The Limbic System

Prof Maja Valić

Department for Neuroscience
University of Split School of Medicine
„ In 1878. France neurologist Paul Broca
described LOBUS LIMBICUS
„ LOBUS LIMBICUS
„ limbic system links a group of functionally
related structures that are interposed
between the cerebral cortex and the
underlying diencephalon
„ 1937 James Papez first proposed that
specific brain circuits are devoted to
emotinal expression and experience
„ Two prominent components of this region
are the CINGULATE GYRUS (above
corpus callosum) and
PARAHIPPOCAMPAL GYRUS (in medial
temporal lobe)
„ Over time, the circuitry initially described
by Papez has been revised to include parts
of the orbital and medial prefrontal
cortex, ventral parts of the basal ganglia,
the mediodorsal nucleus of the thalamus
(a different thalamic nucleus than the one
emphasized by Papez), and a large nuclear
mass in the temporal lobe anterior to the
hippocampus, called the amygdala.
„ This set of structures, together with the
hippocampus and cingulate cortex, is
generally referred to as the limbic system
Neuroscience. 2nd edition.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors.
Sunderland (MA): Sinauer Associates; 2001.
„ About the same time that Papez proposed
that some of these structures were important
for the integration of emotional behavior,
Heinrich Klüver and Paul Bucy were
carrying out a series of experiments on
rhesus monkeys in which they removed a
large part of both medial temporal lobes,
thus destroying much of the limbic system.
„ they reported a set of abnormal behaviors in
these animals that is now known as the
Klüver-Bucy syndrome.
„ Among the most prominent changes was
visual agnosia: The animals appeared to be
unable to recognize objects, although they
were not blind, a deficit similar to that seen
in human patients following lesions of the
temporal cortex
„ the monkeys displayed bizarre oral behaviors. For
instance, these animals would put objects into
their mouths that normal monkeys would not.
„ They exhibited hyperactivity and hypersexuality,
approaching and making physical contact with
virtually anything in their environment; most
importantly, they showed marked changes in
emotional behavior.
The Limbic System
„ consists of the hippocampal formation,
septal area, and amygdala
„ limbic structures communicate with the
hypothalamus or midbrain periaqueductal
gray (PAG).
„ short-term memory
„ epileptogenic activity
The Lymbic System

1) Hippocampal formation connections

a) To the cortex (3-synaptic path)
b) To the hypothalamus and subcortical structures
(Papez circuit)
2) Septal area
3) Basal forebrain nuclei
4) Amigdala
5) Pathological activity within limbic circuits
Inputs from:
1.sensory systems, 2.the cortex,
3.the monoamine neuronal
groups of the brainstem reticular
formation.
Outputs to the:
1.Hypothalamus
hypothalamus provides
the integrating mechanism for
different forms of emotional
behaviors and visceral and
autonomic responses.
2. Cortex
HIPPOCAMPAL FORMATION
HIPPOCAMPAL FORMATION

„ Histology and Local Anatomical

Connections
„ consists of the hippocampus, dentate
gyrus, and subicular cortex
 (2)

(3)

(2)

(1)
(1) inputs from the entorhinal region, which include the perforant and alveolar pathways;
(2) internal circuitry, which includes the connections of the mossy fibers and Schaffer collaterals;
(3) efferent projections of the hippocampal formation through the fimbria-fornix system of fibers.
CA1–CA4 denote the four sectors of the hippocampus.
„ The hippocampus can be viewed as a
primitive form of three-layered cortical
tissue
„ 1. external plexiform layer
„ 2. stratum oriens
„ 3a. pyramidal cell layer
„ 4 (3b). stratum radiatum and stratum
lacunosum-moleculare,
FD:
stratum multiforme
stratum granulare
stratum moleculare
CA:
stratum moleculare
stratum pyramidale
stratum multiforme
„ The hippocampus is divided into a number
of distinct fields.
„ sectors: CA1, CA2, CA3, and CA4
„ The pyramidal cells situated closest to the
subiculum are referred to as the CA1 field
„ the CA4 field is located within the hilus of
the dentate gyrus.
„ Collaterals of axons arising from CA3
pyramidal cells (called recurrent or
Schaffer collaterals) project back to the
CA1 field.
„ The CA1 pyramidal cells are highly
susceptible to anoxia, especially during
periods of temporal lobe epilepsy. This
region is referred to as Sommer’s sector.
„ The dentate gyrus can also be thought of
as a primitive three-layered cortical
structure.
„ principal cell type is the granule cell
„ The axon of the granule cell, called a
mossy fiber, makes synaptic contact with
pyramidal cells in the CA3 region.
 „ The last component of the hippocampal
formation is the subicular cortex
Schaffer collaterals-
-Axons from CA3 pyramidal cells mossy fiber - axon of the granule cell.
Afferent Connections

„ lateral perforant pathway

„ medial perforant pathway
„ Represent:
‹ tertiary olfactory, visual, and auditory

fibers
‹ monoamine neuronal projections from

the brainstem reticular formation (mood

regulation)
Efferent Connections

„ arise from pyramidal cells located in both

the hippocampus and subicular cortex
„ Three components of the fornix system:
„ 1. precommissural fornix passes rostral to
the anterior commissure and supplies the
septal area
„ 2. postcommissural fornix innervates the
diencephalon.
„ The significance of the projections of the
subicular and entorhinal cortex is that they
enable the hippocampal formation to
communicate with widespread regions of
neocortex, including areas that receive
different modalities of sensory information.
„ Such projections may constitute the
substrate by which signals from limbic
regions of the brain serve to provide
affective properties to various modalities of
sensory signals.
„ 3. The third component of the fornix system
is its commissural component.
„ Provides connections between the
hippocampus on each side of the brain
„ Clinical relevance: may provide the
structural basis by which seizures spread
from the hippocampus on one side of the
brain to the hippocampus on the other side.
Functions and Dysfunctions of the
Hippocampal Formation
„ modulation of aggressive behavior
„ autonomic and endocrine functions
„ certain forms of learning and memory
 Aggression and Rage
„ Lesions, tumors, and epileptogenic activity of the
hippocampal formation can be linked with
aggressive reactions.
„ hostility and explosive acts of physical violence
„ The hippocampal formation contributes to the
regulation of aggressive forms of behavior. It is
likely that such effects are mediated on the
hypothalamus via interneurons in the septal area.
 Endocrine Functions
„ The hippocampal formation (like other regions
of the limbic system) has significant inputs to
different parts of the hypothalamus.
„ (1) estradiol-concentrating neurons in the
ventral regions of the hippocampal formation,
„ (2) corticosterone
„ (3) stimulation of the hippocampal formation
inhibits ovulation
„ (4) lesions of the hippocampus disrupt the
diurnal rhythm for ACTH release.
Learning and Memory Functions
of the Hippocampal Formation
„ Theta rhythm (4-7 Hz) when approaching
the goal, in conditioning
„ Spatial learning
„ Cognitive maps
Learning and Memory Functions of the
Hippocampal Formation
„ Korsakoff’s syndrome is a memory
disorder in which the patient displays
memory loss of anterograde and retrograde
memory due to hippocampal damage.
„ Associated with the toxic effects of alcohol
or from a vitamin B deficiency.
„ Neurons in the hippocampal formation and
other parts of the Papez circuit are affected.
Papez cycle
„ In year 1937, James Papez indicated that
emotions are not function of a single center
in the brain, but rather relay on a neuronal
circuit which includes several structures.
Components of the Papez cycle:

‹ HYPOTHALAMUS with CORPORA

MAMILLARIA
‹ THALAMUS (anterior nucleus)

‹ GYRUS CINGULI

‹ HIPPOCAMPUS
„ Papez cyrcuit:: central regulation of
emotions (fear, rage, love, hate, agression)
„ and their expression (autonomic reactions,
heart rate, breathing)
 Memory and learning

„ memory loss due to hippocampal ablation

(lobectomy)
„ patients could not remember of people or
events that happened after the surgery
„ hippocampus contribute to the consolidation
of memory functions by transferring short-
term memories to long-term memories.
„ One hippocampal mechanism that has been
proposed as a model for memory
consolidation is called long-term
potentiation (LTP).
„ It represents a change in synaptic strength
as a manifestation of synaptic plasticity.
FIGURE 25–5 Long-term potentiation
(LTP).
(A) Activity within the CA1 field of
hippocampus is recorded with a
microelectrode following alternate
stimulation of inputs 1 and 2.

(B) In this experiment, high-frequency

(tetanus) stimulation applied in input 1
at the time indicated by the arrow
potentiated the response as shown in the
time period to the right of the arrow.

(C) This graph shows the specificity of

the response because there was no
change in response following stimulation
of input 2. EPSP = excitatory postsynaptic
potentials.

(D) Calcium (Ca2+), which enters

through NMDA receptors and activates
protein kinases, can induce LTP by either
altering the efficiency of AMPA receptors
or inducing new AMPA receptors.

(From Bear MF, et al.: Neuroscience: Exploring the

Brain, 3rd ed. Philadelphia: Lippincott Williams &
Wilkins, 2007, p. 778.)
SEPTAL AREA
Functions of the Septal Area
„ relay for the transmission of hippocampal
impulses to the hypothalamus, but also as a
feedback system
„ aggression, rage, autonomic functions, self-
stimulation, and drinking behavior
RELATED BASAL
FOREBRAIN NUCLEI
„ bed nucleus of the stria terminalis,
„ nucleus accumbens,
„ substantia innominata (basal nucleus of
Meynert, Ach-Alzheimer’s disease)
Amygdala
 AMYGDALA
„ Functions and Dysfunctions of the Amygdala
„ Klüver-Bucy syndrome.
„ Different regions of amygdala exert differential effects
on different forms of aggressive behavior.
„ Stimulation of the amygdala has affects on the
cardiovascular system: increases in blood pressure,
heart rate, and pupillary dilation
„ It affects endocrine function (ovulation, growth
hormone, ACTH)
„ Experiments first performed in the late 1950s by
John Downer at University College London
vividly demonstrated the importance of the
amygdala in aggressive behavior.
„ Downer removed one amygdala in rhesus
monkeys, at the same time transecting the optic
chiasm and the commissures that link the two
hemispheres.
„ he produced an animal with a single amygdala that
had access only to visual inputs from the eye on
the same side of the head.
„ amygdala mediates processes that invest sensory
experience with emotional significance
„ amygdala is a site where neural activity produced
by both tones and shocks can be processed, it is
reasonable to suppose that the amygdala is also the
site where learning about fearful stimuli occurs.
These results, among others, have led to the
broader hypothesis that the amygdala participates
in establishing associations between neutral
sensory stimuli, such as a mild auditory tone or the
sight of inanimate object in the environment
„ The discovery that long-term potentiation (LTP) can be
evoked in the amygdala provides further support for this
hypothesis. Indeed, the acquisition of conditioned fear in
rats is blocked by infusion into the amygdala of NMDA
antagonists, which prevents the induction of LTP. Finally,
the behavior of patients with selective damage to the
anterior-medial temporal lobe indicates that the amygdala
plays a similar role in the human experience of fear
Patient S.M.
„ The patient (S.M.) suffers from a rare, autosomal recessive condition
called Urbach-Wiethe disease.
„ The disorder caused the bilateral calcification and atrophy of the
anterior-medial temporal lobes.
„ As a result, the amygdala in each of S.M.'s hemispheres is extensively
damaged, with little or no detectable injury to the hippocampal
formation or nearby temporal neocortex.
„ She has no motor or sensory impairment, and no notable deficits in
intelligence, memory, or language function.
„ However, when asked to rate the intensity of emotion in a series of
photographs of facial expressions, she cannot recognize the emotion of
fear (figure A). Indeed, S.M.'s ratings of emotional content in fearful
facial expressions were five standard deviations below the ratings of
control patients who had suffered damage outside of the anterior-
medial temporal lobe.
She failed to recognize FEAR (orange line)
AMYGDALA
„ important role in the organization and
regulation of fear responses.
„ Patients with Urbach-Wiethe disease
(calcification of parts of the anterior aspect
of the temporal lobe including the
amygdala) may have difficulties in
recognizing stimuli that one would
normally characterize as fearful.
LIMBIC COMPONENTS OF THE
CEREBRAL CORTEX
„ Functions of the Cerebral Cortex
„ Prefrontal Cortex
„ The prefrontal cortex is associated with
both emotional and intellectual processes
„ The importance of the human prefrontal
cortex in the control of human aggression
has also been recognized for many years
„ prefrontal lobotomy was
developed in 1936 by Egaz
Moniz for controlling human
violence
„ The use of prefrontal
lobotomies has been replaced
by other (noninvasive)
therapeutic measures such as
antipsychotic drugs.
PATHOLOGICAL ACTIVITY WITHIN
LIMBIC CIRCUITS
„ epilepsy is a major disorder associated with the
limbic system
„ If alpha rhythm is slow or absent, there may
be a neurologic problem.
Epilepsy
„ condition in which seizures are recurrent
„ The time of the occurrence of the seizure is
called the ictal period
„ the time following the seizure is called the
postictal period
„ and the time between seizures is called the
interictal period
Jacksonian March epilepsy
„ Seizure activity begins locally over the
cortex, causing either sensory or motor
activity directly corresponding to the
homunculus.
„ The patient experiences a “march” of
sensory or motor activity from muscle to
muscle in the same order as the
homunculus.
 Absence seizures

• very brief (approximately 3–10 seconds long)

• the patient is unresponsive
• commonly described as “daydreaming”
 „ The word “EMOTION” covers a wade
range of states (association of visceral
motor responses, somatic behaviour and
powerful subjective feelings
„ Somatic motor behaviour associated with
emotion is governed by circuits in the
limbic system, hypothalamus, the amygdala,
and several regions of cerebral cortex in the
medial and inferior frontal lobe
Neuroscience. 2nd edition.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors.
Sunderland (MA): Sinauer Associates; 2001.