REVIEW
published: 30 June 2020
doi: 10.3389/fpsyt.2020.00613
Dysregulation of Midbrain Dopamine
System and the Pathophysiology of
Schizophrenia
Susan F. Sonnenschein 1, Felipe V. Gomes 2 and Anthony A. Grace 1*
1
2
Edited by:
Carol A. Tamminga,
University of Texas Southwestern
Medical Center, United States
Reviewed by:
Didier Pinault,
INSERM U1114 Neuropsychologie
Cognitive et Physiophatologie de la
Schizophrénie, France
Francesca Managò,
Italian Institute of Technology (IIT),
Italy
*Correspondence:
Anthony A. Grace
GraceAA@pitt.edu
Specialty section:
This article was submitted to
Schizophrenia,
a section of the journal
Frontiers in Psychiatry
Received: 19 April 2020
Accepted: 12 June 2020
Published: 30 June 2020
Citation:
Sonnenschein SF, Gomes FV and
Grace AA (2020) Dysregulation of
Midbrain Dopamine System and the
Pathophysiology of Schizophrenia.
Front. Psychiatry 11:613.
doi: 10.3389/fpsyt.2020.00613
Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, United States,
Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
Dysregulation of the dopamine system is central to many models of the pathophysiology
of psychosis in schizophrenia. However, emerging evidence suggests that this
dysregulation is driven by the disruption of upstream circuits that provide afferent
control of midbrain dopamine neurons. Furthermore, stress can profoundly disrupt this
regulatory circuit, particularly when it is presented at critical vulnerable prepubertal time
points. This review will discuss the dopamine system and the circuits that regulate it,
focusing on the hippocampus, medial prefrontal cortex, thalamic nuclei, and medial
septum, and the impact of stress. A greater understanding of the regulation of the
dopamine system and its disruption in schizophrenia may provide a more complete
neurobiological framework to interpret clinical findings and develop novel treatments.
Keywords: dopamine, ventral tegmental area, hippocampus, amygdala, thalamus, prefrontal cortex, medial septum
INTRODUCTION
Dopamine (DA) modulates circuit reactivity based on environmental stimuli and prior experience
and thus plays a central role in functions including reward processing, reinforcement, and habit
formation (1–3). Midbrain DA neurons have also been shown respond to novel or aversive stimuli
in the absence of reward (4) and it has been proposed that DA signaling may more generally
influence sensory processing, such as weighting the salience (5) or certainty (6) of perceived stimuli.
Dysregulation of the DA system has been fundamental to many models of the pathophysiology of
schizophrenia (7, 8). It is implicated particularly in psychotic symptoms, which involve profound
perceptual disturbances (hallucinations) and fixed beliefs resistant to contradictory evidence
(delusions). Hallucinations and delusions tend to co-occur and are thus proposed to manifest
due to a common pathophysiological mechanism (6, 9). Psychotic symptoms can be attenuated by
D2 receptor blocking drugs (10, 11) that reduce the abnormal increased DA neuron activity (12–14),
but the underlying cognitive processes likely involve complex connections between numerous brain
regions that remain dysfunctional. This article will discuss some of the circuits that regulate DA
neuron activity and how dysfunction in these upstream circuits may influence the DA system
in schizophrenia.
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neurons that are located at the transition from lateral VTA to
substantia nigra project to the rostral caudate, or associative
striatum, which is most implicated in measures of increased
presynaptic DA function and demonstrates the strongest correlation
to psychotic symptoms in patients with schizophrenia (33, 34). In
primates, the relative position of VTA DA neurons shift, but their
topological organization is retained. Whereas rodents have a
prominent VTA that is located medial to the substantia nigra, in
the primate the DA neurons are shifted, with the rodent VTA
projection to limbic and associative striatum now becoming the
dorsal tier of the substantia nigra and the rodent substantia nigra
that projects to the dorsal striatum now comprising the primate
ventral tier substantia nigra neurons (41, 42).
DOPAMINE DYSFUNCTION IN
SCHIZOPHRENIA
Clinical imaging studies have provided strong support for the
DA hypothesis of schizophrenia. Imaging studies that measured
radioligand displacement from DA receptors as a measure of DA
activity have shown that patients with schizophrenia display
increased DA release in response to low-dose amphetamine,
compared to healthy controls (15–17), which correlates with
transient worsening of psychotic symptoms (17). Patients also
demonstrate increased baseline levels of synaptic DA in the
striatum, measured in a DA depletion paradigm (18), which
has been shown to correlate with their amphetamine-induced
DA release (19). Both measures are observed in antipsychotic
drug-naive patients and drug-free patients with prior APD
treatment, and both predict treatment response of psychosis to
antipsychotic drugs (18–20). Elevated striatal DA synthesis
capacity, measured by fluorodopa uptake into DA terminals, is
also consistently observed in patients and shown to correlate
with psychotic severity (21). Numerous studies have found
increased response capacity of the DA system in individuals at
clinical high risk (CHR) for psychosis, which correlates with
greater severity of prodromal symptoms (22–25). Longitudinal
studies have further shown that there is a progressive increase in
striatal DA function as CHR patients transition to full syndrome
expression (24), which has been shown to predict conversion to
psychosis (23, 25). Elevated DA synthesis capacity is a less
consistent finding in chronic patients in remission, shown to
be significantly elevated compared to healthy controls in some
studies (26–29), though not all (30–32), suggesting that increased
DA function most clearly signals active psychosis. The elevation
in DA is limited to striatal projections (33, 34). In contrast,
mesocortical projections, particularly to the dorsolateral PFC,
display reduced DA release compared to healthy controls, which
may contribute to impaired prefrontal-dependent cognitive
processes (35). It is currently unknown what accounts for these
coexisting differences in DA regulation. Together, these findings
point to dysregulation of the DA system as central to the
development and expression of psychotic symptoms.
ACTIVITY STATES OF MIDBRAIN
DOPAMINE NEURONS
DA neurons exhibit two patterns of activity, known as tonic and
phasic states, that have different functional implications and are
regulated by distinct afferent systems. In vitro in the absence of
inputs, DA neurons maintain a basal activity state through the
generation of a pacemaker conductance (43–45). However, in
vivo recordings in normal rats have shown that not all DA
neurons are showing spontaneous activity; instead, approximately
half of midbrain DA neurons are not spontaneously active, and
instead exist in a hyperpolarized state (45–47) due to inhibitory
input from the ventral pallidum (48), an area that is regulated by
a pathway that arises from the ventral subiculum of the
hippocampus (vHipp). When the vHipp is activated, it provides
a glutamatergic drive of GABAergic projection neurons in the
nucleus accumbens, which in turn inhibits the ventral pallidum
and increases the proportion of VTA DA neurons that are
spontaneously active (i.e. “population activity”; Figure 1).
Spontaneously active DA neurons, in vivo, can display an
irregular tonic firing pattern and rapid, phasic burst firing (45,
49, 50). Burst firing is dependent on glutamatergic afferents from
the pedunculopontine tegmentum via activation of NMDA
receptors (Figure 1) (48, 51). In DA neurons that are nonfiring,
NMDA fails to activate NMDA receptors due to a magnesium
block that is present at hyperpolarized membrane potentials (52).
Thus, only DA neurons that are depolarized (spontaneously
active) have the potential to exhibit burst firing. DA neurons
exhibit burst firing when exposed to a behaviorally salient stimuli,
such as a potential threat or reward (53, 54). Therefore, the
number of neurons firing can control the amplitude of the
behaviorally salient phasic burst response; when there are more
DA neurons firing (i.e., greater population activity), NMDA will
cause a greater number to exhibit phasic bursts, thus amplifying
the phasic response to stimuli (45, 55). In other words, the vHippnucleus accumbens-ventral pallidum (vHipp-NAc-VP) circuit
allows the baseline level of responsivity of the DA system,
which is dependent on population activity, to be adjusted based
on the context in which the stimuli are presented.
DOPAMINE NEURON PROJECTIONS TO
THE STRIATUM
Midbrain DA neurons can be subdivided with respect to their
location, projection target, and functional significance (36, 37).
The striatum is one of the primary targets of DA signaling and
receives dense projections from DA neurons following a
topological gradient. In rodents, more medial DA neurons of
the ventral tegmental area (VTA) innervate more reward-related
ventral striatal regions, including the nucleus accumbens (38).
More lateral DA neurons of the substantia nigra project to the
dorsomedial and dorsolateral striatum, which are relevant to
habit formation and motor function, respectively (39, 40). DA
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FIGURE 1 | Tonic and phasic dopamine (DA) neuron activity are regulated by distinct afferent systems. DA neurons generate their own activity through a pacemaker
conductance. However, a substantial population of DA neurons is not firing spontaneously, being held in a hyperpolarized state by a GABA-mediated inhibitory input from
the ventral pallidum (VP). The VP, in turn, is controlled by a pathway originating from the ventral hippocampus (vHipp). The vHipp projects to the nucleus accumbens
(NAc), which inhibits the VP. By contrast, phasic burst firing is driven by glutamatergic inputs arising from several areas, primary among these being the pedunculopontine
tegmentum (PPTg). This afferent system regulates firing states within the population of spontaneously active DA neurons, because only neurons that are firing
spontaneously can burst fire—NMDA channels on hyperpolarized (“silent”) DA neurons are under magnesium block and won't change state. Therefore, the PPTg
provides the rapid, behaviorally salient phasic signal, whereas the VP, by controlling the number of DA neurons firing, determines the gain of the phasic signal.
more severe psychotic symptoms in patients (60–62) and those at
CHR (63, 64). Increased cerebral blood volume (CBV) has been
reported specifically in the CA1 and subiculum of the
hippocampus in patients with schizophrenia (65). Increased
CBV is also present during the prodromal stage and predicts
conversion to psychosis (66, 67) and hippocampal atrophy (68).
Multiple lines of evidence have suggested that the hippocampal
hypermetabolism is due to reduced parvalbumin (PV)+ GABA
interneuron regulation of pyramidal neuron activity, secondary
to excitotoxic degeneration of PV+ interneurons (69, 70).
NMDA receptor antagonists, such as PCP and ketamine, may
similarly exacerbate or mimic psychosis by blocking NMDA
receptors on PV+ interneurons and thus disinhibiting pyramidal
neurons (71, 72). This can lead to increased levels of glutamate
and loss of PV+ interneurons following chronic NMDA receptor
antagonist administration (68, 73–75).
One can induce an analogous disruption of hippocampal
physiology in animal models based on developmental
CIRCUITS THAT INFLUENCE VTA
DOPAMINE NEURON POPULATION
ACTIVITY THROUGH THE VHIPP-NAC-VP
PATHWAY
Elevated DA system activity in schizophrenia results from
dysfunction in a larger hippocampal-midbrain-striatal circuit,
with a primary locus of pathophysiology that appears to develop
in the vHipp. Deficits in the structure and function of the
hippocampus are consistently observed in imaging and postmortem studies of schizophrenia patients (56). Imaging studies
show that the anterior hippocampus, which is homologous to the
limbic vHipp in rodents (57), is hyperactive in individuals with
schizophrenia (58). Most studies report increased hippocampal
glutamate levels in both first-episode and chronic patients,
independent of medication status (59), and changes in
hippocampal metabolism and blood flow are associated with
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activation of the plPFC had no effect, the plPFC inactivation
decreased VTA DA neuron population activity (88). This is
consistent with the opposite manner that the ilPFC and plPFC
impacts behavioral responses (89, 90). The mechanism by which
the plPFC affects VTA DA system is still not completely
understood, but it may involve the removal of plPFC
attenuation of vHipp activity and/or removal of the inhibitory
influence of the plPFC over the ilPFC.
Whereas vHipp activation upregulates DA responsivity, the
amygdala decreases tonic DA neuron firing. Activation of the
BLA has been shown decrease DA neuron population activity in
the medial affect-related regions of the rat VTA, which is
proposed to be due to a glutamatergic projection to the ventral
pallidum, because blocking glutamate in the ventral pallidum
prevents BLA activation-dependent down-regulation of DA
neuron firing (91). Furthermore, the decrease in DA neuron
population activity observed following activation of the ilPFC
depends on an intact amygdala (88). Therefore, the opposing
modulatory actions of the vHipp and the amygdala are
determined by ilPFC activity.
It is worth noting that the mPFC does not project directly to
the vHipp (92). Thus, the effect of ilPFC inactivation on increases
in VTA DA neuron population activity, that was prevented by
removal of the vHipp influence, may involve other brain regions
such as the entorhinal cortex and thalamic nucleus reuniens (93,
94) since both receive direct excitatory projection from the ilPFC
(92) and in turn provide powerful excitatory influence over the
vHipp (92, 95, 96). Therefore, both the entorhinal cortex and
nucleus reuniens could be a relay between the ilPFC and the
vHipp that could potentially affect activity of DA neurons in
the VTA.
disruption, including the methylazoxymethanol acetate (MAM)
neurodevelopmental rat model (76, 77). The MAM model
involves administration of the mitotoxin MAM to pregnant
dams on gestational day 17, which correlates with the
vulnerable timepoint of the 2nd trimester in humans to
adverse events such as maternal infection (78). The offspring of
MAM-treated dams (“MAM rats”) develop region-specific
disruption of neuronal maturation that results in adult
phenotypes relevant to schizophrenia, in contrast to the
offspring of dams that receive a saline injection, (“SAL rats”)
(76, 79, 80). Adult MAM rats display loss of PV+ interneurons in
the vHipp (81), resulting in a baseline hyperactive state from loss
of inhibitory control of pyramidal cell activity (82). The
increased vHipp drive results in an increase in DA neuron
population activity through the vHipp-NAc-VP circuit and
inactivation of vHipp in MAM rats can normalize the DA
neuron activity and related aberrant behavior (48, 82). Taken
together, these data suggest a that a loss of PV+ interneurons in
the hippocampus leads to increased DA neuron population
activity and a hyper-responsive DA state, in line with clinical
evidence of increased presynaptic DA function (21, 42).
Several brain regions can enhance VTA DA system activity
through interactions with the vHipp-NAc-VP pathway. Here we
discuss evidence indicating the involvement of the medial prefrontal
cortex (mPFC), thalamic nuclei, and medial septum on the VTA
DA system and how changes in the activity of these regions may
lead to a hyperdopaminergic state as seen in schizophrenia.
Medial Prefrontal Cortex and the
Regulation of the DA System
Dysfunction within the mPFC plays a central role in the
pathophysiology of several psychiatric illnesses, including
schizophrenia. For instance, contrary to the increased
presynaptic striatal DA synthesis and release (83), it has been
found that DA transmission is decreased in the PFC of
schizophrenia patients (35). This cortical hypodopaminergic
state is thought to be associated with impairments in cognitive
and executive function in schizophrenia (35, 84). Also, a reduced
PFC activity has been associated with elevated striatal DA
function in schizophrenia patients and at-risk individuals (28, 85).
The mPFC is thought to be a major regulator of the DA
system but with the outcome, either inhibitory and excitatory
responses, reflecting the specific anatomy of mPFC afferents to
the VTA. Two major mPFC subdivisions, the infralimbic (ilPFC)
and the prelimbic (plPFC) cortices, send direct projections to the
VTA (86) as well as to other regions linked with control of the
midbrain DA system, such as the NAc (87). The ilPFC, in
particular, seems to regulate the DA system activity through its
modulation of the activity of the vHipp and basolateral amygdala
(BLA). It was showed that the ilPFC exerts a bidirectional control
over VTA DA system via the BLA and vHipp. Whereas the
inactivation of the ilPFC increases VTA DA neuron population
activity in a vHipp-dependent manner, the activation of the
ilPFC decreased VTA DA neuron population activity (88).
Compared with the ilPFC, the inactivation of the plPFC
produced opposite effects on VTA DA neurons. Whereas the
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Thalamic Nuclei and Regulation of the
DA System
The thalamus has long been implicated as a potential node of
dysfunction in schizophrenia (97) mainly due to its heavily
reciprocal connectivity with the hippocampus and prefrontal
cortex (98–100), thus serving as a critical mediator of
communication between these brain regions. Reductions in
resting-state functional connectivity between the thalamus and
the hippocampus and prefrontal cortex have been reported at
both the chronic and early stages of schizophrenia. It has also
been reported in at-risk individuals and may predict conversion
to psychosis in this group (101–104). Thalamic dysconnectivity
patterns consistent with those seen in schizophrenia were also
observed in healthy individuals after receiving ketamine to model
psychosis (105). Also, a reduction in sleep spindles, which are
non-rapid eye movement sleep oscillations generated by the
thalamic reticular nucleus, has been consistently reported in
schizophrenia patients, and the magnitude of this reduction was
inversely correlated with the severity of psychotic symptoms
(106, 107). These findings suggest that the thalamus may serve as
a hub of wide-scale network dysfunction in schizophrenia.
Recent rodent studies have similarly indicated circuit
abnormalities underlying and resulting from thalamic dysfunction
(108). The thalamus is composed of multiple nuclei, each with their
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of the firing pattern of neurons in the nucleus reuniens (119).
Thus, the nucleus reuniens may mediate the regulation of the
VTA DA system activity by the ilPFC. Overall, these findings
suggest that a loss of top-down prefrontal regulation via
disruption of corticothalamic communication, as has been
observed in schizophrenia, could contribute to hippocampal
overdrive and, consequently, to the hyperdopaminergic state
characteristic of the disorder (Figure 2).
Another thalamic nucleus recently implicated in the
regulation of the VTA DA system is the paraventricular nucleus
of the thalamus. It was observed that the pharmacological
activation of the paraventricular nucleus of the thalamus
enhanced VTA DA neuron population activity, which was
completely prevented by the inactivation of either vHipp or NAc
(120). Both the paraventricular nucleus of the thalamus and vHipp
send extensive glutamatergic innervation to the NAc (121, 122).
Interestingly, the inactivation of the paraventricular nucleus of the
thalamus attenuated the increased VTA DA neuron population
activity induced by the vHipp activation (120). Moreover, this
regulation seems to simultaneously require activity in both the
vHipp and paraventricular nucleus of the thalamus. The
inactivation of the paraventricular nucleus of the thalamus
reverses vHipp-induced increases in VTA DA neuron population
activity. Similarly, vHipp inactivation reverses the paraventricular
nucleus of the thalamus-induced increases (120). Together, these
findings suggest that convergent glutamatergic inputs from the
vHipp and paraventricular nucleus of the thalamus to the NAc
work in concert to regulate VTA DA neuron activity. In addition,
the inactivation of the paraventricular nucleus of the thalamus
reverses the abnormal increase in VTA DA neuron population
activity exhibited by MAM rats (120), similar to what is observed
distinct afferent and efferent projections (109). Our group has
focused on the nucleus reuniens, a thalamic midline nucleus, since
it is bidirectionally connected to the hippocampus and prefrontal
cortex (98, 99, 110). The nucleus reuniens, in rodents, forms the
primary route of communication between the prefrontal cortex and
vHipp and is essential for behaviors involving coordinated action of
these two regions, such as spatial navigation and fear memory (111–
113). Regarding corticothalamic projection to nucleus reuniens,
pyramidal neurons from layers 5 and 6 of the medial prefrontal
cortex send direct projections to the nucleus reuniens (114, 115) and
some neurons from layer 6 of the ilPFC neurons send collaterals to
the antero-medial portion of the thalamic reticular nucleus (116),
the same subregion of the thalamic reticular nucleus that projects to
reuniens (117).
We showed that activation of the nucleus reuniens increases
DA neuron population activity in the VTA via its projection to
the vHipp, since it was prevented by vHipp inactivation (93).
Also, as described above, the inactivation of the ilPFC increases
DA neuron population activity in the VTA, an effect that was
dependent on the vHipp (88). The mPFC, however, does not
send direct projections to the vHipp (92). Besides sending dense
projections to the vHipp (96), the nucleus reuniens drives vHipp
activity (118). The ilPFC inactivation enhances VTA DA system
activity via vHipp likely by disinhibiting the nucleus reuniens
since the inactivation of the nucleus reuniens prevented these
changes (88). These findings suggest that 1) the ilPFC potently
regulates the vHipp via nucleus reuniens and 2) the ilPFC
inhibition leads to disinhibition of nucleus reuniens, likely due
to deactivation of the thalamic reticular nucleus, which in turn,
via its excitatory projections to the vHipp, enhances VTA DA
system activity. The ilPFC was found to modulate several aspects
FIGURE 2 | The ventral hippocampus (vHipp) regulates midbrain DA system activity through a polysynaptic circuit. The vHipp excites neurons in the nucleus
accumbens (NAc) that, in turn, inhibit ventral pallidal (VP) activity. Given that the VP provides an inhibitory tone to VTA DA neurons, activation of the vHipp results in
an enhance VTA DA neuron activity. In schizophrenia, a PV+ interneuron cell loss combined with a disruption of corticothalamic projections contributes to the
hyperactivity of glutamatergic pyramidal (Pyr) neurons in the vHipp that drives an increase in active DA neurons projecting to the associative striatum that underlies
the emergence of psychotic symptoms in schizophrenia. NMDA receptor antagonists, such as PCP and ketamine, may similarly exacerbate or mimic psychosis by
blocking NMDA receptors on PV+ interneurons and thus disinhibiting Pyr neurons. Corticothalamic-hippocampal abnormal interactions can induce a
hyperdopaminergic state, for instance, through a dysfunction of the medial prefrontal cortex (mPFC) that could disinhibit the nucleus reuniens (RE), possibly via loss
of feedforward inhibition from the reticular nucleus of the thalamus (TRN).
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substantia nigra in the normal rat (130, 133), an activation of the
substantia nigra and a reduction of the abnormal increased VTA
DA neuron population activity in MAM rats to baseline levels was
observed (133). A possible explanation for these findings is that, in
MAM rats, medial septum activation leads to an increase in the
pyramidal neuron inhibition which would mitigate the vHipp
hyperactivity (81). For example, the medial septum activation in
normal rats leads to the release of GABA from the medial septum
GABAergic projections to vHipp (123, 125). Since interneurons
tend to be more sensitive to GABA than pyramidal neurons (134,
135), the released GABA would activate GABAA receptors on
interneurons in the vHipp. This would inhibit interneurons,
which in turn leads to the disinhibition of pyramidal neurons.
On the other hand, in MAM rats, GABA released in the vHipp
induced by the medial septum activation would be more likely to
reach pyramidal neurons due to the loss of interneurons in the
vHipp. These changes combined with the loss of cholinergic
activation of a parallel set of GABAergic projections to vHipp
pyramidal neurons that impact the substantia nigra (123, 124)
would increase vHipp drive of the VTA while increasing vHipp
inhibition of the substantia nigra. Therefore, in contrast to
the control condition, in the MAM rats the excitation of
the substantia nigra combined with inhibition of the VTA
would cause the subject to act before thinking, or causing
impulsive behavior (133). Overall, the findings observed in
MAM rats indicate that the medial septum-vHipp pathway as a
potential target to reverse the hyperdopaminergic state in
schizophrenia patients.
after the inactivation of the vHipp in MAM rats (81). These
findings indicate that aberrant thalamic activity may contribute
substantially to the hyperdopaminergic state seen in schizophrenia.
Medial Septum and the Regulation of the
DA System
Another brain region that may influence vHipp activity and, in
turn, regulate midbrain DA system activity is the medial septum.
The medial septum sends dense cholinergic and GABAergic
projections to several hippocampal regions (123, 124), including
the vHipp (125). These projections are critical for hippocampal
theta oscillation (126, 127), a major operational mode of the
hippocampus, which is thought to be indicative of cognitive
processing of environmental information (128).
The GABAergic projections from the medial septum synapse
primarily on PV+ interneurons in the hippocampus (124, 126,
129), which is the interneuron subtype associated with the
hippocampal hyperactivity and downstream hyperdopaminergic
state present in schizophrenia (8, 42). On the other hand, the
cholinergic projections provide slow depolarization of their target
pyramidal neurons (126). Thus, the GABAergic and cholinergic
projections from the medial septum can differently impact the
excitatory-inhibitory balance in the vHipp which could ultimately
lead to changes in the VTA DA system. In this context, our group
recently found that pharmacological activation of the medial
septum by a local infusion of NMDA increased the number of
spontaneously active DA neurons in the VTA (130). An opposite
effect was found in the substantia nigra. These effects induced by
medial septum activation on both the VTA and substantia nigra
depend on the vHipp since they were prevented by the inactivation
of this brain region (130). Moreover, the effects of medial septum
activation on VTA DA neuron population activity were also
prevented by the infusion of the muscarinic receptor antagonist
scopolamine into the vHipp, suggesting that medial septum
cholinergic inputs to the vHipp may be involved in these effects
(130). In addition, the inactivation of the anterior portion of the
VP blocked the increased VTA DA neuron population activity
induced by medial septum activation (130). On the other hand,
inactivation of the posterior portion of the VP blocked the
suppression of substantia nigra DA neuron population activity
by medial septum activation. This suggests that there are
topographically organized parallel circuits by which medial
septum activity can bi-directionally affect DA neurons. Also,
these findings indicate that medial septum seems to modulate
midbrain DA system activity via the vHipp-NAc-VP pathway.
These opposite actions on VTA and substantia nigra DA
neurons mediated by medial septum activation were recently
associated with an enhancement of cognitive flexibility (131), a
process profoundly attenuated in schizophrenia (132). The
concept is that activation of the VTA causes the subject to
think about the action, while attenuation of the substantia nigra
prevents action until after weighing options. Interestingly, the
regulation of the midbrain DA system activity by the medial
septum in the MAM model of schizophrenia is different from that
observed in normal rats (133). Whereas medial septum activation
increases VTA DA neuron population activity and inhibits the
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IMPACT OF STRESS ON VTA DOPAMINE
NEURON REGULATION
A diathesis-stress model proposes that schizophrenia develops
due to stress exposure acting on a pre-existing vulnerability (136).
Indeed, a large body of work highlights the importance of stress as
a risk factor in the development of schizophrenia (43, 137–139).
Early life stress and chronic social stressors, in particular, have
been shown to increase the risk of schizophrenia (140, 141). Acute
stress can trigger psychotic symptoms (142) and impaired stress
tolerance is associated with prodromal symptoms (143). The
correlation between early life stress and severity of positive
symptoms (144) may partially be due to the interaction between
stress, the hippocampus, and the DA system (145, 146).
The vHipp, which is integral in regulating context-dependent
responses (147, 148), also shows marked vulnerability to stress
across many psychiatric conditions. This may in part be due to a
high expression of glucocorticoid receptors to respond to
activation of the hypothalamic-pituitary-adrenal (HPA) axis
(149). While an elevation in glucocorticoids is essential to
respond to perceived threat, chronic elevation can result in
impaired function and hippocampal atrophy (150, 151). This
would be exacerbated by stress-induced activation of amygdalahippocampal glutamatergic projections that target PV+
interneurons (152). Prolonged stressors can lead to dendritic
shrinkage and neuronal loss in the hippocampus (149), including
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differences should be taken into account since female rodents
appear to show greater resilience to schizophrenia-like traits
resulting from developmental stress (169). These findings may be
associated with the delayed onset and lesser severity of
schizophrenia in females (170, 171).
a loss of PV+ interneurons (153). It has thus been hypothesized
that vHipp dysfunction may contribute to the diathesis in
prodromal patients that puts them at risk for developing
psychosis in response to stress (154).
Both CHR individuals and schizophrenia patients demonstrate
elevated DA release in response to stress compared to healthy
controls (155, 156). In adult rats, prolonged stressors, such as
restraint stress (157) or repeated footshock (158), increase DA
neuron population activity and the level of DA in nucleus
accumbens (159). The increase in DA neuron activity can be
normalized by inhibiting the vHipp (157, 158). However, at later
timepoints, there is a compensatory reduction in DA neuron
population activity, referred to as an opponent process (160), and
shown to be dependent on the BLA (146, 161). In contrast, during
puberty, prolonged stress exposure in rats has been shown to
result in a long lasting increase DA neuron activity in adulthood,
suggesting that stress before or during puberty is particularly
impactful to the responsivity of the DA system (162, 163).
Heightened stress responsivity, insufficient prefrontal inhibition
activity in the amygdala (152, 164, 165), and general loss of
corticothalamic communication, may contribute to vHipp
dysfunction and the emergent hyperdopaminergic state. Extreme
stress, or a failure of the PFC to mitigate the impact of stress, could
lead to loss of PV+ interneurons in the hippocampus in late
adolescence or early adulthood. This in turn would lead to
hippocampal hyperactivity and DA system dysregulation. We
have shown previously that peripubertal administration of the
benzodiazepine diazepam, can prevent the increased anxiety-like
behavior and BLA hyperactivity, and normalize hyperdopaminergic
activity typically present in adult MAM rats (166–168). These
studies suggest that increased stress responsivity, particularly at
crucial developmental stages, could lead to the emergence of
psychosis in adults and that decreasing stress or other means of
reducing vHipp activity during peripubertal period has the potential
to circumvent the pathological processes that leads to DA system
dysregulation (8). Evidence from animal studies indicate that sex
CONCLUSION
The DA system has long been implicated in the expression and
treatment of psychotic symptoms in schizophrenia. Study of the
circuits that drive DA dysfunction can provide greater and more
integrative understanding of a system-wide pathophysiology.
Disruption of these circuits through developmental insults and
pathological stressors can lead to DA system dysregulation.
Ultimately, a greater understanding of the circuits that drive
DA system dysfunction in schizophrenia can provide a
neurobiological basis for interpreting clinical studies and
potential targets for the treatment and prevention of
schizophrenia and related psychotic disorders.
AUTHOR CONTRIBUTIONS
All authors contributed to the article and approved the
submitted version.
FUNDING
Research activity of the authors is supported by grants from US
National Institutes of Health (MH57440 to AG) and Sao Paulo
Research Foundation (FAPESP Young Investigators Grant 2018/17597-3 to FG).
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Conflict of Interest: AAG has received consulting fees from Alkermes, Lundbeck,
Takeda, Roche, Lyra, Concert, and research funding from Lundbeck.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
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