terminals release large quantities of norepinephrine
(NE) into the synaptic cleft and consequently into
the bloodstream ([46]; Table 2). Furthermore, during fight
an activation of the hypothalamicpituitarygonadal (HPG)
axis, as reflected by an increase in plasma testosterone, has
been observed [47]. On the other hand, the freezehide
response shown by Doves is characterized by the activation
of the hypothalamicpituitaryadrenal (HPA) axis. More
specifically, the hypothalamus produces a neuropeptide
locally in the brain called corticotropin-releasing factor
(CRF) that, in turn, stimulates the pituitary gland to secrete
adrenocorticotropic hormone (ACTH) into the blood. This
stimulates the adrenal cortex to release corticosterone (in
birds, rodents) or cortisol (in pigs, humans). Interestingly, it
has been suggested that increased levels of corticosterone
operating via hippocampal mineralorticoid receptors (MRs)
Table 3
Structural differences in the dorsal hippocampus of Hawks and Doves
5-HT1A receptors (incl. mRNA)

Activity of MAPK1 cascade
Growth arrest specific 5 (GAS5)
Cytoskeleton gene-expression
Intra and infra-pyramidal mossy fiber
terminal fields
Hawk
Dove
High
Low
High
Low
Small
Low
High
Low
High
Large
Definitions of acronyms: 5-HT1A, 5-hydroxytryptamine 1A; MAPK1,

mitogen-activated protein kinase 1 pathway; mRNA, messenger ribonucleic acid.
induces fear-induced freezing behavior in rats [48]. There is

mounting evidence that individuals that preferentially show
the freezehide response are characterized by high parasympathetic reactivity [46,49]; this is particularly apparent
at times of high attention during the orienting reflex that
often precedes the freezing response [50]. Such individual
differences in physiological traits have also been observed
in fish, chickens, pigs and humans [2832,5153].
Differences at the brain level have also been observed in
aggressive and non-aggressive male mice. For example, the
level of MR mRNA in the CA1 of aggressive mice was
significantly higher than baseline 24 h after forced swimming [54]. Furthermore, forced swimming significantly
increased MR mRNA in all hippocampal regions (CA1,
CA2, CA3 and dentate gyrus) of non-aggressive mice
(Table 2). No effect of forced swimming was observed on
GR mRNA expression [54].
Under baseline conditions, high aggressive mice showed
a clear fluctuation in circulating corticosterone concentrations around the circadian peak with significantly higher
levels than non-aggressive mice in the late night phase [54].
In the dark phase this difference disappeared [54] or even
reversed [55]. No differences have been observed in mRNA
expression of the hippocampal mineralocorticoid receptor
(MR), the hippocampal glucocorticoid receptor (GR), or
hypothalamic CRF between aggressive and non-aggressive
mice under baseline conditions [54,56]. Independent of
circadian rhythm, baseline plasma ACTH levels were
always higher in the aggressive mice [54], suggesting that
the adrenal cortex is less sensitive to ACTH in aggressive
than non-aggressive mice. Furthermore, aggressive mice
had higher prenatal HPG axis activity [57]. Under baseline
conditions though, no differences in sympathetic and
parasympathetic activity were observed between aggressive
and non-aggressive rats [58].
In summary, Section 3.1 clearly shows that Hawks and
Doves differ in their underlying neuroendocrinology.
Hawks are characterized by high sympathetic reactivity
and high HPG axis activity, and by low parasympathetic
reactivity and low HPA axis reactivity. In contrast, Doves
are characterized by low sympathetic reactivity and low
HPG axis activity, but high parasympathetic reactivity
and high HPA axis reactivity. It is well known that the
hippocampus plays an important role in the regulation of

these neuroendocrine responses, but the hippocampus is
also involved in behavioral adaptation during and after
stressful conditions. Therefore in Section 3.2 special
attention is given to the structural neurobiological differences in the hippocampus of Hawks and Doves.
3.2. Structural differences in neurobiology in
Hawks and Doves
The brain plays a central role in maintaining stability
during times of change (allostasis). The structural differences, especially in the hippocampus (Table 3), between
Hawks and Doves may enable their respective ways of
coping, i.e. proactive and reactive. In agreement, high
aggressive rats have greater 5-hydroxy-tryptamine (5HT)1A/1B inhibitory autoreceptor function than non-aggressive ones [34,59]. Postsynaptically, both the number of 5HT1A receptors and the sensitivity of the 5-HT1A receptor
effector system are increased in aggressive rodents [6062].
This could well be a compensatory up-regulation induced by
a lower basal 5-HT neurotransmission, which is in
agreement with the serotonin deficiency hypothesis of
aggression as a trait characteristic [62]. In contrast,
aggressive behavior as a state characteristic shows the
opposite relationship, during aggression 5-HT neuronal
activity increases and the prevention of such activation
inhibits the expression of aggressive behavior [6062].
Other neurotransmitters may also be involved in
aggression. For instance, high levels of vasopressin release
(low storage levels) in the septum of high aggressive rats
and mice are associated with high aggression [34], probably
via the involvement of the vasopressin V1a/1b receptor [63,
64]. There is some evidence that testosterone organizes
aggression during development or that it increases the
likelihood of aggression in a certain context by stimulating
vasopressin synthesis [65]. Higher impulsivity in aggressive
animals may well be a consequence of lowered activity of
the tonic 5-HT neurotransmitter system.
Differences in the dopaminergic system have also been
observed in mice and rats. A relatively low dopaminergic
reactivity of the nigrostriatal system has been reported in
active coping (fleeing) rats whereas a relatively higher
activity was apparent when reactive copers show freezing in
an open-field test [66,67].
Remarkably, the non-aggressive mice are characterized
by a better developed hippocampus (Table 3). Recently, in
Ron de Kloets laboratory [68,69] it has been shown that
non-aggressive mice (Doves) showed a higher expression of
cytoskeleton genes (e.g. alpha-tubulin, cofilin, dynamin) and
signal transduction genes (calmodulin-related genes,
MAPK1 or ERK2, raf-related oncogene, neurogranin), but
lower gene expression of growth arrest specific gene
(GAS5). Therefore, they speculated that in the nonaggressive mice an upregulation of the calmodulin related
ras-raf-ERK2 pathway (MAPK1 cascade) might be related
to differences in the behavioral strategies of non-aggressive

and high aggressive mice [68,69]. It is quite conceivable that
the observed changes in expression of cytoskeleton genes
may differentially influence neuronal outgrowth, morphology, and neural plasticity. In line with these findings
larger hippocampal mossy fibers have been observed in the
non-aggressive mice [70]. Previously, it was shown in mice
that were bred for individual differences in two-way
avoidance performance in a shuttle-box, that those showing
freezing had more mossy fibers synapting on basal dendrites
of hippocampal pyramidal neurons, whereas high avoidance
mice (flight) were characterized by less extended intra and
infra-pyramidal mossy fiber (IIP-MF) projections [71].
Therefore, it is hypothesized that the different behavioral
strategies shown by Hawks and Doves, especially in
behavioral flexibility, are related to the differences in their
hippocampal morphology. Interestingly, the lower GAS5
expression throughout the entire brain of non-aggressive
mice (Doves) suggests that morphological differences may
also be present in other brain structures [68,69].
In summary, with their morphologically better developed
hippocampus, it is suggested that Doves are very well able
to organize contextual information and incoming sensory
input (e.g. predators appearance, location, smell and sound,
avenues of escape, shelter, or storage of food) according to
relevant relationships among them. However, the trade-off
is a higher risk that Doves will develop anxiety disorders,
because Doves are more aware of danger signals in their
environment than are the bold Hawks.
3.3. The inverted U-shape curve of allostasis
Hippocampal functioning is highly dependant on the
circulating levels of corticosteroids. In healthy animals
there is a clear inverted-U relationship between allostasis
and its mediators (e.g. corticosteroids). Interestingly this
inverted-U relationship can also be observed for other
mediators of allostasis (serotonin, cytokines, etc.) and its
effects on emotional behavior, metabolism, immune system
and cardiovascular system. Munck and colleagues [72,73]
described a mechanism that may be relevant to allostasis in
the periphery: opposing curves of mediator concentration
and receptor concentration result in an inverted-U curve of
glucocorticoid concentration and effect [7375]. For
example, glucocorticoids permissively enhance target tissue
sensitivity to cytokine while simultaneously lowering the
concentration of cytokine [73]. However, an inverted-U
curve effect of glucocorticoid on the immune system can
also result from a dose-dependent difference in the
stimulation of mineralocorticoid receptors (MRs) and
glucocorticoid receptors (GRs), because low corticosterone
levels enhance T cell responses through MRs but suppress
them at high concentrations through GRs [76].
The brain is also a target for mediators of allostasis (e.g.
corticosteroids [77], testosterone, cytokines, central serotonin, central CRF, etc.). The presence of two receptor types
(MRs and GRs) for corticosteroids, with a difference in

neuroanatomical distribution and in affinity and binding
capacity for corticosteroids, forms the basis of an invertedU relationship between brain functioning and glucocorticoid
concentrations [78,79]. In rodents, MRs have a high affinity
for corticosterone and aldosterone and are almost saturated
under basal conditions. In contrast, GRs have a 10-fold
lower affinity for corticosterone than MRs and become
occupied only during danger and at the circadian peak, when
glucocorticoid levels are high [78,79]. Due to their
lipophilic nature glucocorticoids readily enter the brain
[80] and either bind to membrane receptors [81] or freely
cross neuronal cell membranes to bind to specific cytoplasmatic receptors [77,82]. Through the latter mechanism,
corticosteroids may lead to altered transcription of specific
genes resulting in changes in protein synthesis and,
consequently, in the regulation of enzymes, neurotransmitters and receptors [80,83]. In neurons, corticosteroids may
bind to two dramatically different intracellular receptors, the
mineralocorticoid receptor (MR) and the glucocorticoid
receptor (GR) [78]. Interestingly, the MRs and GRs are colocated in those brain structures (limbic system) that are
involved in the regulation of allostasis, such as hippocampus, septum, and amygdala [78,84]. GRs are widely
expressed in the brain and the highest concentrations are
found in most monoaminergic nuclei in the brainstem,
cerebral cortex and in regions involved in feedback
regulation of the HPA axis, for example hippocampus,
paraventricular hypothalamus, and pituitary [78,85,86]. The
numbers of MRs display a circadian rhythm whereas the GR
system does not [87]. Therefore, it is postulated that in
healthy organisms the hormone level mainly regulates GR
action while MR action is influenced by receptor density.
The inverted U-shape curve of allostasis has been clearly
demonstrated at the level of the hippocampus. The colocalization of both MRs and GRs in the hippocampus is at
the basis of this phenomenon. Glucocorticoids have
biphasic effects upon excitability of hippocampal neurons
that may underlie their biphasic actions during the diurnal
rhythm and after challenge and influence the magnitude of
long-term potentiation (LTP), as well as producing longterm depression (LDP) [8893]. It has been suggested that
hippocampal cholinergic theta activity, a rhythmic, sinusoidal waveform that occurs in alert, immobile rats
presented with threatening stimuli [94], is modulated by
corticosterone acting through MRs and GRs, and the
rapidity of the response suggests a non-genomic mechanism
[94]. More precisely, MR blockade by spironolactone
produced a marked decrease in theta amplitude whereas
GR blockade by RU 38486 produced exactly the opposite
response [95].
Other evidence for biphasic actions is observed when low
to moderate levels of glucocorticoids enhance acquisition of
tasks that involve the hippocampus, whereas high levels of
glucocorticoids disrupt task acquisition [9698].
10
The above mentioned biphasic actions can be explained

by the following cellular mechanisms in the hippocampus:
(a) under baseline conditions where mostly MRs but few
GRs are activated they are associated with small Ca2C
currents, and stable responses to repeated stimulation of
glutamatergic pathways and relatively small responses to
biogenic amines. Activation of MRs, therefore, seems to
guarantee a stable background of neuronal firing [79,99,
100]; (b) activation of GRs in addition to MRs, as is seen,
for example, after an aversive challenge, results in enhanced
Ca2C influx, and marked responses to biogenic amines, such
as 5-HT-induced hyperpolarization [101106]. Such activation, thus, seems to reduce cellular activity, which agrees
with the feedback mode by which corticosteroids facilitate
recovery [99]; (c) after aversive stimulation high glucocorticoid levels are able to replenish reduced serotonin levels in
the terminals to quicken recovery. In agreement it has been
reported that different challenges, e.g. foot shock, ether
anesthesia, cold exposure and noise stress [107110] or
systemic corticosterone administration enhances 5-HT
turnover in the hippocampus and medial amygdala in rats
[111]. Corticosteroids via GRs [109,112], but not MRs
[112], in the dorsal raphe nucleus increase extracellular 5HT levels by enhancing the catalytic efficiency of
tryptophan hydroxylase [113,114]. In agreement, the
corticosteroid synthesis blocker reduces 5-HT release in
the dorsal hippocampus [115]. Also, through another
mechanism, corticosteroids acting via GRs in the dorsal
raphe nucleus may restore 5-HT levels by functional
desensitization of 5-HT1A autoreceptors, resulting in
increased electrophysiological activity of 5-HT neurons
[116,117,118].
In summary, it can be concluded that in the course of
normal diurnal variation, at the start of an active day,
relatively low levels of corticosteroids exert permissive
effects via MRs. Such a MR-activation brings the mediators
of allostasis to peaks of readiness for the activities of the
day, while via GRs they prevent the mediators of allostasis
from overshooting [79]. As shown below corticosteroid
actions depend highly on the environmental context and
thereby play an important role in allostasis.
3.4. The benefits of allostasis
Before we go into detail about what role corticosteroids
play in the benefits of allostasis in the emotional brain, in
metabolism, in cardiovascular and immune system, it is
important to realize that steroids do not regulate physiology or behavior, rather they mainly induce chemical
changes in particular sets of cells or networks of neurons,
making certain physiological and behavioral outcomes
more likely in a certain context (natural environment) in
time, as a result of the strengthening or weakening of
particular cellular pathways [99,119121]. Thereby, steroids may exert permissive, preparative, stimulating and
suppressive actions [120].
3.4.1. Allostasis in relation to the animals

natural environment
In the laboratory, it has been shown that the effects of
steroids highly depend on the environment, for example
experimental elevation of circulating corticosterone levels
in captive white-crowned sparrows (Zonotrichia leucophrys) resulted in decreased activity [122]. However,
these same birds dramatically increased their perch
hopping activity if food was also removed from their
cages [122,123].
Although in the laboratory physiological differences
related to animal behavior has received much attention, the
question of how phenotypic flexibility of animals in their
natural environment is reflected in neuroendocrine mechanisms is much less well understood. Such natural
environments can be hostile due to unpredictable perturbation factors like food shortage and adverse weather, that
may disrupt the current life history stage, e.g. breeding,
migration [124131]. It has been shown in free-living birds
that the above mentioned labile perturbation factors trigger
an emergency life history stage, which consists of the
following major components [122,123].
1. Deactivation of the current life history stage
2. Active responses to the labile perturbation factors can be:
(a) Movements away from the source of the labile
perturbation factors (leave-it strategy).
(b) If the individual remains it will seek a refuge (takeit strategy).
(c) Seek a refuge first and then move away if conditions
do not improve (take-it at first and then leave-it).
3. Mobilization of stored energy sources such as fat and
protein to fuel the movement or to provide energy while
sheltering in a refuge.
4. Continued movement until a suitable habitat is discovered or the perturbation passes followed by resumption
of the normal life history stage.
As will be shown in several examples below, the
hypothalamicpituitaryadrenal (HPA) axis, plays a major
role in this emergency life history stage via a rapid
increase in corticosterone in order to maximize survival
[126,129,131136]. This emergency life history stage is
temporary (hours to days) and, once the perturbation
passes, the individual will return to its normal life history
stage [129,130].
In breeding pied flycatchers (Ficedula hypoleuca), a
slight increase in circulating corticosterone enhanced the
frequency of parental feeding of young but greater increases
led to decreased feeding of the nestlings and resultant high
mortality [137]. Body weights of adults remained constant
throughout this period. A further increase to very high levels
of corticosterone resulted in abandonment of territories and
nests and the death of all nestlings. The parents, however,
increased their body weight, and probably their survival rate
[137]. Breeding male white-crowned sparrows exposed to
severe storms in spring 1980 abandoned their nests and

territories. Plasma levels of corticosterone three-fold higher
than the normal baseline levels for that time of year [138,
139] and behavioral and physiological changes characteristic of the emergency life history stage were expressed
[140].
The HPA axis is also involved in regulating the
emergency life history stage outside the breeding season.
Willow tits, (Parus montanus), in southwest Sweden form
stable winter flocks with a dominance hierarchy consisting
of two adults that previously bred in the territory and two to
four unrelated juveniles [141144]. Because the forest area
can only host a limited number of winter flocks, competition
among juveniles for membership in a flock is intense, even at
the potential cost of becoming a subdominant individual. No
willow tits survive the winter as solitary floaters [145,146].
Plasma levels of corticosterone were higher in dispersing
juvenile willow tits than in those that had established
themselves in a winter flock [146]. It is possible that a
relatively slight increase in corticosterone secretion may be
sufficient to trigger dispersal behavior thereby providing
floaters with opportunities to find better feeding conditions
and/or empty places in winter flocks. It is unlikely that
elevated corticosterone levels reflected aggression among
juveniles because this has never been found in territorial
juveniles defending their flock status [146]. However, it
cannot be excluded that elevated corticosterone in dispersing
juvenile willow tits were due to the energy demands of the
migratory flight. To address this, free-living willow tits were
given corticosterone implants when juveniles were fighting
to become established in a flock [125]. Corticosterone
treatment resulted in restlessness associated with dispersal in
the juvenile birds, but not in adults. Furthermore, most
juveniles implanted with corticosterone disappeared from
the forest whereas controls remained. Those juveniles that
were treated with corticosterone and remained never actually
settled in a territory, but kept wandering over the entire study
area (several km2). In contrast, adults implanted with
corticosterone never left their territory. Although the latter
observation may reflect prior residency of adults and
dominance, mechanisms underpinning the juveniles
responses remain unknown [125].
It appears that patterns of corticosterone secretion may
also be highly variable in social groups of other birds. In a
wintering population of European blackbirds in southern
Germany subdominant juveniles reacted to labile perturbation factors such as cold and snow, by increasing their
corticosterone secretion whereas adults did not. Because
juvenile blackbirds are subordinate to adults, they migrate
away from the area [132] whereas willow tits are strictly
year-round territorial residents and live in flocks with a
strong hierarchy. Thus, it is highly likely that ecological and
behavioral differences between species have resulted in
differential responses of the HPA axis to adverse conditions.
It is important to bear in mind that the emergency life
history stage (leave it strategy) should ideally be triggered
11
while individuals have sufficient fat storage to fuel their

flight to a more benign area. Indeed, in dark-eyed juncos,
plasma levels of corticosterone were elevated when they
abandoned home ranges and moved away from a storm
[147], suggesting that hormones of the HPA axis are
involved in the regulation of survival strategies. Plasma
levels of corticosterone fell after the birds had found a
refuge [147].
The great tit (Parus major), which is a tree foraging nonhoarding Northern European species, leaves the forests if
the winter weather deteriorates and foraging sites become
covered with snow or ice. A related species, the willow tit,
hoards food as an emergency source and can therefore
remain in its winter territories [148]. Similar endocrine data
documenting the effects of severe winter weather have been
obtained for European blackbirds and Harris sparrows
(Zonotrichia querula) [132,149]. Note, however, that
Harris sparrows did not leave their home range (leave-it
strategy), but instead became inactive and waited for the
storm to pass (take-it strategy).
There may be common endocrine responses to labile
perturbation factors despite differences in taxa, distribution
and habitat. Oceanic birds such as common diving petrels
(Pelecanoides urinatrix) that forage in open ocean also
showed increased corticosterone secretion in response to
severe storms and changed their behavior consistent with an
emergency life history stage, i.e. they flew to islands
presumably to shelter (take it strategy) [134]. Collectively,
the results of field studies and of controlled laboratory
experiments indicate that glucocorticoids play a major role
in the regulation of emergency life history stages. The
biological function of an emergency life history stage is to
increase survival to maximize reproductive success in the
long-term. There is general agreement that natural selection
has favoured the laying and fertilizing of eggs (read genes)
rather than the health or welfare of the individual per se.
The most striking example can be observed in salmon [2]
that migrate back upriver to the waters of their birth where
they spawn the next generation. This trek is initiated by a
rise in cortisol and can take up to 9 months [90]. When they
begin their migration they stop feeding and the digestive
tract atrophies. The newly available energy is used for
migration and to optimize the structures involved in
reproductive success. By the time they spawn, after laying
and fertilizing the eggs, the high levels of cortisol have
exhausted their stores of energy and devastated their
immune systems [150,151]. The prolonged elevation of
cortisol is the presumed cause of death but this fatal
adaptive response enables the inception of the next
generation of salmon.
In summary, the activation of the HPA axis in diverse
hostile natural environments play a major role in the
emergency life history stage via a rapid increase in
corticosterone in order to maximize survival to maximize
reproductive success in the long-term. Corticosteroids
especially may be involved in triggering survival strategies,
12
such as moving away from a storm, dispersal and wandering

in juveniles, and migration.
3.4.2. Allostasis and the emotional brain
In the laboratory in rodents it has been shown that
corticosteroids act via the emotional brain to influence
behavior. Here we start with the preparative action of
corticosteroids. Prior to awakening an increase in corticosteroids stimulates exploratory behavior and food seeking
[152154]. In addition, MRs display a pronounced circadian
rhythmicity peaking around feeding time [87]. Such an
increase in MR function makes it possible that organisms
can detect sensory signals at significantly lower levels,
which may be functional because at feeding time many
species are more vulnerable to predation [155158]. There
is a growing body of evidence that glucocorticoids via MRs
play a critical role in mediating freezing behavior [48,121].
The freezehide strategy (e.g. in Doves) may be a very
adaptive response when a predator or other source of danger
is detected. All ongoing activities, such as feeding, drinking
or exploration, are suppressed. Freezing behavior itself may
reduce the likelihood of detection and attack from an
aggressive animal or a predator. If caught, freezing behavior
or a tonic immobility response may result in the predator or
attacker losing interest and moving away. During freezing
the animal remains very alert.
Early in life glucocorticoids (probably via GRs) can
already exert developmental actions on the septo-hippocampal cholinergic system that may serve to assist in setting
the tone of behavioral inhibition expression by modulating
the individuals underlying levels of threat-induced arousal
and attention to stimuli associated with threat [159,160].
Glucocorticoids via MRs may be involved in the process of
evaluating the situation (including surroundings), and
selecting an appropriate response through increased attention and the sensory integration of the relevant information
[86,161].
Circulating glucocorticoids reach a peak some minutes
after a dangerous event. There is a growing body of
evidence that suggests that glucocorticoids via brain GRmechanisms (especially hippocampal GRs) promote processes underlying contextual fear conditioning and fear
potentiation, consolidation of acquired information, episodic, and spatial memory [86,121,161168]. It is thought that
the hippocampus organizes contextual information and
incoming sensory input (e.g. predators appearance,
location, smell and sound) according to relevant relationships among them [167,168].
Glucocorticoids may also bind to GRs in noradrenergic
cell bodies in the nucleus tractus solitarius (NTS) to
potentiate norepinephrine release in the basolateral amygdala, as well as postsynaptically in the basolateral amygdala
to facilitate the norepinephrine signal cascade [169,170].
The consolidation of such memories is helpful to predict the
occurrence and nature of the next encounter and thereby
maximize the likelihood of survival. Interestingly, besides
glucocorticoids, catecholamines play also an important role

in the formation of strong emotional memories. It has been
reported that behavioral (muscle) activity is associated with
higher norepinephrine levels, while emotional stimuli are
more related to high epinephrine levels [171,172]. This
epinephrine release may also be functional because
epinephrine indirectly affects the brain to strengthen
emotional memory. More precisely, epinephrine does not
cross the bloodbrain barrier but activates vagal afferents to
the NTS. The NTS induces, indirectly via locus coeruleus
(LC), directly the release of norepinephrine into the
basolateral amygdala [169,170]. In agreement, it was
shown that people remember a series of images better
when they are told emotional details about them and
epinephrines memory-enhancing effect can be diminished
by beta-adrenoceptor blockers [173,174].
During a second encounter, visiting the prior dangerous
location, the animals first reaction is conditioned freezing
behavior, which is made possible by a permissive MRaction. Hippocampal MRs are already largely occupied at
low levels of corticosteroids and enable, via a non-genomic
action, the animal to freeze almost immediately after its
perception of warning signals (e.g. mix of contextual stimuli
such as smells, sounds or locations) previously associated
with danger [121,168].
When the environment is safe (e.g. no predators present)
extinction of passive avoidance, via a MR-mechanism [175]
and extinction of active avoidance, probably via a brain GRmechanism will take place [176]. However, when the
situation remains unclear fear potentiation may take place
via a GR mechanism [48,121].
Returning to the HawksDoves, the above mentioned
findings fit with the observation that Doves, with a higher
HPA axis reactivity and corticosteroid output, immediately
freeze via a non-genomic MR-mechanism after warning
signals that make them very alert to environmental changes.
Without any doubt the hippocampus plays an important role
in these corticosteroid-mediated effects. It is speculated that
Hawks, with their higher HPG-axis activity but lower HPA
axis activity, are more aggressive and bold but are less
impressed by or less aware of environmental changes.
Interestingly, the differences in HPA axis may also causally
be related to high aggression in the Hawks at the start of the
dark active period. The low corticosteroid levels in Hawks
may produce high aggression because experimentally
induced glucocorticoid hypofunction in rats increases
aggression [177]. Especially, total MR occupancy at the
beginning of the dark active period is a prerequisite for the
expression of aggressiveness, because MR antagonists
inhibit this type of aggressive behavior in rats [178,179].
Thus, these data suggest the binding of corticosteroids to
MRs is a prerequisite for the stimulation of aggression,
whereas GRs are involved in the suppression of high
aggression.
Differences in HPG-axis reactivity and consequently
testosterone levels may influence territorial aggression in
males during the breeding season, the correlation of plasma

testosterone and aggression appears to be limited to periods
of social instability when a male is challenged for his
territory by another male, or when mate-guarding a sexually
receptive female [180]. From songbirds it is reported that in
the winter non-breeding season, when plasma testosterone is
basal, exogenous dehydroepiandrosterone (DHEA) which is
converted into active sex steroids by steroidogenic enzymes
in the brain, increases malemale aggression and increases
territorial song and the size of an associated brain region in a
male songbird [181,182]. This is consistent with the
hypothesis that DHEA increases territorial behavior.
In summary, it can be concluded that at the start of an
active day, relatively low levels of corticosteroids stimulate
exploratory behavior and food-seeking and exert permissive
(tonic) effects via central MRs to facilitate aggression
(Hawks) or induce freezing (Doves). During freezing, a MR
action makes it possible that Doves can detect sensory
signals at significantly lower levels, which may be
functional because at feeding time they are more vulnerable
to predation. Later during the day, at higher corticosteroid
levels, suppressive actions via central GRs inhibit aggression. After detection of a predator or rival, high levels of
corticosteroids via central GRs promote processes underlying contextual fear conditioning and fear potentiation,
consolidation of acquired information, episodic, and spatial
memory. Since GRs are widely distributed throughout the
brain, including hypothalamus and brainstem nuclei, it is
expected that energy metabolism is also affected.
3.4.3. Allostasis and energy metabolism
Glucocorticoids, so-named because of their ability to
promote conversion of protein and lipids to usable
carbohydrates, serve the body well in the short run by
replenishing energy reserves after a period of activity, like
running away from a predator. Thus, glucocorticoids play an
important role in energy metabolism. Phasically activation
of GRs in the hypothalamic paraventricular nucleus (PVN),
arcuate nucleus or locus coeruleus (LC) is required for the
natural surge in carbohydrate ingestion and metabolism that
is essential at the onset of the active feeding cycle [183
185]. At this time-point glucocorticoid levels are high, the
bodys glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. During
situations when food is unavailable or exploring for food is
too dangerous, GR receptor activation may also cause the
breakdown (catabolic) and utilization of body fat and
protein to produce the essential carbohydrates [185]. In
contrast, glucocorticoids via MRs located within the PVN
tonically stimulate fat intake and fat deposition that occurs
during most meals of the feeding cycle [185].
Storing food as abdominal fat is extremely functional.
The stored fat can be used for migration, hybernation,
during periods of starvation or it can be mobilized in
females for breastfeeding. We still carry the so-called thrifty
(or greedy) genes which enable fat storage when food is
13
plentiful [186,187]. This can clearly be observed in

Australian aborigines, some native Americans, Pima indians
and other recently westernized populations. We still react to
a psychological challenge with an increase in cortisol,
which is followed by greater food consumption, especially
of sweet things (carbohydrates) [188]. In normal rats
glucocorticoid infusion favors anabolic processes, such as
feeding behavior, body weight gain, and insulin output,
while promoting muscle insulin resistance, probably via the
parasympathetic system [189]. In principle, abdominal fat is
a wonderful way of securely storing fuel for times of need. It
is speculated that Doves, because of their higher HPA axis
activity, more easily store fat (Table 2).
In summary, tonic activation via MRs (in PVN)
stimulates fat intake and fat deposition during most meals
of the feeding cycle, while phasic activation of GRs (e.g. in
PVN) is required for the natural surge in carbohydrate
ingestion and metabolism when the bodys glycogen stores
are low. During situations when food is unavailable, GR
receptor activation causes the breakdown and utilization of
body fat and protein to produce essential carbohydrates.
Although fat deposition is an adaptive trait for hibernation
or migration it can be a risk factor for cardiovascular disease
in an overweight person (see Sections 4.2 and 4.3).
3.4.4. Allostasis and the cardiovascular system
Exploring for food, freezing to avoid detection, or
showing fight or flight during a conflict are all behaviors that
need their own specific autonomic changes that favour
redistribution of blood to vascular beds. It is important to
realize that complete behavioral strategies can be evoked by
chemical stimulation of the midbrain, which is associated
with specific autonomic changes favouring redistribution of
blood to vascular beds with increased metabolic needs
[190]. At least four different activation patterns can be
distinguished.
First, the layers of the superior colliculus (SC) receive
direct input from the retina and indirect input from the
visual cortex, and they respond better to the movement
(looming or fluttering) of a stimulus than its form [191,192].
The SC is functionally involved in the orienting reflex that is
characterized by turning the head and eyes toward sudden
changes in the environment to visually identify a potential
threat or prey [193]. Orienting is often followed by freezing
behavior and is associated with a relatively slower heart rate
(bradycardia) and hypertension [194,195]. Interestingly,
from the SC two different anatomical pathways have been
identified, the ipsilateral tecto-cuneiform descending projection that is involved in freezing and fleeing behavior and
the contralateral descending pathway that mediates contralateral movements that are involved in tracking or
pursuit, sometimes in association with biting [192].
Second, stimulation rostrally within the dorsolateral
periaqueductal grey (PAG) and lateral PAG evokes fight/
confrontational defence associated with hypertension and
tachycardia that is characterized by hind limb and renal
14
vasoconstriction, decreased blood flow to skeletal muscle

and viscera, but increased extracranial blood flow to
vasculature supplying skin and muscle of the oralfacial
region [196].
Third, stimulation caudally within the dorsolateral PAG
and lateral PAG evokes flight associated with hypertension
and tachycardia that is characterized by hind limb vasodilatation with increased blood flow to the skeletal muscles,
but extracranial and renal vasoconstriction with decreased
blood flow to viscera and extracranial vasculature [196].
Fourth, stimulation ventrolaterally with the PAG evokes
quiescence/immobility without orienting and is associated
with hypotension and bradycardia. This conservation
withdrawal type of response, first described by Engel and
Schmale in 1972 [197], is thought to support recovery and
healing [196]. It is important to remember that freezing
behavior reflects reactive coping [30], whereas conservationwithdrawal is a more passive coping style [197].
From the PAG and the cuneiform nucleus descending
projections go to brainstem nuclei (e.g. vagal complex and
adrenergic cell groups) where they regulate, respectively,
parasympathetic and sympathetic activity to induce the
necessary cardiovascular responses. The rostral (rVLM) and
caudal ventrolateral medulla (cVLM) are especially
involved in sympathetic activity [194,196]. According to
Porges in 1995 [198] two vagal components have evolved in
the brainstem to regulate parasympathetic functions. The
phylogenetically old reptilian part is the dorsal vagal
complex (DVC), which consists of the nucleus tractus
solitarius (NTS) and the dorsal motor nucleus of the vagus
(DMNX). It was hypothesized that the DMNX-induced
bradycardia may have evolved from an ancient gustatory
response, i.e. the primary method for identifying prey and
other food sources in aquatic environments [198201]. In
line with this hypothesis the DVC plays an important role in
energy conservation, apnoea, sphincter relaxation and
gastrointestinal activation. In mammals, however, bradycardia during orienting should be of short duration because
of their high oxygen need. The phylogenetically younger
mammalian ventral vagal complex (VVC) consists of the
nucleus ambiguus (NA) and nucleus retrofacial (NR). The
VVC is involved in vocalization and in bronchial contraction in favour of high oxygen need and energy utilization.
The VVC also provides a vagal brake that mammals combat
instantaneously (as shown by increased heart rate and
decreased heart rate variability) to increase metabolic output
in favor of fightflight [198201].
There is accumulating evidence that Hawks adopting the
fightflight response are characterized by a shift to
sympathetic dominance, while Doves often show the
orienting reflex and freezinghide responses associated
with increased parasympathetic activity [30,44,202].
3.4.5. Allostasis and the immune system
The risk of being wounded is greater in Hawks because
they are more aggressive and bolder than Doves. We have
already shown that they differ in sympathetic and parasympathetic activation and glucocorticoid secretion, but
how does this affect immune functioning? From an
evolutionary viewpoint it is important to realize that the
central nervous system, circulating adrenal hormones,
behavioral processes and the immune system influence
each other in ways that are central to the survival and wellbeing of the organism in its natural environment [203209].
This was first recognized by Bob Ader in 1975, who showed
that both an antibody response to antigen [210] and the
immunosuppressive effects of a drug can be classically
conditioned [211]. Now, we know that hard wiring links
exist between nerve fibers of both the sympathetic and the
parasympathetic nervous system and the immune system.
Sympathetic noradrenergic nerve fibers innervate the
vasculature and parenchymal fields of lymphocytes and
associated cells in several lymphoid organs, including the
thymus, spleen, lymph nodes, gut-associated lymphoid
tissue and bone marrow, in a variety of mammalian species
[212]. However, the parasympathetic system, with its
neurotransmitter acetylcholine, also innervates the immune
system [213]. Perhaps the best known immune mediators,
circulating glucocorticoids, have now been recognized as
having biphasic effects upon immune function [208,209].
Remarkably, glucocorticoids may produce a Thelper1/
Thelper2 (Th1/Th2) shift, from cellular towards humoral
immunity because Th1-related cytokines (e.g. IL-2, IFNgamma) stimulate cellular immunity Th2-related cytokines
(e.g. IL-4) and enhance humoral immunity [205,214,215].
The Th1 response protects against infections (viruses, m.
tuberculosis, etc.) and tumors, while the Th2 response
protects against gastrointestinal parasites (e.g. helminths).
Communication in the other direction, i.e. from immune
system to brain, also takes place. The immune system
communicates with the brain via a neural and a humoral
pathway [216]. Recently, it became clear that cytokine
receptors also exist in the brain [217]. Previously, it was
shown that interleukin-1 (IL-1), IL-6 and TNF stimulate
HPA axis activity via an increase in CRF in the PVN [218,
219]. Interestingly, the immune system also evokes changes
in hypothalamic noradrenergic neurons and in hippocampal
serotonergic neurons [220]. Finally, the brain itself can
produce cytokines. Further, IL-1beta gene expression is
increased in brain cells and is specifically related to
hippocampal long-term potentiation (LTP), a process
related to learning [221].
With the above mentioned findings it becomes much
easier to understand why differences in immune responses
between Hawks and Doves have been observed [222]. Due
to their different behavioral strategies Hawks and Doves are
confronted with different pathogens and Hawks are at
greater risk of wounding because of their aggressiveness
and boldness. It is speculated that increases in the levels of
catecholamines in Hawks result in elevated leukocyte
numbers in the blood, because it is known that catecholamines recruit the bodys soldiers, especially NK cells
and granulocytes [205]. Thus, this enhanced trafficking of

immune cells to places where they are needed to heal
wounds and fight infections might be a very functional
response in Hawks. Interestingly, humoral immunity
(via Th2) was higher in Doves than in Hawks [222,223].
It is speculated that Doves, because of their high exploration
in the search for new resources, incure a higher risk of
infection by parasites in the food, than the Hawks.
Therefore, from an evolutionary viewpoint a higher humoral
immunity (e.g. IgE) in Doves, directed against parasites, can
be seen as adaptive.
Previous experiments displayed consistent individual
behavioral and physiological HawkDove differences
between aggressive-active and non-aggressive-passive
pigs [222224]. The Hawks responded with a cell-mediated
immune activity, especially the Th1 response to nonspecific and specific antigens [222,223], and a higher natural
killer (NK) cell activity [225]. However, after aversive
stimulation, cellular mediated immunity was reduced to a
greater degree in the Hawk than Dove pigs [222]. This can
be explained as follows: catecholamines drive a Th2 shift at
the level of both antigen presenting cells (APCs) and Th1
cells (via beta2-adrenergic receptors, which are not present
on Th2 cells) [214]. Furthermore, glucocorticoids act
through their GRs on APCs to suppress the production of
the main inducer of Th1, IL-12 [214]. Thus, such
mechanisms may be involved in the prevention of a cellular
mediated immune overshoot. A shift from Th1 to Th2 may
counter the tissue-damaging effects of macrophages and
Th1 cells.
Both Doves and Hawks respond to inescapable threat
with HPA axis activation resulting in the release of
glucocorticoids that, in turn, induce a decrease in circulating
leukocytes. The specific GR agonist RU38362 caused a
rapid decrease in blood lymphocytes, monocytes and NK
cell numbers whereas a MR agonist failed to do so,
suggesting that glucocorticoids via GRs are involved in the
decrease in leukocytes [226,227]. This is not due to
immunosuppression, a widely spread dogma, but rather to
the redistribution of leukocytes, i.e. leukocytes exit from the
blood and take position at potential battle stations, such as
skin, lymph nodes, etc. [206]. Once immune cells have
begun to enter the tissue, other factors become involved as
local mediators of further activation of immune function.
For instance, IFN-gamma is known to induce expression of
antigen-presenting and cell-adhesion molecules on endothelial cells and macrophages and cell adhesion molecules
on leukocytes. It is also significant that glucocorticoids
induce IFN-gamma receptors on monocytes [207]. Thus,
after perception of an acute threat, release of the abovementioned mediators of allostasis prepare an organism for
potential immunologic challenges (i.e. wound or infection
inflicted by attacker). It is thought that peripherally released
cytokines act on the brain via a fast transmission pathway
involving primary afferent nerves innervating the bodily site
of inflammation and a slow transmission pathway involving
15
cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma
by volume transmission [216,228]. It is well accepted that
cytokines may produce sickness behavior, which is not a
maladaptive response, but rather an organized, evolved
behavioral strategy to facilitate the role of fever in
combating viral and bacterial infections [229]. It is thought
that immune overstimulation, which may lead to septic
shock, can be prevented through the vagus nerve pathway,
also named cholinergic anti-inflammatory pathway. Via
this parasympathetic route rapid inhibition of release of the
macrophage TNF, IL-1beta, IL-6 and IL-18 takes place
[230232].
In summary, the Th1 dominated cellular immune
response of Hawks and the Th2 dominated humoral immune
response of Doves are very adaptive and biologically
sensible because Hawks are at greater risk of wounds and
infections during fighting, while Doves with their exploratory nature and greater intake of new resources are more
likely to be contaminated with parasites. However, a shift
towards Th1 can also incur other disadvantages and costs to
the body such as autoimmune disease, whereas a shift
towards Th2 is known to increase vulnerability to viruses.
Now that we have discussed one side of the coin, the
benefits of allostasis, we will continue with the flip side,
the costs of allostatic load, because together they produce
trade-offs in health and disease. We will discuss how
different personalities, such as the aggressive Hawk and the
non-aggressive Dove, each with associated differences in
underlying physiology and behavior, differ in their allostatic
load and vulnerability to stress-related diseases.
4. The costs of allostatic load

4.1. Allostatic state, allostatic load and the emotional brain
Mediators of allostasis (e.g. adrenal hormones, neurotransmitters, and immuno-cytokines) act on receptors in
various tissues and organs to produce effects that are
adaptive in the short term but that can produce an allostatic
state which may be damaging if the mediators are not shut
off. Allostatic state refers to a state of chronic deviation of
the regulatory system from its normal mean operating level
[9]. As a result, the effects of the different mediators on
target cells are prolonged and may produce receptor changes
[233,234]. Four types of allostatic states leading to allostatic
load have been identified: (a) repeated challenges; (b)
failure to habituate with repeated challenges; (c) failure to
shut off the response after the challenge is over; and (d)
failure to mount an adequate response [7,234]. All changes
are not necessarily irreversible; an increasing amount of
data suggest that the body and the brain have a huge
capacity for adaptive plasticity. Below it will be shown that
social conflicts between males, involving high aggression
and threat (psychosocial conflicts), produce both an
16
allostatic state and allostatic load. The costs for the

aggressors (Hawks) and victims/losers tested under semilaboratory conditions, without the possibility of escape, are
quite different.
4.1.1. Aggression, anti-social behavior and violence
Several hormones are involved in the expression of
aggression. It is speculated that Hawks, with their higher
HPG-axis activity but lower HPA axis activity, are more
aggressive and bold but are less influenced by or less aware of
environmental changes than Doves. It is noteworthy that
testosterone does not cause aggression, it simply exaggerates
the pre-existing pattern and response to environmental
triggers of aggression [235]. Prolonged high levels of
circulating testosterone and low levels of corticosteroids
may incur costs that can potentially reduce lifetime fitness,
e.g. exposure to predators, increased risk of injury, loss of fat
stores and possibly altered immune system function [236].
However, Hawks with their higher testosterone levels have
an advantage when food is stable and abundant; consequently
they produce more offspring. Accordingly, it has been shown
in a population of mice, that males with high testosterone
outnumbered those with lower levels , but that eventually the
presence of too many aggressive mice resulted in a collapse
of the population [41]. In humans, especially male offenders,
plasma testosterone correlated positively with aggressive
acts, whereas the 5-HT function was inversely correlated
with impulsivity [237]. Several animal studies suggest the
involvement of tonic low 5-HT neurotransmitter levels in
aggression. For example, chronic anabolicandrogenic
steroid treatment during adolescence facilitated offensive
aggression in male hamsters, probably via significant
reductions in the number of 5-HT immunoreactive varicosities and fibers in anterior hypothalamus, ventrolateral
hypothalamus and medial amygdala [238]. Conversely,
loss of serotonin reuptake function in 5-HT transporter
knock-out mice causes reduced clearance of extracellular 5HT causing reduced aggression, increased anxiety-like
behaviors, and exaggerated hormonal responses [239].
Thus, increased tonic 5-HT neurotransmission may have
contributed to reduced aggression in these knock-outs [240].
Interestingly, lower corticosteroid levels may be causally
related to high aggression in Hawks because at the start of
the dark active period experimentally induced glucocorticoid hypofunction in rats increased aggression [179,241].
Decreased threat (attack signalling) and dramatically
increased targeting of attacks towards vulnerable parts of
the opponents body (mainly the head) were observed under
these conditions [241]. Thus, it is speculated that total MR
occupancy at the beginning of the active period, with low
GR occupancy, is a prerequisite for the expression of
violence [177179]. In agreement, increased aggressive
behavior in adolescent boys with low resting cortisol may be
strongly associated with lack of self-control [242].
Decreased morning cortisol levels also appear to be most
strongly associated with antisocial behavior in girls [243].
In addition to cortisol, the hormone dehydroepiandrosterone

(DHEA) may also be involved. In prepubertal boys suffering
from severe aggression and antisocial behavior, DHEA
levels were significantly positively correlated with the
intensity of aggression [244].
In summary, in Hawks low corticosteroid levels, high
DHEA and testosterone levels may be risk factors for high
aggression, anti-social behavior and violence. Low tonic 5HT neurotransmission may lessen anxiety and increase
impulsivity thereby worsening the situation. Confrontations
with such aggressors are a source of allostatic load in the
opponents and the victims of violence.
4.1.2. Psychosocial challenge in mice
Exposure to high levels of aggression, threat and/or
violence (psychosocial conflict or defeat) produces an
allostatic state in numerous species. The individuals
personality, for example Dove or Hawk, has a major
impact. For example, non-aggressive mice showed a
significant and much stronger corticosterone release and
body weight reduction than aggressive mice after sensory
contact with aggressive opponent for 5 and 25 days
[245,246]. Furthermore, the depressed seminal vesicle
weight after psychosocial challenge in the non-aggressive
mice (Table 4) suggests a lowered testosterone action on
target cells [245247]. The non-aggressive mice also had
lower thymus weights, lower MR mRNA expression and
less 5-HT1A binding in hippocampal CA1 ([245,246]; Table
4). Interestingly, GR mRNA was increased in the dentate
gyrus of non-aggressive mice after sensory contact with an
aggressive opponent for 5 days. Importantly, the aggressive
mice showed no such neuroendocrine effects [245,246]. In
addition, chronic sensory contact with an aggressive
opponent for 25 days induced a decrease in hippocampal
gene-expression in conserved helixloophelix ubiquitous
kinase (CHUK) in the dentate gyrus (DG) of non-aggressive
mice [248]. CHUK is a kinase that is involved in the
translocation of NFkB to the nucleus [249]. Moreover,
several genes belonging to ras-family members and
members of the Bcl-2 family are down-regulated in these
non-aggressive mice [248]. These findings suggest that
NFkB signalling is downregulated; NFkB plays a crucial
role in neuronal survival and synaptic plasticity [250252].
In summary, aggressive mice do not respond to sensory
contact with another aggressive animal, whereas nonaggressive ones do! This is consistent with the notion that
non-aggressive Doves are much more aware of danger in
their environment than bold Hawks (see also Table 1). Thus,
Doves are more responsive to threats, which in turn have
deleterious consequences, including decreased hippocampal
NFkB signaling and the resultant increase in neuronal
vulnerability.
4.1.3. Psychosocial defeat in isolated rats
It is becoming increasingly noticeable that it is primarily
Doves that are used in social defeat experiments because
17
Table 4
Psychosocial challenges in various animal models produce an allostatic state reflected by temporal changes in hormone levels, neurotransmitters, receptor
numbers, etc
Sensory contact with dominant in non-aggressive mice
5 days
25 days
Plasma corticosterone levels in mice

Testosterone action on target cells
5-HT1A receptor or mRNA in CA1
MR mRNA in CA1
GR mRNA in DG
NFkB signal transduction pathway genes
Psychosocial defeat in isolated non-aggressive rats
Sensitivity of the postsynaptic 5-HT1A receptoreffector system
5-HT1A receptor or mRNA in hippocampus
MR receptors in hippocampus and septum
GR receptors in hippocampus and hypothalamus
Feedback resistance
Psychosocial challenge in the visible burrow system with rats
Plasma corticosterone levels in dominants and subordinates
Plasma CBG levels in subordinates
Plasma testosterone levels in subordinates
5-HT1A receptor in DG and CA1 in dominants and subordinates
5-HT2 receptor in layer IV of parietal cortex in subordinates 5-HTT
expression in CA3 in dominants and subordinates
CA3 dendritic remodeling in dominants and subordinates
MR mRNA and GR mRNA in CA1 in subordinates
Tyrosine hydroxylase mRNA and protein in LC in subordinates
CRF mRNA in PVN in the hypothalamus in subordinates
CRF mRNA in CeA in subordinates
Psychosocial challenge in tree shrews
Plasma cortisol levels
Testosterone action on target cells (55 days*)
5-HT1A receptor in DG, CA1 and parietal cortex
CRF receptors in anterior lobe of the pituitary, DG, CA1CA3, SC
CRF receptors in frontal cortex, cingulate cortex, CeA, LA
MR mRNA in CA1, CA3, dentate gyrus: posterior part of hippocampus
MR mRNA in CA1, CA3, dentate gyrus: anterior part of hippocampus:
GR mRNA in CA1 and CA3
GR mRNA in dentate gyrus
Alpha2-adrenoceptor in LC
Alpha2-adrenoceptor in prefrontal cortex
CA3 dendritic remodelling
Neurogenesis in DG
Hippocampal volume
[
Y
Y
4
[
n.m.
7 days
n.m.
n.m.
4
Y
Y
[
n.m.
Y
Y
4
Y
21 days
Y
n.m.
Y
4
Y
1 day
Y
4
n.m.
n.m.
n.m.
14 days
[
Y
Y
Y
[
2 days
[
n.m.
4
n.m.
n.m.
n.m.
n.m.
n.m.
n.m.
Y
4
n.m.
n.m.
n.m.
Y
[
Y
[
[
10 days
[
n.m.
4
n.m.
n.m.
n.m.
n.m.
Y
4
Y
Y
n.m.
n.m.
n.m.
28 days
[
Y*
Y
Y
[
[
Y
Y
Y
Y
[
[
Y
Y
Definitions of acronyms: CeA, central nucleus of the amygdala; LA, lateral amygdala; LC, locus coeruleus; DG, dentate gyrus; CA1, cornu ammonis 1 (both
DG and CA1) are part of the hippocampus; PVN, paraventricular nucleus of the hypothalamus; MR, mineralocorticoid receptor; GR, glucocorticoid receptor;
CBG, corticosterone binding factor; SC, superior colliculus. [, increase; Y, decrease; 4, no difference; n.m., not measured.
the aggressive Hawk type personality is missing from the

Wistar populations prevalent in such studies [34]. This
might explain why similar responses are observed in nonaggressive mice and in Wistar rats [34]. For example, in
defeated rats, plasma testosterone levels were decreased for
several days [47]. GR-binding was also decreased in
the hippocampus and hypothalamus 1 week after social
defeat though no changes were observed in GR-binding in
the pituitary or in MR-binding in any of the regions analysed
[253]. Three weeks after defeat, GR-binding recovered in
the hippocampus and hypothalamus, but MR-binding in
septal and hippocampal tissue was markedly decreased
[253]. Furthermore, the ACTH response to CRF following
dexamethasone was significantly higher in defeated rats
than controls at both 1 and 3 weeks after defeat, suggesting

the development of feedback resistance in the defeated
animals [253]. Additionally, decreased HPA axis activity
after 5-HT1A receptor challenge was observed 24 h after
defeat, reflecting subsensitivity of the 5-HT1A receptor
effector system [254]. In addition, rats that had been
defeated once showed a gradual increase in immobility over
a period of 3 weeks in response to sudden silence. Chronic
treatment with the antidepressant clomipramine abolished
the long-term behavioral effects of social defeat [255].
Recently, an attenuated induction of hippocampal CA1
long-term potentiation (LTP) was observed after social
defeat that lasted for more than 3 months [256] (For more
details see Dr Bauke Buwaldas chapter elsewhere in this
18
issue). Remarkably, when familiar rats are housed together

several of the effects of social defeat are greatly reduced,
suggesting that social support can alleviate its negative
consequences [257]. In other more complex social models
such as the visible burrow system the animals social status,
(dominant or subordinate), can have different consequences.
4.1.4. Psychosocial challenge in the visible burrow
system with rats
The advantage of the visible burrow system as a social
conflict model is that an unstable social hierarchy can
produce different allostatic states depending on the social
status of the animal [258]. In this model five males and two
females are placed in an apparatus that has an open chamber
connecting with tunnels and compartments. A male usually
becomes dominant after some days and then controls access
to the food and water cups and to the females. The most
striking effects have been observed in the subordinates,
including progressive weight loss; strong thymic involution;
decreases in corticosterone binding globulin (CBG);
testosterone, insulin and glucose, whereas both subordinates
and dominants showed elevated plasma corticosterone
levels; adrenal hypertrophy and thymic involution [259,
260]. Furthermore, hippocampal 5-HT concentrations were
increased in subordinate rats [261]. Both subordinates and
dominants showed increased CA3 dendritic remodeling;
decreased 5-HT1A receptors in the hippocampus and
increased CRF mRNA in the PVN of the hypothalamus.
At the hippocampal level the dominants showed somewhat
more dendritic remodeling and somewhat greater downregulation of 5-HT transporter (5-HTT) in the hippocampus
[262], whereas subordinates also showed increased tyrosine
hydroxylase mRNA and protein in the LC; increased 5HT2A receptor binding in layer IV of parietal cortex;
downregulation of MR mRNA and GR mRNA in hippocampal CA1 and increased CRF mRNA in the CeA ([259,
260,262]; Table 4). Thus, an unstable hierarchy produces
robust changes in allostatic state depending on the social
status of the animal. Remarkably, subordinate males
sometimes die within 2 weeks of being exposed to such
an unstable social system [263].
4.1.5. Psychosocial conflict in tree shrews
Psychosocial conflict also elicits very robust changes in
allostatic state in primates, such as the tree shrew. Tree
shrews are very social animals and psychosocial conflict in a
residentintruder paradigm produces dramatic effects [264,
265]. For instance plasma cortisol levels were chronically
elevated in the intruder and hippocampal 5-HT concentrations were increased during conflict [265,266]. The 5HT1A receptor system reacts relatively slowly as shown by
the decreased number of hippocampal and cortex 5-HT1A
receptors. Also, hippocampal GR expression is downregulated 12 days after chronic social conflict [267]. The
numbers of CRF binding sites are reduced in the anterior
lobe of the pituitary, the dentate gyrus, the CA1CA3 areas
of the hippocampus, and in both the stratum griseum

superficiale and the stratum opticum of the superior
colliculus, while CRF binding sites are increased in the
frontal cortex, cingulate cortex, claustrocortex, CeA and the
lateral nucleus of amygdala 24 days after psychosocial
conflict [268]. It has been suggested that high local
concentrations of norepinephrine (NE), released from
terminals originating from the locus coeruleus (LC),
transiently down-regulated beta 1-adrenoceptors after 2
days of psychosocial conflict in the prefrontal cortex and the
olfactory area but that they were decreased after 28 days of
conflict in the parietal cortex and the hippocampus, while
apha2-adrenoceptors in the prefrontal cortex were transiently downregulated after 10 days then upregulated after 28
days [269]. These results indicate that the noradrenergic
system adapts to social conflict by counterbalancing its
receptor numbers relatively rapidly.
Repeated exposure of tree shrews to psychosocial conflict
for 28 days also induced remodelling of dendrites of CA3
neurons, which could be prevented by daily treatment of the
intruders with phenytoin, a drug that blocks the actions of
excitatory amino acids [270]. Chronic exposure to conflict
also resulted in a more substantial inhibition of neurogenesis
in tree shrews than did a single acute encounter [271,272];
moreover, the dentate gyrus was much smaller in the
chronically exposed tree shrew and hippocampal volume
was reduced [273,274]. Such reduction in neurogenesis can
be prevented by daily treatment with the antidepressants
tianeptine [273] or clomipramine [274]. Recently, it was
reported that the tianeptine reduced apoptosis (probably
of non-neuronal cells) in the temporal cortex and dentate
gyrus [275]. Furthermore, anhedonia and reductions in
exploratory activity are prevented by treatment with
antidepressants [276].
In summary, social challenges can produce an allostatic
state as observed by the changes ranging from hours to days
or weeks (Table 4). The temporal dynamics of these changes
may be very important in order to understand where the fine
line lies between the benefits of allostasis (adaptation) and
the potential costs of this adaptation (allostatic load).
4.1.6. Temporal dynamics
It is possible to suggest a sequence of changes in the
production of the allostatic state and allostatic load after a
social challenge. First, activation of the HPA axis, leading to
increased plasma corticosteroid levels, may negatively
affect gonadal function. As a consequence testosterone
secretion is significantly lowered in the (psychologically)
defeated individuals. Similar decreases in testosterone
levels have been observed in human patients [277] and
primates [278]. Decreases in testosterone concentrations
may be responsible for a general decrease in activity and
motivation, often associated with low self-esteem. The
global situation in which an organism is best off withdrawing and decreasing its effort is one in which that
effort would be wasted or would make a situation worse.
A confrontation with a dominant is wasted effort that is

likely to result in injury [279,280]. Thus, depressive-like
feelings (and low self-esteem) are part of a normal defense
[12]. There is some evidence that Doves more readily show
decreases in testosterone concentrations than Hawks. For
instance, high ranking male (by reproductive criteria) wild
olive baboons show a transient increase in testosterone
concentrations in the first hour after rapid capture and
immobilization, probably because of the high sympathetic
activity in these males and their lesser sensitivity to the
suppressive effects of glucocorticoids. In contrast, low
ranking males show a continuous decline in testosterone
levels [278].
4.1.7. Altered MRGR balance in the limbic system
Social conflict-induced HPA axis stimulation may also
produce dramatic differences in central MRGR balance
(Table 4). These observations agree with earlier findings
that MRs rather than GRs are reduced in number when
corticosteroid levels are elevated [281,282]. It has been
shown that glucocorticoid downregulation of the GR
requires extensive and prolonged exposure to extremely
high levels of corticosteroids [283]. In contrast, MR may
rather easily tonically inhibit GR biosynthesis in dorsal
hippocampus [282] by way of binding to glucocorticoid
response elements present in the GR promotor region [284].
Thus, as a consequence of downregulation of the MRs after
a dangerous encounter GR numbers may increase. The
initial MR downregulation and GR upregulation may be
functional. Corticosteroids via MRs prime the different
elements of allostasis, and bring it to peaks of readiness for
action (e.g. increased orientation and freezing, lower
sensory detection thresholds, higher alertness), which is
no longer of use after the threat has disappeared [121]. The
role of GRs is especially important after a dangerous
encounter. There is a growing body of evidence that
glucocorticoids via hippocampal GRs promote the organization of incoming sensory information (e.g. predators
appearance, location, smell and sound) according to
relevant relationships among them [86,121,167,285287].
The benefit of a more active hippocampus is an increased
survival because a second confrontation may be anticipated.
There are costs of such an adaptation: a reduction in the
population of MRs presents a risk of reduced fearextinction, whereas elevated numbers of GRs may increase
contextual fear conditioning and fear potentiation as well as
strenghtened consolidation of traumatic memories, thereby,
making the organism vulnerable to the development of
psychopathologies [121]. In agreement, it has been shown
that the time course of antidepressant actions on corticosteroid receptors closely follows that shown by clinical signs
of reduced depression [288,289], and antiglucocorticoid
therapy (e.g. metyrapone, RU38486) appears to be an
effective tool in the treatment of major depression [290,291,
292295], especially when it is associated with psychotic
features [296298].
19
4.1.8. Increased CRF mRNA expression in the amygdala

The above mentioned disturbances in MRGR balance,
especially the downregulated MRs which were observed in
all animal models shown here (Table 4), occur at the
beginning of a cascade of events that ultimately connect
anxiety with depression. The psychopathology may
develop as follows: a decrease in central MRs (and GRs)
may result, respectively, in elevated baseline plasma
corticosteroid levels (due to decreased MR function) and
prolonged increases corticosteroid levels after exposure to
threat (due to decreased GR function: feedback resistance)
[299]. Such feedback resistance was also observed in
defeated isolated rats. As a consequence, the chronically
elevated corticosteroid levels affect the central amygdala
(CeA). Indeed, corticosterone implants (for 7 days) led to
increases in both the basal level of CRF mRNA per neuron
and the number of neurons with CRF hybridization signal
in the CeA, which produced a concomitant enhanced
anxiety state in the elevated plus-maze [300,301]. In
agreement, that stereotaxic delivery of corticosterone to the
CeA elicited fear-potentiation in the elevated plus-maze as
well as colonic hypersensitivity, probably via descending
neuronal pathways from the CeA [302]. Rapid increases in
CRF mRNA levels have also been observed in the rostral
CeA region after acute restraint [303,304]. These findings
support the idea that chronic elevation of glucocorticoids
may increase anxiety by inducing CRF expression in the
amygdala. A large body of evidence indicates that high
levels of corticosteroids can facilitate the expression of
CRF mRNA in the CeA, in the lateral part of the bed
nucleus of the stria terminalis (BNST), and in the
hypothalamic paraventricular nucleus (PVN) [305312].
These effects are in agreement with the observed increased
concentrations of CRF mRNA in the PVN and CeA of
subordinate rats in the visible burrow system
([259,260,262]; Table 4). There is general agreement that
CRF, via its CRF1 receptors in the amygdala [313], is
involved in the regulation of fear, anxiety and depressed
mood [313,314]. Further, elevated concentrations of
cerebrospinalfluid CRF-like immunoreactivity have been
observed in depressed patients [315]. It has been suggested
that activation of the CeA mediates stimulus-specific (e.g.
lights, tones, touch) fears, whereas somewhat less explicit
information, such as that produced by exposure to a
threatening environment for several minutes, may activate
the BNST [316]. Because the nature of this information
may be less specific than that produced by an explicit cue,
as well as of much longer duration, activation of the BNST
may be more akin to anxiety than to fear [316,317].
Remarkably, in circumstances where attentional resources
are limited, or even in the absence of attention, processing
of emotional stimuli in the amygdala proceeds [318,319].
Thus, a corticosteroid-induced CRF mRNA increase in
BNST and in CeA can produce an allostatic state of
enhanced anxiety and fear, respectively [121,320,321].
This phenomenon might again increase the likelihood of
20
survival because the animal may respond earlier with

fleeing or freezing/hiding. In agreement, monkeys with
high cortisol levels showed longer durations of freezing
when exposed to frightening stimuli than those with
lower levels [322]. Similarly, shy children showed
relatively high morning levels of salivary cortisol and
were more behaviorally inhibited [323,324]. Remarkably,
it has been reported that adults who had been categorized
as inhibited infants showed greater functional MRI signal
response within the amygdala to novel versus familiar
faces than did uninhibited controls [325]. Additional
support comes from the finding that in rats high (but not
low) doses of corticosterone potentiated freezing to an
explicit auditory cue that had been previously been
paired with footshock [163]. However, the costs of an
enhanced state of fear and anxiety make the organism
more vulnerable to the development of psychopathology.
For example, chronic elevation of central CRF levels
produced a depressive-like state [326], HPA axis
dysregulation ([327] and autonomic activation [328]).
Accordingly, depressed patients have left amygdala
hyperactivity, even when processing stimuli outwith
conscious awareness, and this increased amygdala
activation is normalized with antidepressant treatment
[329]. Interestingly, glucose metabolism in the left
amygdala of depressive patients correlates positively
with cortisol levels [330]. Also, the larger amygdala
volumes in patients with first-episode depression suggest
that a hyperactive amygdala is one of the first steps in
the psychopathological cascade [331,332]. Sustained
(left) amygdala activity is observed in depressed
individuals [329,333,334] and may be due to higher
neuronal amygdala activity and blood flow [333].
Because the amygdala integrates information related to
fear and strong emotions and also sends outputs via the
CeA for autonomic arousal and via the basal nucleus for
more active aspects of coping [168], the elevation of
amygdala activity may be a first step that leads to
overactivation of systems involved in physiological and
behavioral coping. Recent findings suggest that the
amygdala has a pivotal role in negative affect as a
specific effect of its more general role in recruiting and
coordinating vigilant behavior towards stimuli with
undetermined (uncertain) contingencies [335]. Therefore
it was speculated that hyperactivation of the amygdala in
major depression may bias initial evaluation of and
response to incoming aversive and emotionally arousing
information [335].
4.1.9. Increased noradrenergic feed-forward

Once the amygdala has become hyperactive, as described
in Section 4.1.8, an organism is ready to enter the wild
roller coaster stage. CRF, originating from the CeA,
activates brainstem noradrenergic activity in the locus
coeruleus (LC), which in turn activates forebrain CRF
activity in the CeA and the BNST, where norepinephrine

(NE) stimulates CRF release. This view is supported by
reports that danger induces NE release in the CeA [336] and
that this stimulates release of CRF [337]. Evidence that CRF
originating from these NE terminal areas innervates the LC
region [338340] suggests that this last projection effectively closes the loop, making it a powerful feed-forward
loop. An increased level of the rate-limiting enzyme
tyrosine hydroxylase in catecholamine biosynthesis in the
LC of subordinate rats and the decreased alpha2-adrenoceptors in the LC of psychosocially challenged tree shrews
supports the existence of such a mechanism (Table 4).
Mounting data also suggest that there is a second positive
feedforward loop. Thus, elevated corticosteroid levels also
increase CRF levels in the hypothalamic paraventricular
nucleus (PVN) [305310]. From here a specific PVN CRF
pathway projects to the brainstem NE LC region, which in
turn innervates the PVN and closes the loop [341]. In
agreement, the amount of CRF mRNA was increased in
hypothalamic neurons of depressed patients who had
committed suicide, especially in those CRF neurons that
projected to brainstem NE nuclei [342]. According to
George Koob [313] such feed-forward CRFnoradrenaline
CRF systems may be especially important for making
behavioral adjustments in anticipation of changing demand.
It is speculated that such a feed-forward circle, with the
hyperactive LC at its center, produces a state of high arousal
and high attention. The benefit is heightened awareness of
possible threats in the environment. However, the costs of
such a feed-forward mechanisms may include greater
vulnerability to dysfunction, especially stress-sensitization
[313]. In agreement, a positive correlation between
hypercortisolism and increased cerebrospinalfluid NE has
been observed in patients suffering from melancholic major
depression [343]. Once the LC has become hyperactive this
core system may enter a vicious circle, because the LC can
inhibit the prefrontal cortex [344,345]. It has been suggested
that inhibition of the left medial prefrontal cortex (or left
sided defect) in melancholic depressed patients and
disinhibition of the right prefrontal cortex, causes activation
of the HPA axis and sympathetic system [346,347].
Moreover, there is some evidence that also the hippocampus
is impaired (see Sections 4.1.11 and 4.1.12). Although the
neural design of such a system favors rapid instinctual
responses over more complex ones to service survival
strategies in acute life-threatening situations (168), the costs
of allostatic load are dramatic. Indeed, it is hypothesized
that it can lead to psychopathological conditions such as
melancholic depression, which is characterized by a state of
pathological hyperarousal and feelings of anxiety, worthlessness and helplessness associated with decreased food
intake and insomnia ([347]; see Table 5). A hyperactive
CRF system may be partially responsible for these effects,
including loss of appetite, weight loss and diminished
activities of the growth hormone and reproductive axes
([341,348,349]; see Table 5).
4.1.10. Altered 5-HT2A receptor, 5-HT1A receptor and 5-HT

transporter expression
In parallel to the noradrenergic mechanisms outlined
above, substantial data suggest that 5-HT is also involved in
mood disorders. Social conflict increases the release of the
neurotransmitter 5-HT, and increased 5-HT levels may
produce an enhanced anxiety state. This notion is
supported by reports that anxiolytic drugs that reduce 5HT release in dorsal hippocampus, lateral septum and cortex
concomitantly decrease anxiety [350]. Psychosocial challenge in mice, rats and tree shrews induced a robust decrease
in expression of the inhibitory 5-HT1A receptor in the
hippocampus (especially CA1 and smaller effects in DG)
after some weeks (Table 4). Decreased HPA axis activity
after 5-HT1A receptor challenge has been observed 24 h
after social defeat in rats, reflecting hyposensitivity of the 5HT1A receptoreffector system [254]. In patients with mood
disorders decreased numbers of 5-HT1A receptors or
hyposensitivity of the 5-HT1A receptoreffector system
have been observed in different cortex areas and sometimes
even in the raphe nucleus [351354]. There is mounting
evidence that the above-mentioned decrease in 5-HT1A
receptor densities in the hippocampus is mediated by
corticosteroids via a MR-dependent mechanism [355,356].
However, other mechanisms may also be involved. For
example, testosterone can enhance 5-HT1A receptor
expression so the opposite effect. i.e. a reduction in 5HT1A receptor expression due to a social conflict-induced
decrease in testosterone, cannot be excluded [357].
Exposure to a visible burrow system produces up-regulation
of 5-HT2A receptors in the cerebral cortex of subordinate
rats [262]. This also has relevance for depressive illness,
since the deactivation of the 5-HT2A receptor by antisense
induces an antidepressant-like effect in mice [358]. In
human patients variability in the 5-HT2A receptor gene is
primarily associated with suicidal behavior and with the
seasonal pattern in major depression [359,360]. Furthermore, in depressed patients dysfunctional attitudes were
positively associated with cortex 5-HT2 binding potential,
suggesting that low levels of 5-HT agonism in the brain
cortex may explain the severely pessimistic, dysfunctional
attitudes associated with major depression [361]
Moreover, in the visible burrow model of psychosocial
challenge in rats, both dominants and subordinates showed
downregulation of 5-HT transporter (5-HTT) expression in
the CA3 region, indicating either a reduced density of
serotonin terminals or a reduced expression of the
transporter [362]. This downregulation in 5-HTT expression
plays a crucial role in the role of 5-HT in anxiety disorders
and depression. In humans 5-HTT promoter polymorphism,
which is associated with anxiety-related traits has been
observed [363]. Remarkably, individuals with one or two
copies of the short allele of the 5-HTT promoter
polymorphism, a phenomenon associated with reduced 5HTT expression and function and increased fear and
anxiety-related behaviors, exhibit greater amygdala
21
neuronal activity in response to fearful stimuli compared

with individuals homozygous for the long allele [364].
Thus, this polymorphism increases 5-HT levels in the
amygdala and produces an enhanced anxiety-state. A major
breakthrough was made recently in a longitudinalepidemiological study, where clear gene-by-environment interactions led to psychopathology. It was shown that
individuals with one or two copies of the short allele of
the 5-HTT promoter polymorphism exhibited more depressive symptoms in relation to stressful life events than
individuals homozygous for the long allele [365].
In summary, the above findings suggest that, both
in animals and humans, an increase in 5-HT levels in
the amygdala is associated with greater amygdala neuronal
activity, fear and anxiety disorders, depression and suicide.
The evidence for a causal connection between anxiety and
depression becomes stronger.
4.1.11. Decreased neurogenesis in the hippocampus
The proposed corticosteroidsamygdala relationship in
depression is relatively new, while the involvement of
the corticosteroidshippocampus link in emotional behavior goes back at least 30 years [176]. Recently, it is
also becoming clearer that the hippocampus has a very
high plasticity in response to environmental changes. For
instance, production of new cells (neurogenesis) in the
dentate gyrus (DG) of rats was increased by housing in
an enriched environment [366], by learning [367] and by
voluntary exercise [368]. Birds that use the space in their
environment to hide and locate food, and voles and deer
mice that traverse long distances to find mates have
larger hippocampal volumes than closely related species
that do not show these behaviors. Moreover, there are
indications that hippocampal volume may change during
the breeding season [369,370], indeed, the rate of
neurogenesis in male and female prairie vole varies
according to the breeding season [371]. Also, neurogenesis has been found in the hippocampus of adult humans
[372]. Remarkably, environmental challenges, such as
psychosocial conflict, can affect hippocampal plasticity,
which in turn impacts on the animals ability to adapt to
environmental demands (Table 4).
Exposure to both acute and chronic frightening experiences, as observed in intruder tree shrews (Table 4), can
suppress ongoing neurogenesis [272,373]. Different
mediators of allostasis can explain this. For example,
glucocorticoids participate with excitatory amino acids in
the inhibition of neurogenesis whereas serotonin, via
hippocampal 5-HT1A receptors and insulin-like growth
factor-1 [374,375], stimulate neurogenesis [376]. The
administration of a specific 5-HT1A receptors antagonist
blocks this hippocampal cell-proliferation [377]. Thus, the
observed increases in plasma cortisol levels may lead to an
inhibition of neurogenesis in the intruder tree shrews, while
serotonin is less able to stimulate neurogenesis due to
decreased numbers of hippocampal 5-HT1A receptors.
22
Recently, it was shown that popular antidepressants,

serotonin selective reuptake inhibitors (SSRIs), produce
their anti-anxiety effects partly by stimulating hippocampal
neurogenesis via the 5-HT1A receptor, because 5-HT1A
receptor null knock-out mice were insensitive to the
neurogenic and anxiolytic effects of SSRIs [378]. It is
quite conceivable that the above effects are involved in fearrelated learning and emotional memory because of the
anatomic and functional connections between the dentate
gyrus and the amygdala [379]. It was also recently
hypothesized that therapeutic interventions for depression
that increase 5-HT neurotransmission act, at least in part, by
augmenting DG neurogenesis and thereby promoting
recovery from depression [380].
Returning to the Hawks and Doves argument, it is known
that aggressive mice (Hawks) have higher hippocampal
5-HT1A recepor expression and binding [54,55] as well as
higher hippocampal 5-HT1A responsiveness [56] than nonaggressive ones (Doves). Consistent with the role of
serotonin, via 5-HT1A receptors, on neurogenesis cell
proliferation in the DG of adult non-aggressive mice
(Doves) was suppressed by stressful stimuli, probably
though a corticosterone-mediated action, while cell proliferation in aggressive mice (Hawks) was resistant to this
downregulation [54]. Thus, Doves are more vulnerable to
stress-induced decreases in hippocampal neurogenesis than
Hawks.
4.1.12. Increased dendritic remodeling in the hippocampus
The plasticity of the hippocampus is not only affected by
neurogenesis but also by dendritic remodelling. In both tree
shrews and rats sustained adrenal hormone release, due to
psychological challenge, was accompanied by dendritic
remodelling, i.e. decreased length and branching of apical
dendrites of CA3 pyramidal neurons (Table 4). There is
mounting evidence that glucocorticoids are involved in this
dendritic remodelling. For instance, daily exposure of rats to
elevated corticosterone levels produced dendritic remodelling [381384] remodelling which was reversible [382,385].
The involvement of glucocorticoids was also confirmed by
the use of an adrenal steroid synthesis blocker, cyanoketone,
which blocked dendritic remodelling [386,387].
Glucocorticoids do not act alone, and their effects can be
blocked by agents that interfere with excitatory amino acids,
such as glutamate [383,384]. As shown in tree shrews,
dendritic remodelling can be blocked by phenytoin which
inhibits glutamate release and antagonizes the sodium
channels and possibly also T-type calcium channels that
are activated during glutamate-induced excitation. Nmethyl-D-aspartate (NMDA) receptor blockade is also
effective in preventing stress-induced dendritic remodelling
[388]. Moreover, involvement of the g-aminobutyric acid
(GABA)benzodiazepine receptor system is revealed by the
ability of a benzodiazepine, adinazolam, to block dendritic
remodelling [382].
The neurotransmitter serotonin (5-HT) is also involved in

dendritic remodelling; 5-HT release is stimulated by social
conflict [261], and tianeptine, an atypical tricyclic antidepressant that enhances 5-HT reuptake and thus reduces
extracellular 5-HT levels, prevents dendritic remodeling of
CA3 pyramidal neurons [382]. There is also evidence of
interaction between serotonin and NMDA receptors,
indicating that serotonin potentiates NMDA receptor
binding as well as the activity of NMDA receptors [389],
and that it may do so via 5-HT2 receptors [390]. Following
upon the widespread activation of NMDA receptors, the
increased levels of intracellular calcium may cause the
dendritic cytoskeleton to become depolymerized or to
undergo proteolysis, thus accounting for the dendritic
remodeling [381].
However, serotonin also binds to astroglial 5-HT1A
receptors to release S-100 beta; this is a major neurite
extension factor that protects microtubule-associated proteins from phosphorylation and stabilizes and promotes the
extension of dendritic processes [391]. Thus, reduced
astroglial 5-HT1A receptor stimulation may result in a
collapse of cellular morphology, e.g. dendritic retraction.
Dendritic remodeling in CA3 apical dendrites is an example
of adaptive plasticity (i.e. resilience), since it is a reversible
process that may protect nerve cells from permanent
damage [383]. To understand this phenomenon, it is
important to consider some key features of the CA3 region.
In terms of circuitry, there are a series of recurrent feedback
loops within the CA3 region that reactivate the mossy fiber
system and sustain CA3 excitation [392]. The CA3 region
has an intrinsic instability that can be driven by stimulation
via the perforant pathway, and the CA3 apical dendritic
remodeling might be a protective adaptation to limit the
increased excitatory input via the recurrent feedback loops.
Down-regulation of GRs in response to repeated exposure
may be another example of a protective response [393],
since glucocorticoids exacerbate permanent damage to
hippocampal nerve cells [394,395]. It has been suggested
that remodelling of dendrites provides one potential
explanation of the hippocampal shrinkage reported in a
number of disorders such as recurrent major depression
[396]. In some depressive patients hippocampal apoptosis
only contributes to a minor extent to volume changes [397].
Remarkably, the duration of depression but not age predicts
hippocampal volume loss in medically healthy women with
recurrent major depression [398]. This suggests that
repeated stress during recurrent depressive episodes may
result in cumulative hippocampal injury as reflected in
volume loss. In primates hippocampal degeneration can be
observed after sustained social conflict, with consequent
ulceration and hyperplastic adrenal cortices indicative of
sustained glucocorticoid release [399]. It has been suggested
that chronic activation of GRs located in the hippocampus
can damage hippocampal neurons, potentially leading to
more severe hypercortisolism [400].
It is important to note that other brain regions besides

the hippocampus are affected in depressive illness and
undergo structural changes. One region is the prefrontal
cortex which loses volume in depressive disorder [401],
autopsy studies also revealed loss of volume and glial cells
as well as neuronal density in both unipolar and bipolar
depression [402404]. Left prefrontal cortex volume
reductions are already present in young women in early
onset depression [405] and chronic glucocorticoid treatment induced loss of dendrites in the rat prefrontal cortex
[406]. However, much more work is required on this brain
region. In male Wistar rats, pyramidal and stellate neurons
in the basolateral complex of the amygdala exhibited
enhanced dendritic arborization in response to chronic
immobilization [407]. Conversely, in the same study,
chronic immobilization induced dendritic atrophy and
debranching in the hippocampal CA3. The authors
suggested that chronic immobilization leads to an imbalance in HPA axis function through a gradual loss of
hippocampal inhibitory control as well as a gain in
excitatory control exerted by the amygdala [407]. Finally,
depressive illness is also associated with shrinkage of the
amygdala with increased duration of depression [408].
There may, however, be a fine line between circumstances that can cause permanent damage and the conditions
that lead to reversible remodeling of neurons [6,260].
Therefore, the challenge for future research is to understand
what triggers the transition from adaptive plasticity to
permanent damage. More research is needed to investigate
whether Doves with their larger mossy fiber system, lower
5-HT1A expression and higher HPA axis reactivity are at
greater risk of hippocampal degeneration.
4.2. Allostatic load and energy metabolism
It is well known that in animals and humans social
conflict not only affects mood and brain functioning but also
food intake. Exposure to high levels of glucocorticoids
inhibits food intake and evokes body weight loss (see Table
5), probably via increased hypothamic CRF levels which
may act as catabolic signals [409]. In agreement, it was
shown that chronic corticosteroid elevations increased CRF
expression in the PVN [259].
However, if the animals can choose between different
diets a more complex picture emerges. Socially defeated
rats preferred carbohydrate intake during the first 2 weeks
after social defeat but thereafter they favoured fat intake
[410]. Following social defeat, high fat intake normalizes
the suppression of body weight gain and speeds recovery of
the body temperature increase relative to control animals
and suppresses home cage locomotor activity [411]. The
serotonergic 5-HT1A receptor hyposensitivity observed for 2
weeks after defeat is absent in rats given a high fat regimen
[411]. There is no doubt that eating high fat and
carbohydrate comfort foods cheers people up and may
make them feel and function better [188,412]. Recently,
23
Dallman and colleagues [413] suggested that people or

animals eat comfort food in an attempt to reduce the activity
in the chronic stress-response network with its attendant
anxiety. They suggested the following mechansism: first, in
the periphery, glucocorticoids stimulate accretion of
mesenteric energy stores; second, as the abdominal
energy-generated (unidentified) signal increases, the negative input to catecholaminergic cells in the NTS reduces the
synthesis of enzymes required for norepinephrine synthesis;
third, the decreased noradrenergic signal to the PVN, in
turn, decreases CRF synthesis and secretion [413]. Thus,
there is a powerful metabolic feedback control of CRF in the
PVN, which may indirectly decrease glucocorticoid-action
in the CeA and thereby lower anxiety.
Eating comfort food, however, is not the solution
because diets rich in saturated fat and refined sugar reduce
hippocampal levels of brain-derived neurotrophic factor
(BDNF), a crucial modulator of synaptic plasticity and a
predictor of learning efficacy [414]. Animals maintained on
such a diet showed a decrease in levels of cyclic AMPresponse element-binding protein (CREB) mRNA; this
protein CREB is required for various forms of memory
formation and is under the regulatory control of BDNF
[415]. A decrease in CREB is assumed to produce negative
mood effects because a genome-wide linkage survey for
genetic loci showed that genes whose products participate in
cellular signaling pathways that converge on CREB, as well
as the target genes whose expression they regulate, may also
harbor alleles that affect the development of recurrent earlyonset major depression [416]. Fortunately, it is now clear
that voluntary exercise can increase levels of BDNF and
other growth factors, increase CREB phosphorylation,
neurogenesis, resistance to brain insult and fat intake, and
improve learning and mental performance [414,417,418].
Thus, exercise could provide a simple means of maintaining
brain function and promoting brain plasticity.
From an evolutionary standpoint, one could argue that
drives to conserve energy by preferential selection of
calory-dense foods would favor survival and fitness. For
instance, a negative mood or a thriftygreedy genotype
that stimulates food intake and the storage of abdominal fat
is beneficial in hunter-gatherers, because the surplus of
energy is necessary for survival in hard times (e.g. survival
at times of shortage, or during migration to an environment
that has more food or is safer). However, the thrifty
greedygenes that were adaptive in promoting food intake
and the storage of abdominal fat in the remote past have now
become maladaptive [419421]. Especially, in our modern
individualistic societies with a lack of strong social support
networks, the effect of corticosteroids is less buffered.
Abundant high calorie food together with inactivity and the
lack of energy expenditure creates a situation where
chronically elevated glucocorticoids can impede the action
of insulin to promote glucose uptake [420,421]. One of the
results of this interaction is that insulin levels increase, and,
together, insulin and glucocorticoid elevations promote
24
the deposition of body fat. The role of obesity as a factor

speeding up other pathologies requires separate reviews. It
is known that high levels of glucocorticoids produce an
allostatic load which may result in obesity, that, if combined
with inactivity, increases the risk of the metabolic syndrome
or syndrome-X ([422]; Table 5). Syndrome-X is a new term
for the cluster of conditions, including insulin resistance,
high blood sugar levels, high triglycerides, decreased HDL
(good) cholesterol, abdominal obesity and raised blood
pressure. When occurring together, this cluster of conditions
may indicate a predisposition to diabetes type II, hypertension and cardiovascular disease. Since Doves predominantly
respond with high HPA axis activation leading to increased
plasma corticosteroid levels it is speculated that they are
more vulnerable to these metabolic diseases. On the other
hand, Hawks have low HPA axis reactivity but their high
sympathetic system activivity and reduced parasympathetic
counteraction result in other cardiac risks (see below).
4.3. Allostatic load and the cardiovascular system
Meyer Friedman and Ray Rosenman [32] were the first to
point out that a relationship exists between cardiovascular
disease and ones behavioral strategy, which they described
as type A behavior. They observed that humans with a Type
A personality are more aggressive and hostile, extremely
competitive, impatient and always in a hurry whereas Type B
individuals show more social behavior, are non-aggressive,
non-hostile and seldom become angry or irritable. Personality type A closely resembles the Hawk type (see Table 1).
Several investigators did not show a relationship between
type A personality and increased cardiovascular risk but one
explanation for this seeming inconsistency is that type A
behavior is an especially strong predictor of when incident
coronary heart disease (or a coronary event) may occur rather
than if it will occur [423]. Another explanation may be the
component hostility, rather than Type A behavior in general,
is the predictor for coronary heart disease and atherosclerosis
[424,425]. Several mechanisms may be responsible for
differences in cardiovascular disease development between
Hawks and Doves. First, Hawks are characterized by high
levels of testosterone. These increased testosterone concentrations in Hawks may play a negative role because coronary
atherosclerosis was found to be approximately twice as
extensive in testosterone-treated female cynomologus monkeys as in untreated controls [426]. Second, increased
sympathetic activity in Hawks is a risk factor for cardiovascular disease. Jim Henry showed that in colonies of mice
dominants that experienced threat to control developed aortic
arteriosclerosis and myocardial fibrosis [427,428]. In these
studies, threat to control was induced by housing the mice
in an intercommunicating system of cages (at least six
containing both females and males) that were connected in a
circle by plastic tubes around a central supply of food and
water; thus, the multiple entrances to each box made defence
of territory extremely difficult. These conditions could cause
the sudden death of dominants or sustained elevation of

blood pressure with arteriosclerotic lesions in the heart and
blood vessels [428]. Clinical, experimental and pathological
studies strongly indicate that hypertension is a major factor in
coronary heart disease, sudden death, stroke congestive heart
failure and renal insufficiency [429]. Similar sustained high
blood pressure has been observed in aggressive male rats
(Hawks) but not in non-aggressive ones (Doves) [430]. The
more aggressive males generally reacted with higher blood
pressure and catecholamine responses than more passive rats
and they had higher baseline levels of norepinephrine [431].
Increased sympathoadrenal activation can also be observed
in dominant male monkeys when they are housed in unstable
social groups and these animals suffer more extensive
atherosclerosis than subordinates [432,433]. In rabbits it
was shown that such profound sympathetic activation
induced endothelial injury and abnormal increases in platelet
accumulation that could be blocked by beta-adrenoceptor
blockade [434]. Moreover norepinephrine stimulated apoptosis in ventricular myocytes via activation of the betaadrenergic pathway [435]. Third, a shift of autonomic
balance toward sympathetic dominance, poorly antagonized
by vagal rebound, is associated with the occurrence of
cardiac tachyarrhythmias in rats (see Dr Andrea Sgoifos
contribution elsewhere in this issue). These effects were
particularly severe in the aggressive wild-type strain of rats
compared to non-aggressive Wistars [30,436,437]. In agreement, a weaker parasympathetic antagonism of sympathetic
effects on the heart [438] and chronic sympathetic nervous
system activation have been observed in Type A men, which
could account for epidemiological findings of increased
coronary risk in this group [439]. Thus, Hawks with their
high sympathetic reactivity and relatively low parasympathetic counteraction are more vulnerable to developing
tachyarrhythmias than Doves. It is speculated that shift of
autonomic balance toward sympathetic dominance makes
Hawks vulnerable to sudden death once apoptosis has
developed in the heart.
Although Doves are not characterized by high sympathetic activation, they do develop cardiovascular disease. The
mechanism, however, differs from the one described above
for Hawks. As reviewed in earlier sections, Doves are more
vulnerable to the development of depression-like syndromes. In humans it is widely accepted that depression
increases the risk of coronary artery disease [440,441].
Hypercortisolism and a deficiency of sex steroids in
depressive patients each contribute to increases in the
visceral fat mass, leading to increases in free fatty acids.
Hypercortisolism and the increases in free fatty acids both
contribute to insulin resistance, which exacerbates the
increase in visceral fat mass and promotes activation of
the sympathetic nervous system and hypertension [442].
These observations provide a partial explanation for why
Doves are also vulnerable to artheriosclerosis. They may
also be more vulnerable to bradyarrhythmia due to
parasympathetic dominance of the dorsal vagal complex.
25
Table 5
Different costs of adaptation in Hawks and Doves reflecting inefficient management of mediators of allostasis (e.g. decreased tonic 5-HT neurotransmission;
decreased negative feedback by blunted HPA axis reactivity; low parasympathetic counteractivation) and a too frequent release of mediators of allostasis (e.g.
increased 5-HT neurotransmission; increased glucocorticoid positive feedforward; high parasympathetic counteractivation), respectively
Costs of adaptation (allostatic load)
Hawk
Dove
Mediators of allostasis inefficiently managed

Violence/impulse control disorders
Hypertension/cardiac arrhythmias/sudden death
Atypical depression
Chronic fatigue states/hypersomnia
Inflammation/autoimmune disease
Mediators of allostasis released too often (surplus)

Anxiety disorders
Weight loss/metabolic syndrome
Melancholic depression
Psychotic states/insomnia
Infection
The massive increase in vagal tone slows the heart and

constricts the bronchi thereby contributing to the conservation of available oxygen [198]. This originally adaptive
reptilian response was useful for diving in aquatic
environments or during freezing or tonic immobility (i.e.
feigning death) in terrestrial environments [198]. In
mammals, however, this phylogenetically old strategy
may be maladaptive under certain conditions. Based on
Porges Polyvagal Theory [198], it has been proposed that
fetal distress and sudden death, including sudden infant
death syndrome, due to lethal bradycardia and apnea, are
potential examples of the harmful impact of the reptilian
vagal surge.
4.4. Allostatic load and the immune system
Sympathetic system hyperactivity affects not only the
cardiovascular system but also the immune system.
Allostatic load can be produced by a hyperactive sympathetic system and a hyporeactive HPA axis. A growing
number of animal findings strongly suggest that a
hyporeactive HPA axis may be pathologically significant
through a shift to Th1 cytokines that increases susceptibility
to chronic inflammation [214]. For example, a defect in the
biosynthesis of CRF and the resultant reduction in HPA axis
activity was associated with high susceptibility to streptococcal cell wall-induced arthritis in Lewis rats as compared
to the virtually syngenic Fischer rats [443]. Thus, Lewis rats
are vulnerable to inflammatory and autoimmune disturbances that are not found in Fischer rats, and yet these can be
overcome by the administration of exogenous glucocorticoids [444]. In addition, it is known that rheumatoid
inflammatory T-cell clones express mostly Th1 [445]. Other
examples of lower-than-needed cortisol disorders are
fibromyalgia [446], asthma [214,447], atopic dermatitis
[448,449], Chronic Fatigue Syndrome [450] and burnout
[451]. Patients with this atopic skin disease showed a
significant attenuation of the cortisol response to free speech
and mental tasks, whereas catecholamines were significantly elevated in comparison to healthy controls [449]. In
humans suffering from Chronic Fatigue Syndrome a lower
cortisol response to awakening, heightened negative HPA
axis feedback, increased GR function and impaired cortisol
responses have all been observed [450,452454]. Improvement in some patients during low-dose hydrocorticosterone
therapy has been reported and this also reversed the blunted
cortisol response to CRF [455].
Moreover, in atypical depression and chronic fatigue it
has been shown that corticosteroid (prednisone) augmentation may be useful [456]. There are some data suggesting
that hypoactivity of the HPA axis and hypofunction of CRF
neurons results in hyperimmune fatigue states such as
chronic fatigue syndrome and atypical depression, e.g.
seasonal affective disorder [341]. Atypical depression is
characterized by excessive sleepiness (hypersomnia; see
Table 5), increased food intake and weight gain; patients
also often feel walled off from themselves and they find
social contact too demanding and tiring [347]. Atypical
depression can be conceptualized as an allostatic state of
HPA axis hypoactivity with strong counter-regulatory
restraints. Theoretically, in patients with atypical depression
the left prefrontal cortex could be hyperactive leading to
excessive restraint of the right side (or defect in the right
side) and consequently hypoactivity of amygdala and LC
[347]. A more active prefrontal cortex may also be involved
in the lessening of anxiety. It was suggested that the dorsal
region of the medial prefrontal cortex produces a general
decrease in fear reactivity (freezing responses) in response
to fear conditioning during both the acquisition and
extinction phases [457], and that the medial prefrontal
cortex may also be involved in the extinction of conditioned
freezing in rats, via the formation of a memory of safety
[458]. It is thought that the medial prefrontal cortex gates
impulse transmission from the basolateral amygdala to
central amygdala (CeA), thereby gating the expression of
conditioned fear via feedforward inhibition [458]. The
above mentioned mechanisms produce a hypoactive
amygdala and LC and this may lead to lower central CRF
anxiety levels but also to a hyperimmune system [341,347].
Recently, the possible involvement of cytokines in
depression and in chronic fatigue syndrome has drawn the
attention of many researchers. This is because the
administration of the cytokines interferon-alpha (IFNalpha) and interleukin-2 (IL-2) which are used for the
treatment of various viral illnesses, such as hepatitis C and
various forms of cancer in humans, induce neuropsychiatric
26
effects, including depression, fatigue, anorexia and anhedonia [217,228,459]. In animals it is generally accepted that
proinflammatory cytokines, such as IL-1beta, IFN-alpha,
IFN-gamma and tumor necrosis factor-alpha (TNF-alpha)
induce sickness behavior which might resemble the
vegetative symptoms of depression in humans [216,217].
Direct activation of neurons by slowly diffusing IL-1beta
takes place in the basolateral amygdala and nucleus
parabrachialis, which both project to the CEA to mediate
behavioral depression [228]. It has been suggested that
repeated immune stimulation also makes the brain more
sensitive to other classes of stimuli, a phenomenon known
as cross-sensitization [216].
Growing evidence suggests that cytokines produce the
above mentioned effects via changes in the neural 5-HT
system. Cytokines like IFN-gamma and IFN-alpha induce
the enzyme indoleamine 2,3-dioxygenase which has various
negative consequences for the brain [217,228,459460].
First, this enzyme converts tryptophan along the kynurenine
pathway into several neuroactive intermediates and then
into kynurenine; this chain of events results in reduced
levels of tryptophan, the precursor of 5-HT, and thus to
reduced central 5-HT synthesis. Second, kynurenine
metabolites such as 3-hydroxy-kynurenine and quinolinic
acid have toxic effects on brain function; The former
metabolite can lead to oxidative stress by increasing the
production of reactive oxygen species, while quinolinic acid
may produce overstimulation of hippocampal N-methyl-Daspartate (NMDA) receptors and thereby lead to apoptosis
and hippocampal atrophy [216,228]. Indeed, hippocampal
atrophy can be caused by NMDA overstimulation and this
has been associated with depression [461]. Accumulating
evidence suggests that the above mechanisms take place in
humans because lower tryptophan values, associated with
significantly higher IFN-gamma secretion, have been
observed during major depression [462]. Moreover; (a)
antidepressants (especially selective serotonin reuptake
inhibitors such as paroxetine) are effective in reducing
IFN-induced depression [463] and (b) in major depression
reductions in tryptophan correlate with depressive, anxious,
and cognitive symptoms but not with neurovegetative or
somatic ones [464].
In summary, returning to our central theme, in Hawks
with their hypoactive HPA axis there is evidence that a Th1
cellular immune response dominates, while in Doves a Th2
dominated humoral immune response is observed. Therefore, it is assumed that although they are more resistant to
infections, the trade-off in Hawks is that they are more
vulnerable to autoimmune diseases, atypical depression and
chronic fatigue. The lower parasympathetic reactivity found
in Hawks also suggests that they are less well equipped to
inhibit the release of macrophage TNF, IL-1beta, IL-6 and
IL-18 via the vagal parasympathetic route; the release of
these cytokines may then produce sickness behavior and
chronic fatigue. In contrast, Doves are better equipped to
combat parasites, but the trade-off for them may be a higher
vulnerability to infections. In agreement, it has been shown

in male cynomologus monkeys that animals with lower
social status (greater elevated cortisol responses to social
reorganizations, lower body weight, and less aggressive
behavior) are at higher risk of infection with (adenovirus)
that causes a common-cold-like illness than are animals
with higher social status [465].
5. Conclusions
With the exception of the past few thousand years, a
drop in the bucket of evolutionary time, humans and
animals have evolved in natural habitats and are therefore
intricately tied to nature. It has become clear that natural
selection maintains a balance of different traits, e.g.
preserving genes for high aggression (Hawks) and low
aggression (Doves) within a population. The existence of
the HawkDove strategy is widespread in the animal
kingdom, not only between males and females, but also
within the same gender across species. Both behavioral
strategies can be successful, but under different environmental conditions. Bold Hawks preferentially adopt the
fightflight strategy when attempting to establish a new
territory or to defend an existing territory, while cautious
Doves adopt the freezehide strategy to avoid to threats in
their environment. The fitness of Hawks is increased when
the population density is high and food availability is stable
and abundant. In contrast, Doves have an increased fitness
during food scarcity and low population density because
they explore their environment more thoroughly for new
resources and they have greater behavioral flexibility.
Hawks and Doves have their own specific underlying
physiological characteristics that lead to differences in the
trade-offs between the various benefits of allostasis and
costs of allostatic load (Table 5).
The cost benefit analysis of the Hawk and Dove
strategies is summarized below (A to D).
(A1) Bold Hawks with their relatively low corticosteroid
levels, high testosterone and high DHEA concentrations have a higher motivation to express aggressive behavior, but the trade-off is an increased
incidence of antisocial and violent behavior. The
presence of low tonic 5-HT neurotransmission in
Hawks may produce less anxiety but it increases the
risk of impulse control disorders.
(A2) In contrast, cautious Doves with their high levels of
HPA axis reactivity, corticosteroids, and tonic 5-HT
neurotransmission have a higher motivation to
express orienting and freezing behavior. Freezing
behavior itself may reduce the likelihood of detection
and attack from an attacker or predator. Further, if
caught, freezing or tonic immobility responses may
result in the predator or attacker losing interest and
moving away [466]. In combination with their
(B1)
(B2)
(C1)
(C2)
(D1)
morphologically better developed hippocampus,

Doves are very well able to organize contextual
information and incoming sensory input (e.g. predators appearance, location, smell and sound,
avenues of escape, shelter) according to relevant
relationships among them. Doves are therefore more
aware of danger and safety signals in their environment than are the bold Hawks. However, the trade-off
is a higher risk that Doves will develop anxiety
disorders.
In Hawks, the high sympathetic reactivity and
relatively low parasympathetic counteraction favors
redistribution of blood to muscles, speeds up heartbeat, dilates bronchi, blocks the digestive process,
activates adrenal glands, etc. thereby preparing the
body for vigorous emergency action during fight
flight responses. The trade-offs, however, are an
increased risk of hypertension and cardiac arrhythmias due to a shift of autonomic balance toward
sympathetic dominance. Once apoptosis has developed in the Hawks heart, cardiac arrhythmias may
cause sudden death.
In Doves, negative mood stimulates food intake (in
order to lower anxiety via a powerful metabolic
feedback to control CRF in the hypothalamus which
may indirectly decrease glucocorticoid-action in the
central amygdala) and the storage of abdominal fat.
This surplus of energy is beneficial for survival in hard
times. However, the costs if the fat stores are not used
is an increased risk of developing syndrome-X, a
metabolic syndrome leading to diabetes type II,
hypertension and cardiovascular disease.
Hawks have an increased risk of wounds and
infections because they are more aggressive and
bolder than Doves. Not surprisingly therefore, the Th1
dominated cellular immune response in Hawks is very
adaptive in the fight against infections. However, this
hyperimmune state together with a blunted HPA axis
activity incures costs such as the risk of inflammation
and autoimmune disease.
Conversely, Doves with their higher motivation to
explore the environment for new resources are at
greater risk of being contaminated with parasites.
Therefore, their Th2 dominated humoral response is
very adaptive for dealing with parasites. However, the
trade-off may be an increased vulnerability to
infections such as the common cold, etc.
The lower parasympathetic reactivity of Hawks
suggests that they are less well equipped to inhibit
the release of macrophage cytokines via the vagal
parasympathetic route. The increased release of
cytokines can lead to a chronic fatigue state. It is
speculated that the hypoactivity of the HPA axis in
Hawks combined with hypofunction of CRF neurons
may cause atypical depression.
27
(D2) In Doves, the higher HPA axis reactivity may

represent the start of a stress-sensitization cascade.
Corticosteroids increase CRF levels in central and
extended amygdala and paraventricular hypothalamus. These areas make feed-forward loops with the
locus coeruleus producing a state of high arousal and
high attention. The benefit is high awareness of
potential dangers in the environment. The costs of
such a feed-forward mechanisms, however, may be
particular vulnerability to dysfunction and the development of melancholic depression and psychotic
states. Recurrent depression itself may become a
source of allostatic load through initial hypertrophy
giving way to atrophy of limbic brain structures.
We hope to have demonstrated that a Darwinian
approach to the concept of stress leads to a more refined
understanding of the factors underlying differential vulnerability to stress-related diseases. In the past, stress-induced
behavioral and physiological changes have been too easily
interpreted in terms of pathology. The Darwinian concept of
stress requires a detailed analysis of not only the costs of
allostatic load, but also of the benefits of stress-induced
changes, especially allostasis.
Acknowledgements
We thank Dr Bryan Jones for helpful criticism of the
manuscript.
References
[1] Selye H. What is stress? Metabolism 1956;5:52530.
[2] McEwen B, Lasley EN. The end of stress ass we know it. New York:
Joseph Henry Press; 2002.
[3] Tausk M. Hat die Nebenniere tatsachlich eine Verteidigungsfunktion? Das Hormon (Organon Holland) 1951;3:124.
[4] McEwen BS. Protective and damaging effects of stress. N Engl
J Med 1998;338:1719.
[5] McEwen BS, Stellar E. Stress and the individual: mechanisms
leading to disease. Arch Int Med 1993;153:2093101.
[6] McEwen BS. Effects of adverse experiences for brain structure and
function. Biol Psychiatry 2000;48:72131.
[7] McEwen BS, Wingfield JC. The concept of allostasis in biology and
biomedicine. Horm Behav 2003;43:215.
[8] Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal
pathology. In: Fisher S, Reason J, editors. Handbook of life stress,
cognition and health. New York: Wiley; 1988. p. 62949.
[9] Koob GF, LeMoal M. Drug addiction, dysregulation of reward, and
allostasis. Neuropsychopharmacology 2001;24:97129.
[10] Darwin C. On the origin of the species by means of natural selection,
or, the preservation of favoured races in the struggle for life. London:
John Murray; 1859.
[11] Nesse R. Proximate and evolutionary studies of anxiety, stress and
depression: synergy at the interface Neurosci Biobehav Rev 1999;
23:895903.
[12] Nesse RM. Is depression an adaptation? Arch Gen Psychiatry 2000;
57:1420.
28
[13] Nesse RM. On the difficulty of defining disease: a Darwinian

perspective. Med Health Care Philos 2001;4:3746.
[14] Tinbergen N. On aims and methods of ethology. Zeitschrift fur
Tierpsychologie 1963;20:41033.
[15] Nesse RM. What good is feeling bad: the evolutionary benefits of
feeling bad. Sciences 1991;307.
[16] Maynard Smith J. Evolution and the theory of games. Cambridge:
Cambridge University Press; 1982.
[17] Johnstone RA. Eavesdropping and animal conflict. Proc Natl Acad
Sci USA 2001;98:917780.
[18] Whitfield J. Behavioural ecology: nosy neighbours. Nature 2002;
419:2423.
[19] Berglund A, Bisazza A, Pilastro A. Armaments and ornaments: an
evolutionary explanation of traits of dual utility. Biol J Linnean Soc
1996;58:38599.
[20] Verbeek MEM, Boon A, Drent PJ. Exploration, aggressive
behaviour and dominance in pair-wise confrontations of juvenile
male great tits. Behaviour 1996;133:94563.
[21] Verbeek MEM, De Goede P, Drent PJ, Wiepkema PR. Individual
behavioural characteristics and dominance in aviary groups of great
tits. Behaviour 1999;136:2348.
[22] Carere C, Groothuis TG, Mostl E, Daan S, Koolhaas JM. Fecal
corticosteroids in a territorial bird selected for different personalities:
daily rhythm and the response to social stress. Horm Behav 2003;43:
5408.
[23] Drent PJ, Oers K, van Noordwijk AJ. Realized heritability of
personalities in the great tit (Parus major). Biol Sci 2003;27010:
4551.
[24] Verbeek MEM, Drent PJ, Wiepkema PR. Consistent individual
differences in early exploratory behaviour of male great tits. Anim
Behav 1994;48:111321.
[25] Dingemanse NJ, Both C, van Noordwijk AJ, Rutten AL, Drent PJ.
Natal dispersal and personalities in great tits (Parus major). Biol Sci
2003;270:7417.
[26] Price T, Langen T. Evolution of correlated characters. Trends Ecol
Evol 1992;7:30710.
[27] Marchetti C, Drent PJ. Individual differences in the use of social
information in foraging by captive great tits. Anim Behav 2000;60:
13140.
[28] Korte SM, Beuving G, Ruesink W, Blokhuis HJ. Plasma cathecolamine and corticosterone levels during manual restraint in chicks
from a high and low feather pecking line of laying hens. Physiol
Behav 1997;62:43741.
[29] Korte SM, Ruesink W, Blokhuis HJ. Heart rate variability during
manual restraint in chicks from high- and low-feather pecking lines
of laying hens. Physiol Behav 1999;65:64952.
[30] Koolhaas JM, Korte SM, De Boer SF, Van Der Vegt BJ, Van
Reenen CG, et al. Coping styles in animals: current status in behavior
and stress-physiology. Neurosci Biobehav Rev 1999;23:92535.
[31] Hessing MJC, Hagels AM, van Beek JAM, Wiepkema PR,
Schouten WGP, Krukow R. Individual behavioural characteristics
in pigs. Appl Anim Behav Sci 1993;37:28595.
[32] Friedman M, Rosenman RH, Type A. Type A behavior and your
heart. New York: Knopf; 1974.
[33] Van Oortmerssen GA, Bakker TCM. Artificial selection for short and
long attack latencies in wild Mus musculus domesticus. Behav Genet
1981;11:11526.
[34] De Boer SF, van der Vegt BJ, Koolhaas JM. Individual variation in
aggression of feral rodent strains: a standard for the genetics of
aggression and violence? Behav Genet 2003;33:485501.
[35] Sluyter F, Korte SM, Bohus B, Van Oortmerssen GA. Behavioral
stress response of genetically selected aggressive and nonaggressive
wild house mice in the shock-probe/defensive burying test.
Pharmacol Biochem Behav 1996;54:1136.
[36] Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM. Genetic
selection for coping style predicts stressor susceptibility.
J Neuroendocrinol 2003;15:25667.
[37] Korte SM, De Kloet ER, Buwalda B, Bouman SD, Bohus B.

Antisense to the glucocorticoid receptor in hippocampal dentate
gyrus reduces immobility in forced swim test. Eur J Pharmacol 1996;
301:1925.
[38] File SE, Gonzalez LE, Andrews N. Comparative study of pre- and
postsynaptic 5-HT1A receptor modulation of anxiety in two
ethological animal tests. J Neurosci 1996;16:48105.
[39] Benus RF, Den Daas S, Koolhaas JM, van Oortmerssen GA. Routine
formation and flexibility in social and non-social behaviour of
aggressive and nonaggressive mice. Behaviour 1990;112:17693.
[40] Benus RF, Bohus B, Koolhaas JM, van Oortmerssen GA. Heritable
variation for aggression as a reflection of individual coping
strategies. Experientia 1991;47:100819.
[41] Koolhaas JM, de Boer SF, Buwalda B, Vegt van der BJ. How and
why coping systems vary among individuals. In: Broom DM, editor.
Coping with challenge: welfare in animals including humans.
Dahlem workshop report 87. Berlin: Dahlem University Press;
2001. p. 197209.
[42] Van Oortmerssen G, Busser J. Studies in wild house mice III:
disruptive selection on aggression as a possible force in evolution.
In: Brain PF, Mainardi D, Parmigiani S, editors. House mouse
aggression: a model for understanding the evolution of social
behavior. Chur, New York: Harwood Academic Publishers; 1989. p.
87117.
[43] Henry JP, Stephens PM. Stress, Health and the social environment: a
sociobiological approach to medicine. Berlin: Springer; 1977.
[44] Bohus B, Benus RF, Fokkema DS, Koolhaas JM, Nyakas C, van
Oortmerssen GA, et al. Neuroendocrine states and behavioral and
physiological stress responses. Prog Brain Res 1987;72:5770.
[45] Cannon WB. Bodily changes in pain, hunger, fear and rage. New
York: Appleton; 1915.
[46] Korte SM, Buwalda B, Bouwss GAH, Koolhaas JM, Maes FW,
Bohus B. Conditioned neuroendocrine and cardiovascular stress
responsiveness accompanying behavioral passivity and activity in
aged and in young rats. Physiol Behav 1992;51:81522.
[47] Schuurman T. Dissertation: Endocrine processes underlying victory
and defeat in the male rat. Groningen: Groningen University; 1980.
[48] Korte SM, De Boer SF, De Kloet ER, Bohus B. Anxiolytic-like
effects of selective mineralocorticoid and glucocorticoid antagonists
on fear-enhanced behavior in the elevated plus-maze. Psychoneuroendocrinology 1995;20:38594.
[49] Buwalda B, Koolhaas JM, Bohus B. Behavioral and cardiac
responses to mild stress in young and aged rats: effects of
amphetamine and vasopressin. Physiol Behav 1992;51:2116.
[50] Graham FK, Clifton RK. Heart-rate change as a component of the
orienting response. Psychol Bull 1966;65:30520.
[51] Coleman K, Wilson Ds. Shyness and boldness in pumpkinseed
sunfish: individual differences are context-specific. Anim Behav
1998;56:92736.
[52] Hessing MJ, Hagelso AM, Schouten WG, Wiepkema PR, van
Beek JA. Individual behavioral and physiological strategies in pigs.
Physiol Behav 1994;55:3946.
[53] Van Hierden YM, Korte SM, Ruesink EW, van Reenen CG, Engel B,
Korte-Bouws GAH, et al. Adrenocortical reactivity and central
serotonin and dopamine turnover in young chicks from a high and
low feather-pecking line of laying hens. Physiol Behav 2002;75:
6539.
[54] Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM, Bohus BG.
Differences in basal and stress-induced HPA regulation of wild
house mice selected for high and low aggression. Horm Behav 2003;
43:197204.
[55] Korte SM, Meijer OC, de Kloet ER, Buwalda B, Keijser J, Sluyter F,
van Oortmerssen G, Bohus B. Enhanced 5-HT1A receptor
expression in forebrain regions of aggressive house mice. Brain
Res 1996;736:33843.

[56] Van Riel E, Meijer OC, Veenema AH, Joels M. Hippocampal
serotonin responses in short and long attack latency mice.
J Neuroendocrinol 2002;14(3):2349.
[57] Compaan JC, Hutchison JB, Wozniak A, de Ruiter AJ, Koolhaas JM.
Brain aromatase activity and plasma testosterone levels are elevated
in aggressive male mice during early ontogeny. Brain Res Dev Brain
Res 1994;82:18592.
[58] Sgoifo A, De Boer SF, Buwalda B, Korte-Bouws G, Tuma J,
Bohus B, et al. Vulnerability to arrhythmias during social stress in
rats with different sympathovagal balance. Am J Physiol 1998;275:
H460H6.
[59] De Boer SF, Lesourd M, Mocaer E, Koolhaas JM. Selective
antiaggressive effects of alnespirone in residentintruder test are
mediated via 5-hydroxytryptamine1A receptors: a comparative
pharmacological study with 8-hydroxy-2-dipropylaminotetralin,
ipsapirone, buspirone, eltoprazine, and WAY-100635. J Pharmacol
Exp Ther 1999;288:112533.
[60] Van der Vegt BJ, de Boer SF, Buwalda B, de Ruiter AJ, de Jong JG,
Koolhaas JM. Enhanced sensitivity of postsynaptic serotonin-1A
receptors in rats and mice with high trait aggression. Physiol Behav
2001;74:20511.
[61] Van der Vegt BJ, Lieuwes N, van de Wall EH, Kato K, MoyaAlbiol L, Martinez-Sanchis S, et al. Activation of serotonergic
neurotransmission during the performance of aggressive behavior in
rats. Behav Neurosci 2003;117:66774.
[62] Van der Vegt BJ, Lieuwes N, Cremers TI, de Boer SF, Koolhaas JM.
Cerebrospinal fluid monoamine and metabolite concentrations and
aggression in rats. Horm Behav 2003;44:199208.
[63] Young LJ, Nilsen R, Waymire KG, MacGregor GR, Insel TR.
Increased affiliative response to vasopressin in mice expressing the
V1a receptor from a monogamous vole. Nature 1999;400:7668.
[64] Wersinger SR, Ginns EI, OCarroll AM, Lolait SJ, Young III WS.
Vasopressin V1b receptor knockout reduces aggressive behavior in
male mice. Mol Psychiatry 2002;7:97584.
[65] Viau V. Functional cross-talk between the hypothalamicpituitary
gonadal and -adrenal axes. J Neuroendocrinol 2002;14:50613.
[66] Cools AR, Brachten R, Heeren D, Willemen A, Ellenbroek B. Search
after neurobiological profile of individual-specific features of Wistar
rats. Brain Res Bull 1990;24:4969.
[67] Benus RF, Bohus B, Koolhaas JM, Van Oortmerssen GA.
Behavioural differences between artificially selected aggressive
and non-aggressive mice: response to apomorphine. Behav Brain
Res 1991;43:2038.
[68] Feldker DE, Datson NA, Veenema AH, Proutski V, Lathouwers D,
De Kloet ER, et al. GeneChip analysis of hippocampal gene
expression profiles of short- and long-attack-latency mice: technical
and biological implications. J Neurosci Res 2003;74:70116.
[69] Feldker DE, Datson NA, Veenema AH, Meulmeester E, de
Kloet ER, Vreugdenhil E. Serial analysis of gene expression predicts
structural differences in hippocampus of long attack latency and
short attack latency mice. Eur J Neurosci 2003;17:37987.
[70] Sluyter F, Jamot L, van Oortmerssen GA, Crusio WE. Hippocampal
mossy fiber distributions in mice selected for aggression. Brain Res
1994;646:1458.
[71] Schwegler H, Lipp HP, Van der Loos H, Buselmaier W. Individual
hippocampal mossy fiber distribution in mice correlates with twoway avoidance performance. Science 1981;214:8179.
[72] Munck A, Guyre PM. Glucocorticoid physiology, pharmacology and
stress. Adv Exp Med Biol 1986;196:8196.
[73] Munck A, Naray-Fejes-Toth A. The ups and downs of glucocorticoid
physiology. Permissive and suppressive effects revisited. Mol Cell
Endocrinol 1992;90:C1C4.
[74] McEwen BS, Angulo J, Cameron H, Chao HM, Daniels D,
Gannon MN, et al. Paradoxical effects of adrenal steroids on the
brain: protection versus degeneration. Biol Psychiatry 1992;31:
17799.
29
[75] Sapolsky RM. McEwen-induced modulation of endocrine history: a

partial review. Stress 1997;2:112.
[76] Wiegers GJ, Croiset G, Reul JM, Holsboer F, de Kloet ER.
Differential effects of corticosteroids on rat peripheral blood Tlymphocyte mitogenesis in vivo and in vitro. Am J Physiol 1993;
265:E825E30.
[77] McEwen BS, Weiss JM, Schwartz LS. Selective retention of
corticosterone by limbic structures in rat brain. Nature 1968;220:
9112.
[78] Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat
brain: microdistribution and differential occupation. Endocrinology
1985;117(6):250511.
[79] De Kloet ER. Brain corticosteroid receptor balance and homeostatic
control. Front Neuroendocrinol 1991;12:95164.
[80] McEwen BS, Davis PG, Parsons B, Pfaff DW. The brain as a target
for steroid hormone action. Annu Rev Neurosci 1979;2:65112.
[81] Orchinik M, Murray TF, Franklin PH, Moore FL. Guanyl
nucleotides modulate binding to steroid receptors in neuronal
membranes. Proc Natl Acad Sci USA 1992;89:38304.
[82] McEwen BS, De Kloet ER, Rostene W. Adrenal steroid receptors
and actions in the nervous system. Physiol Rev 1986;66:112188.
[83] Axelrod J, Reisine TD. Stress hormones: their interaction and
regulation. Science 1984;224:4529.
[84] Fuxe K, Wikstrom AC, Okret S, Agnati LF, Harfstrand A, Yu ZY,
et al. Mapping of glucocorticoid receptor immunoreactive neurons in
the rat tel- and diencephalon using a monoclonal antibody against rat
liver glucocorticoid receptor. Endocrinology 1985;117:180312.
[85] Sawchenko PE, Bohn MC. Glucocorticoid receptor-immunoreactivity in C1, C2, and C3 adrenergic neurons that project to the
hypothalamus or to the spinal cord in the rat. J Comp Neurol 1989;
285:10716.
[86] Lupien SJ, McEwen BS. The acute effects of corticosteroids on
cognition: integration of animal and human model studies. Brain Res
Rev 1997;24:127.
[87] Reul JM, van den Bosch FR, de Kloet ER. Differential response of
type I and type II corticosteroid receptors to changes in plasma
steroid level and circadian rhythmicity. Neuroendocrinology 1987;
45:40712.
[88] Diamond DM, Bennett MC, Fleshner M, Rose GM. InvertedU
relationship between the level of peripheral corticosterone and the
magnitude of hippocampal primed burst potentiation. Hippocampus
1992;2:42130.
[89] Pavlides C, Kimura A, Magarinos AM, McEwen BS. Type I adrenal
steroid receptors prolong hippocampal long-term potentiation.
Neuroreport 1994;5:26737.
[90] Pavlides C, Watanabe Y, Magarinos AM, McEwen BS. Opposing
role of adrenal steroid type I and type II receptors in hippocampal
long-term potentiation. Neuroscience 1995;68:38794.
[91] Pavlides C, McEwen BS. Effects of mineralocorticoid and
glucocorticoid receptors on long-term potentiation in the CA3
hippocampal field. Brain Res 1999;851:20414.
[92] Kerr DS, Huggett AM, Abraham WC. Modulation of hippocampal
long-term potentiation and long-term depression by corticosteroid
receptor activation. Psychobiology 1994;22:12333.
[93] De Kloet ER, Oitzl MS, Joels M. Stress and cognition: are
corticosteroids good or bad guys? Trends Neurosci 1999;22:4226.
[94] McNaughton N. Cognitive dysfunction resulting from hippocampal
hyperactivitya possible cause of anxiety disorder? Pharmacol
Biochem Behav 1997;56:60311.
[95] Murphy D, Costall B, Smythe JW. Regulation of hippocampal theta
activity by corticosterone: opposing functions of mineralocorticoid
and glucocorticoid receptors. Brain Res Bull 1998;45:6315.
[96] Conrad CD, Lupien SJ, McEwen BS. Support for a bimodal role for
type II adrenal steroid receptors in spatial memory. Neurobiol Learn
Mem 1999;72:3946.
30
[97] Diamond DM, Park CR, Heman KL, Rose GM. Exposing rats to a
predator impairs spatial working memory in the radial arm water
maze. Hippocampus 1999;9:54252.
[98] Pugh CR, Fleshner M, Rudy JW. Type II glucocorticoid receptor
antagonists impair contextual but not auditory-cue fear conditioning
in juvenile rats. Neurobiol Learn Mem 1997;67:759.
[99] De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid
receptor balance in health and disease. Endocr Rev 1998;19:
269301.
[100] De Kloet ER, Oitzl MS, Joels M. Stress and cognition: are
corticosteroids good or bad guys? Trends Neurosci 1999;22:4226.
[101] Joels M, de Kloet ER. Effects of glucocorticoids and norepinephrine
on the excitability in the hippocampus. Science 1989;245:15025.
[102] Kerr DS, Campbell LW, Hao SY, Landfield PW. Corticosteroid
modulation of hippocampal potentials: increased effect with aging.
Science 1989;245:15059.
[103] Joels M, Hesen W, de Kloet ER. Mineralocorticoid hormones
suppress serotonin-induced hyperpolarization of rat hippocampal
CA1 neurons. J Neurosci 1991;11:228894.
[104] Diamond JM, Bennett MC, Fleshner M, Rose GM. InvertedU
relationship between the level of peripheral corticosterone and the
magnitude of hippocampal primed burst potentiation. Hippocampus
1992;2:42130.
[105] Joels M, de Kloet ER. Corticosteroid actions on amino acidmediated transmission in rat CA1 hippocampal cells. J Neurosci
1993;13:408290.
[106] Beck SG, List TJ, Choi KC. Long- and short-term administration of
corticosterone alters CA1 hippocampal neuronal properties. Neuroendocrinology 1994;60:26172.
[107] Azmitia EC, McEwen BS. Adrenalcortical influence on rat brain
tryptophan hydroxylase activity. Brain Res 1974;78:291302.
[108] Boadle-Biber MC, Corley KC, Graves L, Phan T-H, Rosecrans J.
Increase in the activity of tryptophan hydroxylase from cortex and
midbrain of male Fischer 344 rats in response to acute or repeated
sound stress. Brain Res 1989;482:30616.
[109] Singh VB, Corley KC, Phan T-H, Boadle-Biber MC. Increases in the
activity of tryptophan hydroxylase from rat cortex and midbrain in
response to acute or repeated sound stress are blocked by
adrenalectomy and restored by dexamethasone treatment. Brain
Res 1990;516:6676.
[110] Shimizu N, Take S, Hori T, Oomura Y. In vivo measurement of
hypothalamic serotonin release by intracerebral microdialysis:
significant enhancement by immobilization stress in rats. Brain
Res Bull 1992;28:72734.
[111] Summers CH, Larson ET, Ronan PJ, Hofmann PM, Emerson AJ,
Renner KJ. Serotonergic responses to corticosterone and testosterone
in the limbic system. Gen Comp Endocrinol 2000;117(1):1519.
[112] Singh VB, Corley KC, Krieg RJ, Phan T-H, Boadle-Biber MC.
Sound stress activation of tryptophan hydroxylase blocked by
hypophysectomy and intracanial RU 38486. Eur J Pharmacol 1994;
256:17784.
[113] Azmitia EZ, McEwen BS. Corticosterone regulation of tryptophan
hydroxylase in midbrain of the rat. Science 1969;166:12746.
[114] Azmitia EZ, Liao B, Chen Y-S. Increase of tryptophan hydroxylase
enzyme protein by dexamethasone in adrenalectomized rat midbrain.
J Neurosci 1993;13:504155.
[115] Korte-Bouws GAH, Korte SM, De Kloet ER, Bohus B. Blockade of
corticosterone synthesis reduces serotonin turnover in the dorsal
hippocampus of the rat as measured by microdialysis.
[116] Roozendaal B, Bohus B, McGaugh JL. Dose-dependent suppression
of adrenocortical activity with metyrapone: effects on emotion and
memory. Psychoneuroendocrinology 1996;21:68193.
[117] Laaris N, Haj-Dahmane S, Hamon M, Lanfumey L. Glucocorticoid
receptor-mediated inhibition by corticosterone of 5-HT1A autoreceptor functioning in the rat dorsal raphe nucleus. Neuropharmacology 1995;34:120110.
[118] Laaris N, Le Poul E, Hamon M, Lanfumey L. Stress-induced

alterations of somatodendritic 5-HT1A autoreceptor sensitivity in
the rat dorsal raphe nucleusin vitro electrophysiological evidence.
Fundam Clin Pharmacol 1997;11:20614.
[119] McEwen BS. Endocrine effects on the brain and their relationship to
behavior. In: Siegel SJ, editor. Basic neurochemistry: molecular,
cellular, and medical aspects. New York: Raven Press; 1993. p.
100323.
[120] Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids
influence stress responses? Integrating permissive, suppressive,
stimulatory, and preparative actions Endocr Rev 2000;21:5589.
[121] Korte SM. Corticosteroids in relation to fear, anxiety and
psychopathology. Neurosci Biobehav Rev 2001;25:11742.
[122] Astheimer LB, Buttemer WA, Wingfield JC. Interactions of
corticosterone with feeding, activity and metabolism in passerine
birds. Ornis Scand 1992;23:35565.
[123] Wingfield JC, Ramenofsky M. Hormones and the behavioral ecology
of stress. In: Balm PHM, editor. Stress physiology in animals.
Sheffield UK: Sheffield Academic Press; 1999. p. 151.
[124] Jacobs JD. PhD diss: regulation of life history strategies within
individuals in predictable and unpredictable environments. Univ
Washington Seattle USA; 1996.
[125] Silverin B. The stress response and autumn dispersal behavior in
willow tits. Anim Behav 1997;53:4519.
[126] Silverin B. Territorial behavior and hormones of pied flycatchers in
optimal and suboptimal habitats. Anim Behav 1998;56:8118.
[127] Silverin B. Stress responses in birds. Poultry Av Rev 1998;9:15368.
[128] Wingfield JC. Changes in reproductive function of free-living birds
in direct response to environmental perturbations. In: Stetson MH,
editor. Processing of environmental information in vertebrates.
Berlin: Springer; 1988. p. 12148.
[129] Wingfield JC, Breuner C, Jacobs J, Lynn S, Maney D,
Ramenofsky M, et al. Ecological bases of hormonebehavior
interactions: the emergency life history stage. Am Zool 1998;38:
191206.
[130] Wingfield JC, Jacobs JD, Tramontin AD, Perfito N, Meddle S,
Maney DL, et al. Toward and ecological basis of hormonebehavior
interactions in reproduction of birds. In: Wallen K, Schneider J,
editors. Reproduction in context. Cambridge: MIT Press; 2000. p.
85128.
[131] Wingfield JC, Ramenofsky M. Corticosterone and facultative
dispersal in response to unpredictable events. Ardea 1997;85:
15566.
[132] Schwabl H, Wingfield JC, Farner DS. Influence of winter on
endocrine state and behavior in European blackbirds Turdus merula.
Z Tierpsychol 1985;68:24452.
[133] Wingfield JC, Moore MC, Farner DS. Endocrine responses to
inclement weather in naturally breeding populations of whitecrowned sparrows. Auk 1983;100:5662.
[134] Smith GT, Wingfield JC, Veit RR. Adrenocortical response to stress
in the common diving petrel, Pelecanoides urinatrix. Physiol Zool
1994;67:52637.
[135] Astheimer LB, Buttemer WA, Wingfield JC. Seasonal and acute
changes in adrenocortical responsiveness in an Arctic-breeding bird.
Horm Behav 1995;29:44257.
[136] Romero ML, Reed JM, Wingfield JC. Effects of weather on
corticosterone responses in wild free-living passerine birds. Gen
Comp Endocrinol 2000;118:11322.
[137] Silverin B. Corticosterone-binding proteins and behavioral effects of
high plasma levels of corticosterone during the breeding period in
the pied flycatcher. Gen Comp Endocrinol 1986;64:6774.
[138] Wingfield JC. Influences of weather on reproduction. J Exp Zool
1984;232:58994.
[139] Wingfield JC. Influences of weather on reproductive function in male
song sparrows, Melospiza melodia. J Zool 1985;205:52544.

[140] Wingfield JC. Modulation of the adrenocortical response to stress in
birds. In: Davey KG, Peter RE, Tobe SS, editors. Perspectives in
comparative endocrinology. Ottawa: National Research Council
Canada; 1994. p. 5208.
[141] Ekman J. Coherence, composition and territories of winter social
groups of the willow tit Parus montanus and the crested tit P.
Cristatus. Ornis Scand 1979;10:5668.
[142] Ekman J. Ecology of non-breeding social systems of Parus. Wilson
Bull 1989;101:26388.
[143] Hogstad O. Social rank in winter flocks of willow tits Parus
montanus. Ibis 1987;129:19.
[144] Hogstad O. Social organization and dominance behaviour in some
Parus species. Wilson Bull 1989;101:25462.
[145] Ekman J, Cederholm G, Askenmo C. Spacing and survival in winter
groups of willow tits Parus montanus and crested tits P. Cristatus: a
removal study. J Anim Ecol 1981;50:19.
[146] Silverin B, Viebke PA, Westin J. Hormonal correlates of migration
and territorial behavior in juvenile willow tits during autumn. Gen
Comp Endocrinol 1989;75:14856. Oxford University Press; 2000.
p. 21136.
[147] Rogers CM, Ramenofsky M, Ketterson ED, Nolan Jr. JC,
Wingfield V. Plasma corticosterone, adrenal mass, winter weather,
and season in non-breeding populations of dark-eyed juncos (Junco
hyemalis hyemalis). Auk 1993;110:27985.
[148] Wingfield JC, Silverin B. Ecophysiological studies of hormone
behavior relations in birds. In: Pfaff DW, Arnold AP, Etgen AM,
Fahrbach SE, Rubin RT, editors. Hormones, brain and behavior, vol.
2. Amsterdam: Elsevier Science; 2002. p. 587647.
[149] Rohwer S, Wingfield JC. A field study of social dominance; plasma
levels of luteinizing hormone and steroid hormones in wintering
Harris sparrows. Z Tierpsychol 1981;47:17383.
[150] Carruth LL, Dores RM, Maldonado TA, Norris DO, Ruth T,
Jones RE. Elevation of plasma cortisol during the spawning
migration of landlocked kokanee salmon (Oncorhynchus nerka
kennerlyi). Comp Biochem Physiol C Toxicol Pharmacol 2000;127:
12331.
[151] Fagerlund UH. Plasma cortisol concentration in relation to stress in
adult sockeye salmon during the freshwater stages of their life cycle.
Gen Comp Endocrinol 1967;8:197207.
[152] Veldhuis HD, De Kloet ER, Van Zoest I, Bohus B. Adrenalectomy
reduces exploratory activity in the rat: a specific role of
corticosterone. Horm Behav 1982;16:1918.
[153] Jhanwar-Uniyal M, Roland CR, Leibowitz SF. Diurnal rhythm of
alpha 2-noradrenergic receptors in the paraventricular nucleus and
other brain areas: relation to circulating corticosterone and feeding
behavior. Life Sci 1986;38:47382.
[154] Wust S, Wolf J, Hellhammer DH, Federenko I, Schommer N,
Kirschbaum C. The cortisol awakening responsenormal values
and confounds. Noise Health 2000;2:7988.
[155] Henkin RI. The effects of corticosteroids and ACTH on sensory
systems. In: De Wied D, Weijnen JAWM, editors. Progress in brain
research: pituitary, adrenal and the brain, vol. 32. Amsterdam:
Elsevier; 1970. p. 27094.
[156] Fehm-Wolfsdorf G, Scheible E, Zenz H, Born J, Fehm HL. Taste
thresholds in man are differentially influenced by hydrocortisone
anddexamethasone. Psychoneuroendocrinology 1989;14:43340.
[157] Fehm-Wolfsdorf G, Soherr U, Arndt R, Kern W, Fehm HL, Nagel D.
Auditory reflex thresholds elevated by stress-induced cortisol
secretion. Psychoneuroendocrinology 1993;18:57989.
[158] Fehm-Wolfsdorf G, Nagel D. Differential effects of glucocorticoids
on human auditory perception. Biol Psychol 1996;42:11730.
[159] Takahashi LK. Organizing action of corticosterone on the development of behavioral inhibition in the preweanling rat. Brain Res Dev
Brain Res 1994;81:1217.
[160] Takahashi LK. Glucocorticoids and the hippocampus. Developmental interactions facilitating the expression of behavioral
inhibition. Mol Neurobiol 1996;13:21326.
31
[161] Oitzl MS, de Kloet ER. Selective corticosteroid antagonists

modulate specific aspects of spatial orientation learning. Behav
Neurosci 1992;106:6271.
[162] Sandi C, Rose SP. Corticosterone enhances long-term retention in
one-day-old chicks trained in a weak passive avoidance learning
paradigm. Brain Res 1994;647:10612.
[163] Corodimas KP, LeDoux JE, Gold PW, Schulkin J. Corticosterone
potentiation of learned fear. Ann NY Acad Sci 1994;746:392.
[164] Pugh CR, Tremblay D, Fleshner M, Rudy JW. A selective role for
corticosterone in contextual-fear conditioning. Behav Neurosci
1997;111:50311.
[165] Cordero MI, Merino JJ, Sandi C. Correlational relationship between
shock intensity and corticosterone secretion on the establishment and
subsequent expression of contextual fear conditioning. Behav
Neurosci 1998;112:88591.
[166] Roozendaal B. 1999 Curt P. Richter award. Glucocorticoids and the
regulation of memory consolidation. Psychoneuroendocrinology
2000;25:21338.
[167] Phillips RG, LeDoux JE. Differential contribution of amygdala and
hippocampus to cued and contextual fear conditioning. Behav
Neurosci 1992;106:27485.
[168] LeDoux LE. The emotional brain. New York: Simon and Schuster;
1996.
[169] McGaugh JL, Roozendaal B. Role of adrenal stress hormones in
forming lasting memories in the brain. Curr Opin Neurobiol 2002;
12:20510.
[170] Roozendaal B. Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol
Learn Mem 2002;78:57895.
[171] De Boer SF, Van der Gugten J, Slangen JL. Plasma catecholamine
and corticosterone responses to predictable and unpredictable noise
stress in rats. Physiol Behav 1989;45:78995.
[172] Korte SM, Bouws GA, Koolhaas JM, Bohus B. Neuroendocrine and
behavioral responses during conditioned active and passive behavior
in the defensive burying/probe avoidance paradigm: effects of
ipsapirone. Physiol Behav 1992;52:35561.
[173] Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic
activation and memory for emotional events. Nature 1994;371:
7024.
[174] Cahill L, Babinsky R, Markowitsch HJ, McGaugh JL. The amygdala
and emotional memory. Nature 1995;377:2956.
[175] Bohus B, de Kloet ER. Adrenal steroids and extinction behavior:
antagonism by progesterone, deoxycorticosterone and dexamethasone of a specific effect of corticosterone. Life Sci 1981;28:43340.
[176] Bohus B. Central nervous structures and the effect of ACTH and
corticosteroids on avoidance behavior: a study with intracerebral
inplantation of corticosteroids in the rat. Prog Brain Res 1970;32:
17184.
[177] Haller J, van de Schraaf J, Kruk MR. Deviant forms of aggression in
glucocorticoid hyporeactive rats: a model for pathological aggression? J Neuroendocrinol 2001;13:1027.
[178] Haller J, Millar S, Kruk MR. Mineralocorticoid receptor blockade
inhibits aggressive behaviour in male rats. Stress 1998;2:2017.
[179] Haller J, Millar S, van de Schraaf J, de Kloet RE, Kruk MR. The
active phase-related increase in corticosterone and aggression are
linked. J Neuroendocrinol 2000;12:4316.
[180] Wingfield JC, Lynn S, Soma KK. Avoiding the costs of
testosterone: ecological bases of hormonebehavior interactions.
Brain Behav Evol 2001;57:23951.
[181] Soma KK, Wissman AM, Brenowitz EA, Wingfield JC. Dehydroepiandrosterone (DHEA) increases territorial song and the size of an
associated brain region in a male songbird. Horm Behav 2002;41:
20312.
[182] Soma KK, Wingfield JC. Dehydroepiandrosterone in songbird
plasma: seasonal regulation and relationship to territorial aggression.
Gen Comp Endocrinol 2001;123:14455.
32
[183] Tempel DL, McEwen BS, Leibowitz SF. Effects of adrenal steroid
agonists on food intake and macronutrient selection. Physiol Behav
1992;52:11616.
[184] Tempel DL, McEwen BS, Leibowitz SF. Adrenal steroid receptors in
the PVN: studies with steroid antagonists in relation to macronutrient
intake. Neuroendocrinology 1993;57:110613.
[185] Tempel DL, Leibowitz SF. Adrenal steroid receptors: interactions
with brain neuropeptide systems in relation to nutrient intake and
metabolism. J Neuroendocrinol 1994;6:479501.
[186] Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental
by progress? Am J Hum Genet 1962;14:35362.
[187] Neel JV. Lessons from a primitive people. Science 1970;170:
81522.
[188] Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to
appetite in women: a laboratory study of stress-induced cortisol and
eating behavior. Psychoneuroendocrinology 2001;26:3749.
[189] Cusin I, Rouru J, Rohner-Jeanrenaud F. Intracerebroventricular
glucocorticoid infusion in normal rats: induction of parasympatheticmediated obesity and insulin resistance. Obes Res 2001;9:4016.
[190] Keay KA, Bandler R. Anatomical evidence for segregated input
from the upper cervical spinal cord to functionally distinct regions of
the periaqueductal gray region of the cat. Neurosci Lett 1992;139:
1438.
[191] Schiller PH, Koerner F. Discharge characteristics of single units in
superior colliculus of the alertrhesus monkey. J Neurophysiol 1971;
34:92036.
[192] Dean P, Redgrave P, Westby GW. Event or emergency? Two
response systems in the mammalian superior colliculus Trends
Neurosci 1989;12:13747.
[193] Ingle D. Focal attention in the frog: behavioral and physiological
correlates. Science 1975;188:10335.
[194] Korte SM, Jaarsma D, Luiten PG, Bohus B. Mesencephalic
cuneiform nucleus and its ascending and descending projections
serve stress-related cardiovascular responses in the rat. J Auton Nerv
Syst 1992;41:15776.
[195] Korte SM, Buwalda B, Bouws GA, Koolhaas JM, Maes FW,
Bohus B. Conditioned neuroendocrine and cardiovascular stress
responsiveness accompanying behavioral passivity and activity in
aged and in young rats. Physiol Behav 1992;51:81522.
[196] Keay KA, Bandler R. Parallel circuits mediating distinct emotional
coping reactions to different types of stress. Neurosci Biobehav Rev
2001;25:66978.
[197] Engel GL, Schmale AH. Conservation withdrawal: a primary
regulatory process for organic homeostasis. Physiology, emotions
and psychosomatic illness. New York: Elsevier; 1972 p. 5795.
[198] Porges SW. Cardiac vagal tone: a physiological index of stress.
Neurosci Biobehav Rev 1995;19:22533.
[199] Porges SW. Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A polyvagal theory. Psychophysiology 1995;32:30118.
[200] Porges SW. Emotion: an evolutionary by-product of the neural
regulation of the autonomic nervous system. Annu NY Acad Sci
1997;807:6277.
[201] Porges SW, Doussard-Roosevelt JA, Stifter CA, McClenny BD,
Riniolo TC. Sleep state and vagal regulation of heart period patterns
in the human newborn: an extension of the polyvagal theory.
Psychophysiology 1999;36:1421.
[202] Buwalda B, Nyakas C, Koolhaas JM, Luiten PG, Bohus B.
Vasopressin prolongs behavioral and cardiac responses to mild
stress in young but not in aged rats. Physiol Behav 1992;52:112731.
[203] Ader R, Cohen N. Psychoneuroimmunology: interactions between
the nervous system and the immune system. Lancet 1995;349:
99103.
[204] Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic
nervean integrative interface between two supersystems: the brain
and the immune system. Pharmacol Rev 2000;52:595638.
[205] Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Effects of stress
on immune cell distribution: dynamics and hormonal mechanisms.
J Immunol 1995;154:551127.
[206] Dhabhar FS, McEwen BS. Stress-induced enhancement of antigenspecific cell-mediated immunity. J Immunol 1996;156:260815.
[207] Dhabhar FS, Satoskar AR, Bluethmann H, David JR, McEwen BS.
Stress-induced enhancement of skin immune function: a role for
interferon. Proc Natl Acad Sci USA 2000;97:2284651.
[208] Dhabhar FS, McEwen BS. Acute stress enhances while chronic
stress suppresses cell-mediated immunity in vivo: a potential role for
leukocyte trafficking. Brain Behav Immun 1997;11:286306.
[209] Dhabhar FS, McEwen BS. Enhancing versus suppressive effects of
stress hormones on skin immune function. Proc Natl Acad Sci USA
1999;96105964.
[210] Ader R, Cohen N. Behaviorally conditioned immunosuppression.
Psychosom Med 1975;37:33340.
[211] Ader R, Cohen N. Behaviourally conditioned immunosuppression
and murine systemic lupus erythematosus. Science 1982;215:
15346.
[212] Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S.
Noradrenergic and peptidergic innervation of lymphoid tissue.
J Immunol 1985;135:755s765.
[213] Bulloch K, Pomerantz W. Autonomic nervous system innervation of
thymic-related lymphoid tissue in wildtype and nude mice. J Comp
Neurol 1984;228:5768.
[214] Elenkov IJ, Chrousos GP. Stress hormones, Th1/Th2 patterns,
Pro/Anti-inflammatory cytokines and susceptibility to disease.
Trends Endocrinol Metab 1999;10:35968.
[215] Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory disease. J Endocrinol 2001;169:42935.
[216] Dantzer R. Cytokine-induced sickness behavior: where do we stand?
Brain Behav Immun 2001;15:724.
[217] Kronfol Z, Remick DG. Cytokines and the brain: implications for
clinical psychiatry. Am J Psychiatry 2000;157:68394.
[218] Besedovsky H, del Rey A, Sorkin E, Dinarello CA. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones.
Science 1986;233:6524.
[219] Besedovsky H, del Rey A, Sorkin E, Da Prada M, Burri R,
Honegger C. The immune response evokes changes in brain
noradrenergic neurons. Science 1983;221:5646.
[220] Linthorst AC, Flachskamm C, Holsboer F, Reul JM. Activation of
serotonergic and noradrenergic neurotransmission in the hippocampus after peripheral administration of bacterial endotoxin:
involvement of the cyclo-oxygenase pathway. Neuroscience 1996;
72:98997.
[221] Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A,
Besedovsky HO. A neuromodulatory role of interleukin-1beta in the
hippocampus. Proc Natl Acad Sci USA 1998;95:777883.
[222] Hessing MJ, Coenen GJ, Vaiman M, Renard C. Individual
differences in cell-mediated and humoral immunity in pigs. Vet
Immunol Immunopathol 1995;45:97113.
[223] Bolhuis JE, Parmentier HK, Schouten WG, Schrama JW,
Wiegant VM. Effects of housing and individual coping characteristics on immune responses of pigs. Physiol Behav 2003;79:28996.
[224] Schrama JW, Schouten JM, Swinkels JW, Gentry JL, de Vries
Reilingh G, Parmentier HK. Effect of hemoglobin status on humoral
immune response of weanling pigs differing in coping styles. J Anim
Sci 1997;75:258896.
[225] Kavelaars A, Heijnen CJ, Ellenbroek B, van Loveren H, Cools A.
Apomorphine-susceptible and apomorphine-unsusceptible Wistar
rats differ in their susceptibility to inflammatory and infectious
diseases: a study on rats with group-specific differences in structure
and reactivity of hypothalamicpituitaryadrenal axis. J Neurosci
1997;17:25804.
[226] Dhabhar FS, Miller AH, McEwen BS, Spencer RL. Stress-induced
changes in blood leukocyte distribution. Role of adrenal steroid
hormones. J Immunol 1996;157:163844.

[227] McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH,
Dhabhar FS, et al. The role of adrenocorticoids as modulators of
immune function in health and disease: neural, endocrine and
immune interactions. Brain Res Brain Res Rev 1997;23:79133.
[228] Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness
behaviour: mechanisms and implications. Trends Neurosci 2002;25:
1549.
[229] Hart BL. Biological basis of the behavior of sick animals. Neurosci
Biobehav Rev 1988;12:12337.
[230] Tracey KJ, Czura CJ, Ivanova S. Mind over immunity. FASEB J
2001;15:15756.
[231] Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI,
Watkins LR, et al. Vagus nerve stimulation attenuates the systemic
inflammatory response to endotoxin. Nature 2000;405:45862.
[232] Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al.
Nicotinic acetylcholine receptor alpha7 subunit is an essential
regulator of inflammation. Nature 2003;421:3848.
[233] McEwen BS. Mood disorders and allostatic load. Biol Psychiatry
2003;54:2007.
[234] McEwen BS. Interacting mediators of allostasis and allostatic load:
towards an understanding of resilience in aging. Metabolism 2003;
52:1016.
[235] Sapolsky RM. The trouble with testosterone and other assays on the
biology of the human predicament. New York: Simon and Schuster;
1997.
[236] Wingfield JC, Lynn S, Soma KK. Avoiding the costs of
testosterone: ecological bases of hormonebehavior interactions.
Brain Behav Evol 2001;57:23951.
[237] Dolan M, Anderson IM, Deakin JF. Relationship between 5-HT
function and impulsivity and aggression in male offenders with
personality disorders. Br J Psychiatry 2001;178:3529.
[238] Grimes JM, Melloni Jr RH. Serotonin modulates offensive attack in
adolescent anabolic steroid-treated hamsters. Pharmacol Biochem
Behav 2002;73(1982):71321.
[239] Holmes A, Murphy DL, Crawley JN. Abnormal behavioral
phenotypes of serotonin transporter knockout mice: parallels with
human anxiety and depression. Biol Psychiatry 2003;54:9539.
[240] Holmes A, Murphy DL, Crawley JN. Reduced aggression in mice
lacking the serotonin transporter. Psychopharmacology 2002;161:
1607.
[241] Haller J, Halasz J, Mikics E, Kruk MR, Makara GB. Ultradian
corticosterone rhythm and the propensity to behave aggressively in
male rats. J Neuroendocrinol 2000;12:93740.
[242] Shoal GD, Giancola PR, Kirillova GP. Salivary cortisol, personality,
and aggressive behavior in adolescent boys: a 5-year longitudinal
study. J Am Acad Child Adolesc Psychiatry 2003;42:11017.
[243] Pajer K, Gardner W, Rubin RT, Perel J, Neal S. Decreased cortisol
levels in adolescent girls with conduct disorder. Arch Gen Psychiatry
2001;58:297302.
[244] van Goozen SH, Matthys W, Cohen-Kettenis PT, Thijssen JH, van
Engeland H. Adrenal androgens and aggression in conduct disorder
prepubertal boys and normal controls. Biol Psychiatry 1998;43:
1568.
[245] Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM. Genetic
selection for coping style predicts stressor susceptibility.
[246] Veenema AH. Coping style and stressor susceptibility: neuroendocrine and neurochemical studies with genetically selected mouse
lines. Thesis. University of Groningen: The Netherlands; 2003.
[247] Almenara A, Escalante G, Gazzo E, Gonzales GF. Transillumination
to evaluate spermatogenesis: effect of testosterone enanthate in adult
male rats. Arch Androl 2000;46:218.
[248] Feldker D. Towards the molecular basis of individual differences in
vulnerability to stress: application of large scale gene expression
profiling. Thesis. University of Leiden: The Netherlands; 2003.
33
[249] Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the

control of NF-[kappa]B activity. Annu Rev Immunol 2000;18:
62163.
[250] Guo Q, Robinson N, Mattson MP. Secreted beta-amyloid precursor
protein counteracts the proapoptotic action of mutant presenilin-1 by
activation of NF-kappaB and stabilization of calcium homeostasis.
J Biol Chem 1998;273:1234151.
[251] Maggirwar SB, Sarmiere PD, Dewhurst S, Freeman RS. Nerve
growth factor-dependent activation of NF-kappaB contributes to
survival of sympathetic neurons. J Neurosci 1998;18:1035665.
[252] Mattson MP, Culmsee C, Yu Z, Camandola S. Roles of nuclear
factor kappaB in neuronal survival and plasticity. J Neurochem
2000;74:44356.
[253] Buwalda B, de Boer SF, Schmidt ED, Felszeghy K, Nyakas C,
Sgoifo A, et al. Long-lasting deficient dexamethasone suppression of
hypothalamicpituitaryadrenocortical activation following peripheral CRF challenge in socially defeated rats. J Neuroendocrinol
1999;11:51320.
[254] Korte SM, Buwalda B, Meijer O, De Kloet ER, Bohus B. Socially
defeated male rats display a blunted adrenocortical response to a low
dose of 8-OH-DPAT. Eur J Pharmacol 1995;272:4550.
[255] Koolhaas JM, Hermann PM, Kemperman C, Bohus B, van der
Hoofdakker R, Beersma DGM. Single social interaction leading to
defeat in male rats induces a gradual, but long lasting behavioral
change: a model of depression? Neurosci Res Commun 1990;7:
3541.
[256] Von Frijtag JC, Kamal A, Reijmers LG, Schrama LH, van den Bos R,
Spruijt BM. Chronic imipramine treatment partially reverses the
long-term changes of hippocampal synaptic plasticity in socially
stressed rats. Neurosci Lett 2001;309(3):1536.
[257] Ruis MA, te Brake JH, Buwalda B, De Boer SF, Meerlo P, Korte SM,
Blokhuis HJ, et al. Housing familiar male wildtype rats together
reduces the long-term adverse behavioural and physiological effects
of social defeat. Psychoneuroendocrinology 1999;24:285300.
[258] Blanchard RJ, Blanchard DC, Rodgers J, Weiss SM. The
characterization and modelling of antipredator defensive behavior.
Neurosci Biobehav Rev 1990;14:46372.
[259] Albeck DS, McKittrick CR, Blanchard DC, Blanchard RJ,
Nikulina J, McEwen BS, et al. Chronic social stress alters levels of
corticotropin-releasing factor and arginine vasopressin mRNA in rat
brain. J Neurosci 1997;17:4895903.
[260] McEwen BS. Allostasis and allostatic load: implications for
neuropsychopharmacology. Neuropsychopharmacology 2000;22:
10824.
[261] Blanchard DC, Sakai RR, McEwen B, Weiss SM, Blanchard RJ.
Subordination stress: behavioral, brain, and neuroendocrine correlates. Behav Brain Res 1993;58:11321.
[262] McKittrick CR, Blanchard DC, Blanchard RJ, McEwen BS,
Sakai RR. Serotonin receptor binding in a colony model of chronic
social stress. Biol Psychiatry 1995;37:38393.
[263] Blanchard DC, Spencer RL, Weiss SM, Blanchard RJ,
McEwen B, Sakai RR. Visible burrow system as a model of
chronic social stress: behavioral and neuroendocrine correlates.
Psychoneuroendocrinology 1995;20:11734.
[264] Fuchs E, Flugge G. Social stress in tree shrews: effects on
physiology, brain function, and behavior of subordinate individuals.
[265] Fuchs E, Flugge G. Chronic social stress: effects on limbic brain
structures. Physiol Behav 2003;79:41727.
[266] Fuchs E, Johren O, Flugge G. Psychosocial conflict in the tree shrew:
effects on sympathoadrenal activity and blood pressure. Psychoneuroendocrinology. 1993;18(8):55765.
[267] Johren O, Flugge G, Fuchs E. Hippocampal glucocorticoid receptor
expression in the tree shrew: regulation by psychosocial conflict.
Cell Mol Neurobiol 1994;14:28196.
34
[268] Fuchs E, Flugge G. Modulation of binding sites for corticotropinreleasing hormone by chronic psychosocial stress. Psychoneuroendocrinology 1995;20:3351.
[269] Flugge G, Van Kampen M, Mijnster MJ. Perturbations in brain
monoamine systems during stress. Cell Tissue Res 2004;315:
114.
[270] Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic
psychosocial stress causes apical dendritic atrophy of hippocampal
CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 1996;
16:353440.
[271] Gould E, McEwen BS, Tanapat P, Galea LAM, Fuchs E.
Neurogenesis in the dentate gyrus of the adult tree shrew is regulated
by psychosocial stress and NMDA receptor activation. J Neurosci
1997;17:24928.
[272] Gould E, Tanapat P, Rydel T, Hastings N. Regulation of
hippocampal neurogenesis in adulthood. Biol Psychiatry 2000;48:
71520.
[273] Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van
Kampen M, et al. Stress-induced changes in cerebral metabolites,
hippocampal volume and cell proliferation are prevented by
antidepressant treatment with tianeptine. Proc Natl Acad Sci USA
2001;98:12796801.
[274] Van der Hart MG, Czeh B, de Biurrun G, Michaelis T, Watanabe T,
Natt O, et al. Substance P receptor antagonist and clomipramine
prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume. Mol Psychiatry
2002;7:93341.
[275] Lucassen PJ, Fuchs E, Czeh B. Antidepressant treatment with
tianeptine reduces apoptosis in the hippocampal dentate gyrus and
temporal cortex. Biol Psychiatry 2004;55:78996.
[276] Van Kampen M, Kramer M, Hiemke C, Flugge G, Fuchs E. The
chronic psychosocial stress paradigm in male tree shrews: evaluation
of a novel animal model for depressive disorders. Stress 2002;5:
3746.
[277] Schweiger U, Deuschle M, Weber B, Korner A, Lammers CH,
Schmider J, et al. Testosterone, gonadotropin, and cortisol secretion
in male patients with major depression. Psychosom Med 1999;61:
2926.
[278] Sapolsky RM. Stress-induced elevation of testosterone concentration
in high ranking baboons: role of catecholamines. Endocrinology
1986;118:16305.
[279] Price JS. The dominance hierarchy and the evolution of mental
illness. Lancet 1967;2:2436.
[280] Price J, Sloman L, Gardner R, Gilbert R, Rohde P. The social
competition hypothesis of depression. Br J Psychiatry 1994;64:
30915.
[281] Lopez JF, Chalmers DT, Little KY, Watson SJ. A.E. Bennett
research award. Regulation of serotonin1A, glucocorticoid, and
mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998;43:
54773.
[282] Herman JP, Spencer R. Regulation of hippocampal glucocorticoid
receptor gene transcription and protein expression in vivo.
J Neurosci 1998;18:746273.
[283] Spencer RL, Miller A, Stein MH, McEwen BS. Corticosterone
regulation of type I and type II adrenal steroid receptors inbrain,
pituitary, and immune tissue. Brain Res 1991;549:23646.
[284] Arriza JL, Simerly RB, Swanson LW, Evans RM. The neuronal
mineralocorticoid receptor as a mediator of glucocorticoid response.
Neuron 1988;1:887900.
[285] Sandi C, Rose SP. Corticosteroid receptor antagonists are amnestic
for passive avoidance learning in day-old chicks. Eur J Neurosci
1994;6:12927.
[286] Sandi C. The role and mechanisms of action of glucocorticoid
involvement in memory storage. Neural Plast 1998;6:4152.
[287] Roozendaal B, Nguyen BT, Power AE, McGaugh JL. Basolateral

amygdala noradrenergic influence enables enhancement of memory
consolidation induced by hippocampal glucocorticoid receptor
activation. Proc Natl Acad Sci 1999;96(20):116427.
[288] Holsboer F, Liebl R. Repeated dexamethasone suppression test
during depressive illness. Normalisation of test result compared with
clinical improvement. J Affect Disord 1982;4:93101.
[289] Holsboer-Trachsler E, Stohler R, Hatzinger M. Repeated administration of the combined dexamethasone-human corticotropin releasing hormone stimulation test during treatment of depression.
Psychiatry Res 1991;38:16371.
[290] Murphy BE, Filipini D. Possible use of glucocorticoid receptor
antagonists in the treatment of major depression: preliminary results
using RU 486. J Psychiatry Neurosci 1993;18:20913.
[291] ODwyer AM, Lightman SL, Marks MN, Checkley SA. Treatment
of major depression with metyrapone and hydrocortisone. J Affect
Disord 1995;33:1238.
[292] Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosom Med 1999;61:698711.
[293] Murphy BE. Antiglucocorticoid therapies in major depression: a
review. Psychoneuroendocrinology 1997;22:S125S32.
[294] Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L,
Weingartner H. Ketoconazole administration in hypercortisolemic
depression. Am J Psychiatry 1993;150:8102.
[295] Thakore JH, Dinan TG. Cortisol synthesis inhibition: a new
treatment strategy for the clinical andendocrine manifestations of
depression. Biol Psychiatry 1995;37:3648.
[296] Belanoff JK, Flores BH, Kalezhan M, Sund B, et al. Rapid reversal of
psychotic depression using mifepristone. J Clin Psychopharmacol
2001;21:51621.
[297] Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE,
Schold C, Schatzberg AF. An open label trial of C-1073
(mifepristone) for psychotic major depression. Biol Psychiatry
2002;52:38692.
[298] Van der Lely AJ, Foeken K, van der Mast RC, Lamberts SW. Rapid
reversal of acute psychosis in the Cushing syndrome with the
cortisol-receptor antagonist mifepristone (RU 486). Ann Intern Med
1991;114:1434.
[299] Ratka A, Sutanto W, Bloemers M, De Kloet ER. On the role of brain
mineralocorticoid (type I) and glucocorticoid (type II) receptors in
neuroendocrine regulation. Neuroendocrinology 1989;50:11723.
[300] Shepard JD, Barron KW, Myers DA. Corticosterone delivery to the
amygdala increases corticotropin-releasing factor mRNA in the
central amygdaloid nucleus and anxiety-like behavior. Brain Res
2000;861:28895.
[301] Shepard JD, Barron KW, Myers DA. Stereotaxic localization of
corticosterone to the amygdala enhances hypothalamopituitary
adrenal responses to behavioral stress. Brain Res 2003;963:20313.
[302] Greenwood-Van Meerveld B, Gibson M, Gunter W, Shepard J,
Foreman R, Myers D. Stereotaxic delivery of corticosterone to the
amygdala modulates colonic sensitivity in rats. Brain Res 2001;893:
13542.
[303] Kalin NH, Takahashi LK, Chen FL. Restraint stress increases
corticotropin-releasing hormone mRNA content in the amygdala and
paraventricular nucleus. Brain Res 1994;656:1826.
[304] Hsu DT, Chen FL, Takahashi LK, Kalin NH. Rapid stress-induced
elevations in corticotropin-releasing hormone mRNA in rat central
amygdala nucleus and hypothalamic paraventricular nucleus: an in
situ hybridization analysis. Brain Res 1998;788:30510.
[305] Swanson LW, Simmons DM. Differential steroid hormone and
neural influences on peptide mRNA levels in CRH cells of the
paraventricular nucleus: a hybridization histochemical study in the
rat. J Comp Neurol 1989;285:41335.
[306] Imaki T, Nahan JL, Rivier C, Sawchenko PE, Vale W. Differential
regulation of corticotropin-releasing factor mRNA in rat brain
regions by glucocorticoids and stress. J Neurosci 1991;11:58599.

[307] Makino S, Gold PW, Schulkin J. Corticosterone effects on
corticotropin-releasing hormone mRNA in the central nucleus of
the amygdala and the parvocellular region of the paraventricular
nucleus of the hypothalamus. Brain Res 1994;640:10512.
[308] Makino S, Gold PW, Schulkin J. Effects of corticosterone on CRH
mRNA and content in the bed nucleus of the stria terminalis;
comparison with the effects in the central nucleus of the amygdala
and the paraventricular nucleus of the hypothalamus. Brain Res
1994;657:1419.
[309] Makino S, Schulkin J, Smith MA, Pacak K, Palkovits M, Gold PW.
Regulation of corticotropin-releasing hormone receptor messenger
ribonucleic acid in the rat brain and pituitary by glucocorticoids and
stress. Endocrinology 1995;136:451725.
[310] Makino S, Hashimoto K, Gold PW. Multiple feedback mechanisms
activating corticotropin-releasing hormone system in the brain
during stress. Pharmacol Biochem Behav 2002;73:14758.
[311] Watts AG, Sanchez-Watts G. Region-specific regulation of neuropeptide mRNAs in rat limbic forebrain neurones by aldosterone and
corticosterone. J Physiol 1995;484:72136.
[312] Palkovits M, Young WS, Kovacs K, Toth ZS, Makara GB.
Alterations in corticotropin-releasing hormone gene expression of
central amygdaloid neurons following long-term paraventricular
lesions and adrenalectomy. Neuroscience 1998;85:13547.
[313] Koob GF. Corticotropin-releasing factor, norepinephrine, and stress.
Biol Psychiatry 1999;46:116780.
[314] Koob GF, Heinrichs SC. A role for corticotropin releasing factor and
urocortin in behavioral responses to stressors. Brain Res 1999;848:
1415.
[315] Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I,
Eklund K, et al. Elevated concentrations of CSF corticotropinreleasing factor-like immunoreactivity in depressed patients. Science
1984;226:13424.
[316] Davis M. Are different parts of the extended amygdala involved in
fear versus anxiety? Biol Psychiatry 1998;44:123947.
[317] De Jongh R, Groenink L, van der Gugten J, Olivier B. Lightenhanced and fear-potentiated startle: temporal characteristics and
effects of alpha-helical corticotropin-releasing hormone. Biol
Psychiatry 2003;54:10418.
[318] Dolan RJ. Emotion, cognition, and behavior. Science 2002;298:
11914.
[319] Morris JS, Ohman A, Dolan RJ. Conscious and unconscious
emotional learning in the human amygdala. Nature 1998;393:
46770.
[320] Schulkin J, McEwen BS, Gold PW. Allostasis, amygdala, and
anticipatory angst. Neurosci Biobehav Rev 1994;18:38596.
[321] Erickson K, Drevets W, Schulkin J. Glucocorticoid regulation of
diverse cognitive functions in normal and pathological emotional
states. Neurosci Biobehav Rev 2003;27:23346.
[322] Kalin NH, Shelton SE, Rickman M, Davidson RJ. Individual
differences in freezing and cortisol in infant and mother rhesus
monkeys. Behav Neurosci 1998;112:2514.
[323] Kagan J, Reznick JS, Snidman N. Biological bases of childhood
shyness. Science 1988;240:16771.
[324] Schmidt LA, Fox NA, Rubin KH, Sternberg EM, Gold PW,
Smith CC, et al. Behavioral and neuroendocrine responses in shy
children. Dev Psychobiol 1997;30:12740.
[325] Schwartz CE, Wright CI, Shin LM, Kagan J, Whalen PJ,
McMullin KG, Rauch SL. Differential amygdalar response to
novel versus newly familiar neutral faces: a functional MRI probe
developed for studying inhibited temperament. Biol Psychiatry
2003;53(10):85462.
[326] Buwalda B, Van Kalkeren AA, de Boer SF, Koolhaas JM.
Behavioral and physiological consequences of repeated daily
intracerebroventricular injection of corticotropin-releasing factor in
the rat. Pychoneuroendocrinology 1998;23:20518.
35
[327] Groenink L, Dirks A, Verdouw PM, Schipholt M, Veening JG, van

der Gugten J, Olivier B. HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol Psychiatry 2002;
51:87581.
[328] Dirks A, Groenink L, Bouwknecht JA, Hijzen TH, Van Der
Gugten J, Ronken E, et al. Overexpression of corticotropin-releasing
hormone in transgenic mice and chronic stress-like autonomic and
physiological alterations. Eur J Neurosci 2002;16:175160.
[329] Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ,
Mintun MA. Increased amygdala response to masked emotional
faces in depressed subjects resolves with antidepressant treatment:
an fMRI study. Biol Psychiatry 2001;50:6518.
[330] Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD,
Raichle ME. Glucose metabolism in the amygdala in depression:
relationship to diagnostic subtype and plasma cortisol levels.
[331] Frodl T, Meisenzahl E, Zetzsche T, et al. Enlargement of the
amygdala in patients with a first episode of major depression. Biol
Psychiatry 2002;51:70814.
[332] Frodl T, Meisenzahl EM, Zetzsche T, Born C, Jager M, Groll C,
Bottlender R, Leinsinger G, Moller HJ. Larger amygdala volumes in
first depressive episode as compared to recurrent major depression
and healthy control subjects. Biol Psychiatry 2003;53:33844.
[333] Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST,
Raichle ME. A functional anatomical study of unipolar depression.
J Neurosci 1992;12:362841.
[334] Siegle GJ, Steinhauer SR, Thase ME, Stenger VA, Carter CS. Cant
shake that feeling: event-related fMRI assessment of sustained
amygdala activity in response to emotional information in depressed
individuals. Biol Psychiatry 2002;51:693707. Erratum in: Biol
Psychiatry, 2002;52:771.
[335] Davidson RJ. Darwin and the neural bases of emotion and affective
style. Ann NY Acad Sci 2003;1000:31636.
[336] Quirarte GL, Galvez R, Roozendaal B, McGaugh JL. Norepinephrine release in the amygdala in response to footshock and opioid
peptidergic drugs. Brain Res 1998;808:13440.
[337] Raber J, Koob GF, Bloom FE. Interleukin-2 (IL-2) induces
corticotropin-releasing factor (CRF) release from the amygdala
and involves a nitric oxide-mediated signaling; comparison with the
hypothalamic response. J Pharmacol Exp Ther 1995;272:81524.
[338] Van Bockstaele EJ, Colago EE, Valentino RJ. Amygdaloid
corticotropin-releasing factor targets locus coeruleus dendrites:
substrate for the co-ordination of emotional and cognitive limbs of
the stress response. J Neuroendocrinol 1998;10:74357.
[339] Van Bockstaele EJ, Peoples J, Valentino RJ. A.E. Bennett research
award. Anatomic basis for differential regulation of the rostrolateral
peri-locus coeruleus region by limbic afferents. Biol Psychiatry
1999;46:135263.
[340] Van Bockstaele EJ, Bajic D, Proudfit H, Valentino RJ. Topographic
architecture of stress-related pathways targeting the noradrenergic
locus coeruleus. Physiol Behav 2001;73:27383.
[341] Gold PW, Chrousos GP. Organization of the stress system and its
dysregulation in melancholic and atypical depression: high vs low
CRH/NE states. Mol Psychiatry 2002;7:25475.
[342] Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ,
Tilders FJ, Swaab DF. Corticotropin-releasing hormone mRNA
levels in the paraventricular nucleus of patients with Alzheimers
disease and depression. Am J Psychiatry 1995;152:13726.
[343] Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P,
et al. Pronounced and sustained central hypernoradrenergic function
in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci
USA 2000;97:32530.
[344] Arnsten A. Through the looking glass: differential noradrenergic
modulation of prefrontal cortical function. Neural Plast 2000;7:
13346.
36
[345] Arnsten AF. The biology of being frazzled. Science 1998;280:

17112.
[346] Sullivan RM, Gratton A. Lateralized effects of medial prefrontal
cortex lesions on neuroendocrine and autonomic stress responses in
rats. J Neurosci 1999;19:283440.
[347] Gold PW, Chrousos GP. The endocrinology of melancholic and
atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Phys 1999;111:2234.
[348] Wingfield JC, Sapolsky RM. Reproduction and resistance to stress:
when and how. J Neuroendocrinol 2003;15:71124.
[349] Heilig M, Koob GF, Ekman R, Britton KT. Corticotropin-releasing
factor and neuropeptide Y: role in emotional integration. Trends
Neurosci 1994;17:805.
[350] Dourish CT, Hutson PH, Curzon G. Putative anxiolytics 8-OHDPAT, buspirone and TVX Q 7821 are agonists at 5-HT1A
autoreceptors in the raphe nuclei. Trends Pharm Sci 1986;7:2124.
[351] Lesch KP, Mayer S, Disselkamp-Tietze J, Hoh A,
Schoellnhammer G, Schulte HM. Subsensitivity of the 5-hydroxytryptamine1A (5-HT1A) receptor-mediatedhypothermic response to
ipsapirone in unipolar depression. Life Sci 1990;46:12717.
[352] Lesch KP, Mayer S, Disselkamp-Tietze J, Hoh A, Wiesmann M,
Osterheider M, et al. 5-HT1A receptor responsivity in unipolar
depression. Evaluation ofipsapirone-induced ACTH and cortisol
secretion in patients and controls. Biol Psychiatry 1990;28:6208.
[353] Drevets WC, Frank E, Price JC, Kupfer DJ, Greer PJ, Mathis C.
Serotonin type-1A receptor imaging in depression. Nucl Med Biol
2000;5:499507.
[354] Neumeister A, Bain E, Nugent AC, Carson RE, Bonne O,
Luckenbaugh DA, et al. Reduced serotonin type 1A receptor binding
in panic disorder. J Neurosci 2004;24:58991.
[355] Meijer OC, de Kloet ER. Corticosterone suppresses the expression of
5-HT1A receptor mRNA in rat dentate gyrus. Eur J Pharmacol 1994;
266:25561.
[356] Meijer OC, de Kloet ER. A role for the mineralocorticoid receptor in
a rapid and transient suppression of hippocampal 5-HT1A receptor
mRNA by corticosterone. J Neuroendocrinol 1995;7:6537.
[357] Flugge G, Kramer M, Rensing S, Fuchs E. 5HT1A-receptors and
behaviour under chronic stress: selective counteraction by testosterone. Eur J Neurosci 1998;10:268593.
[358] Sibille E, Sarnyai Z, Benjamin D, Gal J, Baker H, Toth M. Antisense
inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice. Mol Pharmacol 1997;52:105663.
[359] Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L. The
5-HT(2A) receptor gene 102T/C polymorphism is associated with
suicidal behavior in depressed patients. Am J Med Genet 2001;105:
8014.
[360] Arias B, Gutierrez B, Pintor L, Gasto C, Fananas L. Variability in the
5-HT(2A) receptor gene is associated with seasonal pattern in major
depression. Mol Psychiatry 2001;6:23942.
[361] Meyer JH, McMain S, Kennedy SH, Korman L, Brown GM,
DaSilva JN, et al. Dysfunctional attitudes and 5-HT2 receptors
during depression and self-harm. Am J Psychiatry 2003;160:909.
[362] McKittrick CR, Magarinos AM, Blanchard DC, Blanchard RJ,
McEwen BS, Sakai RR. Chronic social stress reduces dendritic
arbors in CA3 of hippocampus and decreases binding to serotonin
transporter sites. Synapse 2000;36:8594.
[363] Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al.
Association of anxiety-related traits with a polymorphism in the
serotonin transporter gene regulatory region. Science 1996;274:
152731.
[364] Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F,
Goldman D, et al. Serotonin transporter genetic variation and the
response of the human amygdala. Science 2002;297:4003.
[365] Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H,
McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of
life stress on depression: moderation by a polymorphism in the 5HTT gene. Science 2003;301:3869.
[366] Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in

adult mice living in an enriched environment. Nature 1997;586:
4935.
[367] Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning
enhances adult neurogenesis in the hippocampal formation. Nat
Neurosci 1999;2:2605.
[368] van Praag H, Kempermann G, Gage FH. Running increases cell
proliferation and neurogenesis in the adult mouse dentate gyrus. Nat
Neurosci 1999;2:26670.
[369] Nottebohm F. A brain for all seasons: cyclical anatomical changes in
song control nuclei of the canary brain. Science 1981;214:136870.
[370] Galea LAM, Kavaliers M, Ossenkopp K-P, Innes D, Hargreaves EL.
Sexually dimorphic spatial learning varies seasonally in two
populations of deer mice. Brain Res 1994;635:1826.
[371] Galea LAM, McEwen BS. Sex and seasonal differences in the rate of
cell proliferation in the dentate gyrus of adult wild meadow voles.
Neuroscience 1999;89:95564.
[372] Eriksson PS, Permlieva E, Bjork-Eriksson T, Alborn A-M,
Nordborg C, Peterson DA, et al. Neurogenesis in the adult human
hippocampus. Nat Med 1998;4:13137.
[373] McEwen BS. The neurobiology of stress: from serendipity to clinical
relevance. Brain Res 2000;886:17289.
[374] Aberg MAI, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS.
Peripheral infusion of IGF-1 selectively induces neurogenesis in the
adult rat hippocampus. J Neurosci 2000;20:2896903.
[375] OKusky JR, Ye P, DErcole AJ. Insulin-like growth factor-1
promotes neurogenesis and synaptogenesis in the hippocampal
dentate gyrus during postnatal development. J Neurosci 2000;20:
843542.
[376] Gould E. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 1999;21:S46S51.
[377] Radley JJ, Jacobs BL. 5-HT1A receptor antagonist administration
decreases cell proliferation in the dentate gyrus. Brain Res 2002;955:
2647.
[378] Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, et al.
Requirement of hippocampal neurogenesis for the behavioral effects
of antidepressants. Science 2003;301:8059.
[379] Ikegaya Y, Saito H, Abe K. The basomedial and basolateral
amygdaloid nuclei contribute to the induction of long-term
potentiation in the dentate gyrus in vivo. Eur J Neurosci 1997;8:
18339.
[380] Jacobs BL, Praag H, Gage FH. Adult brain neurogenesis and
psychiatry: a novel theory of depression. Mol Psychiatry 2000;5:
2629.
[381] McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin
Neurobiol 1995;5:20516.
[382] Magarinos AM, Deslandes A, McEwen BS. Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3
pyramidal neurons after chronic stress. Eur J Pharm 1999;371:
11322.
[383] McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci
1999;22:10522.
[384] Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, PaulaBarbosa MM. Reorganization of the morphology of hippocampal
neurites and synapses after stress-induced damage correlates with
behavioral improvement. Neuroscience 2000;97:25366.
[385] Conrad CD, Magarinos AM, LeDoux JE, McEwen BS. Repeated
restraint stress facilitates fear conditioning independently of causing
hippocampal CA3 dendritic atrophy. Behav Neurosci 1999;113:
90213.
[386] Magarinos AM, McEwen BS. Stress-induced atrophy of apical
dendrites of hippocampal CA3 neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience
1995;69:8998.
[387] Lowy MT, Gault L, Yamamoto BK. Adrenalectomy attenuates
stress-induced elevations in extracellular glutamate concentrations
in the hippocampus. J Neurochem 1993;61:195760.

[388] Magarinos AM, McEwen BS, Flugge G, Fuchs E. Chronic
psychosocial stress causes apical dendritic atrophy of hippocampal
CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 1996;
16:353440.
[389] Mennini T, Miari A. Modulation of 3H glutamate binding by
serotonin in rat hippocampus: an autoradiographic study. Life Sci
1991;49:28392.
[390] Rahmann S, Neumann RS. Activation of 5-HT2 receptors facilitates
depolarization of neocortical neurons by N-methyl-Daspartate. Eur
J Pharmacol 1993;231:34754.
[391] Azmitia EC. Cajals hypotheses on neurobiones and neurotropic
factor match properties of microtubules and S-100 beta. Prog Brain
Res 2002;136:87100.
[392] Buzsaki G. Hippocampal sharp waves: their origin and significance.
Brain Res 1986;398:24252.
[393] Eldridge JC, Brodish A, Kute TE, Landfield PW. Apparent agerelated resistance of type II hippocampal corticosteroid receptors to
down-regulation during chronic escape training. J Neurosci 1989;9:
323742.
[394] Sapolsky R, Pulsinelli W. Glucocorticoids potentiate ischemic injury
to neurons: therapeutic implications. Science 1985;229:13979.
[395] Sapolsky R. Stress, the aging brain and the mechanisms of neuron
death. vol. 1. Cambridge MA: MIT Press; 1992.
[396] Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression
duration but not age predicts hippocampal volume loss in medically
healthy women with recurrent major depression. J Neurosci 1999;19:
503443.
[397] Lucassen PJ, Vollmann-Honsdorf GK, Gleisberg M, Czeh B, De
Kloet ER, Fuchs E. Chronic psychosocial stress differentially affects
apoptosis in hippocampal subregions and cortex of the adult tree
shrew. Eur J Neurosci 2001;14:1616.
[398] Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression
duration but not age predicts hippocampal volume loss in medically
healthy women with recurrent major depression. J Neurosci 1999;19:
503443.
[399] Uno H, Ross T, Else J, Suleman M, Sapolsky R. Hippocampal
damage associated with prolonged and fatal stress in primates.
J Neurosci 1989;9:170911.
[400] Sapolsky R, Krey L, McEwen BS. The neuroendocrinology of stress
and aging: the glucocorticoid cascade hypothesis. Endocr Rev 1986;
7:284301.
[401] Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M,
et al. Subgenual prefrontal cortex abnormalities in mood disorders.
Nature 1997;386:8247.
[402] Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD,
Meltzer HY, et al. Morphometric evidence for neuronal and glial
prefrontal cell pathology in major depression. Biol Psychiatry 1999;
45:108598.
[403] Rajkowska G. Postmortem studies in mood disorders indicate altered
numbers of neurons and glial cells. Biol Psychiatry 2000;48:76677.
[404] Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and
glial density characterize the dorsolateral prefrontal cortex in bipolar
disorder. Biol Psychiatry 2001;49:74152.
[405] Botteron KN, Raichle ME, Drevets WC, Heath AC, Todd RD.
Volumetric reduction in left subgenual prefrontal cortex in early
onset depression. Biol Psychiatry 2002;51:3424.
[406] Wellman CL. Dendritic reorganization in pyramidal neurons in
medial prefrontal cortex after chronic corticosterone administration.
J Neurobiol 2001;49:24553.
[407] Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic
stress induces contrasting patterns of dendritic remodeling in
hippocampal and amygdaloid neurons. J Neurosci 2002;22:68108.
[408] Sheline YI, Gado MH, Price JL. Amygdala core nuclei volumes are
decreased in recurrent major depression. Neuroreport 1998;9:
20238.
37
[409] Kellendonk C, Eiden S, Kretz O, Schutz G, Schmidt I, Tronche F,

et al. Inactivation of the GR in the nervous system affects energy
accumulation. Endocrinology 2002;143:233340.
[410] Koolhaas JM, Meerlo P, De Boer SF, Strubbe JH, Bohus B. The
temporal dynamics of the stress response. Neurosci Biobehav Rev
1997;21:77582.
[411] Buwalda B, Blom WA, Koolhaas JM, van Dijk G. Behavioral and
physiological responses to stress are affected by high-fat feeding in
male rats. Physiol Behav 2001;73:3717.
[412] Canetti L, Bachar E, Berry EM. Food and emotion. Behav Process
2002;60:15764.
[413] Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F,
Houshyar H, et al. Chronic stress and obesity: a new view of
comfort food. Proc Natl Acad Sci USA 2003;100:11696701.
[414] Molteni R, Wu A, Vaynman S, Ying Z, Barnard RJ, GomezPinilla F. Exercise reverses the harmful effects of consumption of a
high-fat diet on synaptic and behavioral plasticity associated to the
action of brain-derived neurotrophic factor. Neuroscience 2004;123:
42940.
[415] Molteni R, Barnard RJ, Ying Z, Roberts CK, Gomez-Pinilla F. A
high-fat, refined sugar diet reduces hippocampal brain-derived
neurotrophic factor, neuronal plasticity, and learning. Neuroscience
2002;112:80314.
[416] Zubenko GS, Maher B, Hughes III HB, Zubenko WN, Stiffler JS,
Kaplan BB, et al. Genome-wide linkage survey for genetic loci that
influence the development of depressive disorders in families with
recurrent, early-onset, major depression. Am J Med Genet 2003;
123B:118.
[417] Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. Exercise and brain
neurotrophins. Nature 1995;373:109.
[418] Cotman CW, Berchtold NC. Exercise: a behavioral intervention to
enhance brain health and plasticity. Trends Neurosci 2002;25:
295301.
[419] Lev-Ran A. Human obesity: an evolutionary approach to understanding our bulging waistline. Diabetes Metab Res Rev 2001;17:
34762.
[420] Eaton SB, Cordain L, Lindeberg S. Evolutionary health promotion: a
consideration of common counterarguments. Prev Med 2002;34:
11923.
[421] Lieberman LS. Dietary, evolutionary, and modernizing influences on
the prevalence of type 2 diabetes. Annu Rev Nutr 2003;23:34577.
[422] Bray GA. Obesity: a time bomb to be defused. Lancet 1998;352:
1601.
[423] Gallacher JE, Sweetnam PM, Yarnell JW, Elwood PC, Stansfeld SA.
Is type A behavior really a trigger for coronary heart disease events?
Psychosom Med 2003;65:33946.
[424] Williams Jr. RB. Psychological factors in coronary artery disease:
epidemiologic evidence. Circulation 1987;76:111723.
[425] Williams Jr. RB, Suarez EC, Kuhn CM, Zimmerman EA,
Schanberg SM. Biobehavioral basis of coronary-prone behavior in
middle-aged men. Part I: Evidence for chronic SNS activation in
Type As. Psychosom Med 1991;53:51727.
[426] Adams MR, Williams JK, Kaplan JR. Effects of androgens on
coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arterioscler Thromb Vasc Biol
1995;15:56270.
[427] Henry JP, Ely DL, Stephens PM. Changes in catecholaminecontrolling enzymes in response to psycosocial activation of the
defence and alarm reactions. In: Porter R, Knight J, editors.
Physiology, emotion and psychosomatic illness. Amsterdam:
Elsevier; 1972. p. 22546.
[428] Henry JP. The induction of acute and chronic cardiovascular disease
in animals by psychosocial stimulation. Int J Psychiatry Med 1975;6:
14758.
[429] Hollander W. Role of hypertension in atherosclerosis and cardiovascular disease. Am J Cardiol 1976;38:786800.
38
[430] Fokkema DS, Koolhaas JM, van der Gugten J. Individual

characteristics of behavior, blood pressure, and adrenal hormones
in colony rats. Physiol Behav 1995;57:85762.
[431] Fokkema DS, Smit K, Van der Gugten J, Koolhaas JM. A coherent
pattern among social behavior, blood pressure, corticosterone and
catecholamine measures in individual male rats. Physiol Behav
1988;42:4859.
[432] Kaplan JR, Manuck SB. Status, stress, and atherosclerosis: the role
of environment and individual behavior. Ann NY Acad Sci 1999;
896:14561.
[433] Kaplan JR, Adams MR, Clarkson TB, Manuck SB, Shively CA,
Williams JK. Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models. Psychosom Med 1996;58:
598611.
[434] Kaplan JR, Pettersson K, Manuck SB, Olsson G. Role of
sympathoadrenal medullary activation in the initiation and progression of atherosclerosis. Circulation 1991;84:VI23VI32.
[435] Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine
stimulates apoptosis in adult rat ventricular myocytes by activation
of the beta-adrenergic pathway. Circulation 1998;98:132934.
[436] Sgoifo A, de Boer SF, Haller J, Koolhaas JM. Individual differences
in plasma catecholamine and corticosterone stress responses of wildtype rats: relationship with aggression. Physiol Behav 1996;60:
14037.
[437] Sgoifo A, Koolhaas JM, Musso E, De Boer SF. Different
sympathovagal modulation of heart rate during social and nonsocial stress episodes in wild-type rats. Physiol Behav 1999;67:
7338.
[438] Fukudo S, Lane JD, Anderson NB, Kuhn CM, Schanberg SM,
McCown N, et al. Accentuated vagal antagonism of beta-adrenergic
effects on ventricular repolarization. Evidence of weaker antagonism
in hostile type A men. Circulation 1992;85:204553.
[439] Williams Jr. RB, Suarez EC, Kuhn CM, Zimmerman EA,
Schanberg SM. Biobehavioral basis of coronary-prone behavior in
middle-aged men. Part I: Evidence for chronic SNS activation in
Type As. Psychosom Med 1991;53:51727.
[440] Barefoot JC, Schroll M. Symptoms of depression, acute myocardial
infarction, and total mortality in a community sample. Circulation
1996;93:197680.
[441] Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A,
et al. Depressed affect, hopelessness, and the risk of ischemic heart
disease in a cohort of U.S. adults. Epidemiology 1993;4:28594.
[442] Brindley DN, Rolland Y. Possible connections between stress,
diabetes, obesity, hypertension and altered lipoprotein metabolism
that may result in atherosclerosis. Clin Sci (Lond) 1989;77:45361.
[443] Sternberg EM, Young III WS, Bernardini R, Calogero AE,
Chrousos GP, Gold PW, et al. A central nervous system defect in
biosynthesis of corticotropin-releasing hormone is associated with
susceptibility to streptococcal cell wall-induced arthritis in Lewis
rats. Proc Natl Acad Sci USA 1989;86:47715.
[444] Sternberg EM. Neuralimmune interactions in health and disease.
J Clin Invest 1997;100:26417.
[445] Quayle AJ, Chomarat P, Miossec P, Kjeldsen-Kragh J, Forre O,
Natvig JB. Rheumatoid inflammatory T-cell clones express mostly
Th1 but also Th2 and mixed (Th0-like) cytokine patterns. Scand
J Immunol 1993;38:7582.
[446] Crofford LJ, Pillemer SR, Kalogeras KT, Cash JM, Michelson D,
Kling MA, et al. Hypothalamicpituitaryadrenal axis perturbations
in patients with fibromyalgia. Arthritis Rheum 1994;37:158392.
[447] Webster EL, Torpy DJ, Elenkov IJ, Chrousos GP. Corticotropinreleasing hormone and inflammation. Ann NY Acad Sci 1998;840:
2132.
[448] Buske-Kirschbaum A, Jobst S, Wustmans A, Kirschbaum C,

Rauth W, Hellhammer DH. Attenuated free cortisol response to
psychosocial stress in children with atopic dermatitis. Psychosom
Med 1997;59:41926.
[449] Buske-Kirschbaum A, Geiben A, Hollig H, Morschhauser E,
Hellhammer D. Altered responsiveness of the hypothalamus
pituitaryadrenal axis and the sympathetic adrenomedullary system
to stress in patients with atopic dermatitis. J Clin Endocrinol Metab
2002;87:424551.
[450] Poteliakhoff A. Adrenocortical activity and some clinical findings in
acute and chronic fatigue. J Psychosom Res 1981;25:915.
[451] Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived
stress, and cortisol responses to awakening. Psychosom Med 1999;
61:197204.
[452] Roberts AD, Wessely S, Chalder T, Papadopoulos A, Cleare AJ.
Salivary cortisol response to awakening in chronic fatigue syndrome.
Br J Psychiatry 2004;184:13641.
[453] Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic
fatigue syndrome and in health. Clin Endocrinol (Oxf) 1998;48:
7337.
[454] Cleare AJ. The neuroendocrinology of chronic fatigue syndrome.
Endocr Rev 2003;24:23652.
[455] Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, et al.
Hypothalamopituitaryadrenal axis dysfunction in chronic fatigue
syndrome, and the effects of low-dose hydrocortisone therapy. J Clin
Endocrinol Metab 2001;86:354554.
[456] Bouwer C, Claassen J, Dinan TG, Nemeroff CB. Prednisone
augmentation in treatment-resistant depression with fatigue and
hypocortisolaemia: a case series. Depress Anxiety 2000;12:4450.
[457] Morgan M, LeDoux JE. Differential contribution of dorsal and
ventral medial prefrontal cortex to the acquisition and extinction of
conditioned fear. Behav Neurosci 1995;109:6818.
[458] Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal
memory for fear extinction. Nature 2002;420:704.
[459] Widner B, Ledochowski M, Fuchs D. Interferon-gamma-induced
tryptophan degradation: neuropsychiatric and immunological consequences. Curr Drug Metab 2000;1:193204.
[460] Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase
(IDO) in the pathophysiology of interferon-alpha-induced
depression. Psychiatry Neurosci 2004;29:1117.
[461] Schwarcz R, Pellicciari R. Manipulation of brain kynurenines: glial
targets, neuronal effects, and clinical opportunities. J Pharmacol Exp
Ther 2002;303:110.
[462] Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, DHondt P,
et al. Increased neopterin and interferon-gamma secretion and lower
availability of L-tryptophan in major depression: further evidence for
an immune response. Psychiatry Res 1994;54:14360.
[463] Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S,
Goodkin RS, et al. Paroxetine for the prevention of depression
induced by high-dose interferon alfa. N Engl J Med 2001;344:9616.
[464] Capuron L, Neurauter G, Musselman DL, Lawson DH,
Nemeroff CB, Fuchs D. Interferon-alpha-induced changes in
tryptophan metabolism. Relationship to depression and paroxetine
treatment. Biol Psychiatry 2003;54:90614.
[465] Cohen S, Line S, Manuck SB, Rabin BS, Heise ER, Kaplan JR.
Chronic social stress, social status, and susceptibility to upper
respiratory infections in nonhuman primates. Psychosom Med 1997;
59:21321.
[466] Jones RB. The tonic immobility reaction of the domestic fowl: a
review. World Poult Sci J 1986;42:8296.

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Neuroscience and Biobehavioral Reviews 29 (2005) 338

The Darwinian concept of stress:

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

2. Evolutionary explanations for individual variation in behavior . . . . . . . . . . . . . . . . . .

3. Proximate explanations for individual differences in physiology . . . . . .

4. The costs of allostatic load . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

toll on physical and mental health. There is, however, no

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

usage can lead to a loss of water pressure, thereby making

Second, we give proximate (causal) explanations for the

2. Evolutionary explanations for individual

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

Fast and superficial

also within the same gender across species. In the following

when slow-explorers extended their search to many feeders

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

3. Proximate explanations for individual

Definitions of acronyms: HPG, hypothalamicpituitarygonadal; HPA,

underlying physiology, neuroendocrinology (Table 2) and

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

5-HT1A receptors (incl. mRNA)

Definitions of acronyms: 5-HT1A, 5-hydroxytryptamine 1A; MAPK1,

induces fear-induced freezing behavior in rats [48]. There is

hippocampus plays an important role in the regulation of

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

to differences in the behavioral strategies of non-aggressive

(MRs and GRs) for corticosteroids, with a difference in

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

The above mentioned biphasic actions can be explained

3.4.1. Allostasis in relation to the animals

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

severe storms in spring 1980 abandoned their nests and

while individuals have sufficient fat storage to fuel their

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

such as moving away from a storm, dispersal and wandering

glucocorticoids, catecholamines play also an important role

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

males during the breeding season, the correlation of plasma

plentiful [186,187]. This can clearly be observed in

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

vasoconstriction, decreased blood flow to skeletal muscle

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

and granulocytes [205]. Thus, this enhanced trafficking of

4. The costs of allostatic load

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

allostatic state and allostatic load. The costs for the

In addition to cortisol, the hormone dehydroepiandrosterone

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

Plasma corticosterone levels in mice

the aggressive Hawk type personality is missing from the

than controls at both 1 and 3 weeks after defeat, suggesting

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

issue). Remarkably, when familiar rats are housed together

of the hippocampus, and in both the stratum griseum

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338

A confrontation with a dominant is wasted effort that is

4.1.8. Increased CRF mRNA expression in the amygdala

S.M. Korte et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 338