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Nat Rev Neurosci. Author manuscript; available in PMC 2018 September 21.
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Published in final edited form as:

Nat Rev Neurosci. 2018 September ; 19(9): 535–551. doi:10.1038/s41583-018-0039-7.

Brain circuit dysfunction in post-traumatic stress disorder: from

mouse to man
Robert J. Fenster1,2, Lauren A. M. Lebois1,2, Kerry J. Ressler1,*, and Junghyup Suh1,*
1Division
of Depression and Anxiety Disorders, McLean Hospital Department of Psychiatry,
Harvard Medical School, Belmont, MA, USA.
2These authors contributed equally: Robert J. Fenster, Lauren A. M. Lebois.
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Abstract
Post-traumatic stress disorder (PTSD) is a prevalent, debilitating and sometimes deadly
consequence of exposure to severe psychological trauma. Although effective treatments exist for
some individuals, they are limited. New approaches to intervention, treatment and prevention are
therefore much needed. In the past few years, the field has rapidly developed a greater
understanding of the dysfunctional brain circuits underlying PTSD, a shift in understanding that
has been made possible by technological revolutions that have allowed the observation and
perturbation of the macrocircuits and microcircuits thought to underlie PTSD-related symptoms.
These advances have allowed us to gain a more translational knowledge of PTSD, have provided
further insights into the mechanisms of risk and resilience and offer promising avenues for
therapeutic discovery.
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Post-traumatic stress disorder (PTSD) is, from a historical point of view, a recent diagnosis.
There are loose strands of the idea that trauma may inflict psychological distress throughout
ancient Western literature; however, more recent works have been mostly silent on the topic
of the syndrome we have come to call PTSD, a situation that may have arisen as a result of
cultural norms and social stigma surrounding trauma survival1. This silence is especially
true for the suffering of women after trauma2. The establishment of PTSD as a medical
diagnosis in 1980 (REF3) has allowed for its acceptance by the wider culture and has
facilitated research into this previously neglected psychiatric disorder.
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*
[email protected]; [email protected].
Author contributions
R.J.F., L.A.M.L., K.J.R. and J.S. researched data for the article, made substantial contributions to discussions of the con tent, wrote the
article and reviewed and/or edited the manuscript before submission.
Competing interests
K.J.R. is on the scientific advisory boards for Resilience Therapeutics, the Sheppard Pratt-Lieber Research Institute, the Laureate
Institute for Brain Research, the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) project, the University of
California-San Diego VA Center of Excellence for Stress and Mental Health (CESAMH) and the Anxiety and Depression Association
of America; provides fee-for-service consultation for Biogen and Resilience Therapeutics; and holds patents for the use of d-
cycloserine and psychotherapy, targeting the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor for extinction,
targeting tachykinin 2 for prevention of fear and targeting angiotensin to improve extinction of fear. R.J.F., L.A.M.L. and J.S. declare
no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
 Fenster et al. Page 2

It is now widely accepted that there is considerable genetic heritability in the development of
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PTSD (Box 1). Recently, the groundwork has been laid for the establishment of large-scale
genome-wide association studies (GWAS) that aim to identify the genes that contribute to
PTSD risk4. However, when compared with other psychiatric disorders (such as
schizophrenia and autism), there has been relatively little progress made in our
understanding of the definitive molecular changes involved in determining vulnerability to
PTSD. As a result, there are few identified therapeutic targets for pharmacological
intervention in this disorder.

Increasingly, psychiatric disorders — including PTSD — are becoming understood as

disorders of circuits5. Indeed, most of the recent advances in PTSD research have come from
the elucidation of the brain circuits implicated in the disorder. Functional neuroimaging of
human patients has identified brain regions with altered activity and connectivity6. In
parallel, the expansion of the use of optogenetics, chemogenetics, fibre photometry and
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other circuit-perturbing and circuit-monitoring tools in animal models has led to terrific
progress in our understanding of the microcircuitry that underlies the normal behavioural
processes that become per turbed in PTSD. These include those involved in fear and threat
detection7, reward processing8,9 and valence representation10, among others.

Alongside the growing emphasis on circuits, there has also been a move away from a
categorical under standing of psychiatric illness towards a dimensional approach, as
embodied within the Research Domain Criteria (RDoC) issued by the National Institute of
Mental Health5. If circuits control behaviours and there is a dimensional continuum between
normal and mala daptive processes, then it becomes important to under stand how normal
circuits function in both humans and animal models. This understanding will allow us to
develop better hypotheses about how circuits are altered to produce maladaptive behaviours
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and will also provide avenues for future therapeutic discovery by suggesting how circuits
can be targeted to restore normal function.

In this Review, we will examine the brain circuit mechanisms underlying each of the main
clusters of symptoms identified in the Diagnostic and Statistical Manual of Mental
Disorders, fifth edition (DSM-5)11 classification of PTSD by considering evidence from
human neurobiological studies and animal model approaches (Figs 1,2). Although there
have been recent reviews of PTSD that have included a discussion of the functional
neuroimaging literature12 and several recent reviews of the microcircuitry involved in brain
regions implicated in PTSD-related circuits7,8,10, there has not yet been an attempt to bridge
human and animal literatures in the discussion of PTSD pathophysiology. Because the
DSM-5 remains dominant in clinical academic medicine, we have chosen to structure this
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Review according to its criteria rather than the categories outlined in the RDoC; however, we
provide an attempt to align the DSM-5 criteria with the current RDoC matrix (TABLE 1).
We also offer a brief summary of progress in our under standing of the genetics underlying
PTSD risk and suggest future strategies for research. We hope to convey our belief that the
intersection of PTSD biology and neuro science is driving these fields towards interesting
and potentially feasible new neurobiology-driven approaches to treatment and prevention.

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Symptoms and diagnosis

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Epidemiological studies show that PTSD is quite prevalent, with lifetime estimates ranging
from 1.3% to 12.2% depending on the population studied13. PTSD is also very costly to our
society in terms of both treatment cost and loss of productivity14. Furthermore, PTSD is
highly comorbid with depression, other anxiety disorders and substance abuse and is a
leading cause of suicide. Women are at much greater risk of developing PTSD than men and
suffer from more debilitating symptoms after trauma15.

A diagnosis of PTSD according to DSM-5 relies upon several key criteria: an individual
must have been exposed to a death, threatened death, actual or threatened serious injury, or
actual or threatened sexual violence (criterion A) and this must have been followed by
ongoing symptoms of intrusive re-experiencing (criterion B, at least one such symptom
required), avoidance (criterion C, at least one such symptom required), negative cognitions
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and mood (criterion D, at least two such symptoms required) and arousal and reactivity
(criterion E, at least two such symptoms required), resulting in functional impairment and
not being caused by other medical or psychiatric illness11. However, evidence suggests that
considerable heterogeneity exists within the syndrome and that the set of symptoms present
is dependent on factors including the timing of the traumatizing events (in childhood versus
adulthood, for example) and the type of exposure. For example, early-onset chronic
interpersonal trauma and adult sexual assault are associated with more severe PTSD
symptoms and more emotional dysregulation than late-onset or single-event traumas16–17.
Recent neurobiological evidence of a dissociative subtype of PTSD and its subsequent
addition to DSM-5 confirms that considerable heterogeneity remains within the syn drome18
(Box 2). Within the RDoC, these DSM-5-defined symptoms of PTSD can be seen to be
distributed across multiple domains, including systems related to negative valence, positive
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valence, cognition, social processing and arousal19 (TABLE 1).

Intrusion symptoms
Criterion B of the DSM-5 criteria for PTSD diagnosis focuses on intrusion symptoms, in
which the traumatic event is persistently re-experienced11. This re-experiencing can occur in
a number of ways, including recurring, involuntary intrusive memories, dissociative
reactions (such as flashbacks), distressing dreams and physiological reactivity11. It has been
suggested that these intrusive symptoms are a product of emotional under modulation —
that is, a failure of the cortex to inhibit the limbic system20. In support of this theory,
individuals with PTSD often demonstrate increased activity in the amygdala and decreased
medial prefrontal cortex (mPFC) activity during symptom provocation studies when
compared with individuals without PTSD21–30. The amygdala is a key limbic structure
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involved in emotional reactivity, over which regions of the mPFC exert an inhibitory
effect31. Furthermore, reports of in-the-moment re-experiencing symptoms in individuals
with PTSD have shown some association with increased insula activity and decreased rostral
anterior cingulate cortex (rACC) and inferior frontal cortex activity32. The insula is thought
to be involved in interoception and bodily awareness33, whereas the rACC and lateral
prefrontal cortex are often involved in attention, emotion and arousal regulation34. Together,
these results suggest that, in PTSD, there is a failure of top-down cortical inhibition (from

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the mPFC or rACC, for example) of the reactivation of memory traces associated with
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trauma-related thoughts and feelings, many of which may be centred around the visceral
experience of one’s body (in which the amygdala and insula have a role).

The failure of such top-down cortical inhibition has also been suggested to be related to
impairments of fear extinction35. In classical conditioning theory, fear conditioning occurs
when a neutral cue (such as a tone or an image) is paired with an intrinsically aversive cue
(such as an electric shock). Subsequent presentations of the neutral cue provoke a fear
response. Fear extinction refers to the gradual decrement of the fear response to a
conditioned stimulus when it fails to be reinforced (by the repeated presentation of the
conditioned stimulus in the absence of the aversive cue, for example)36. There is strong
evidence that fear extinction involves the formation of a competing new memory that
inhibits the fear response, rather than an erasure of the original memory36,37; however, fear
memories may also weaken during recall through a process called reconsolidation38. There
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have been studies showing that individuals with PTSD are able to encode such new fear
extinction memories but have difficulty retaining them35,39–41, suggesting that deficits in
fear extinction retention underlie PTSD. Furthermore, there is evidence that the size and
activity of the ventromedial prefrontal cortex (vmPFC) is associated with the extent of fear
extinction deficits in individuals with PTSD42 as well as evidence for changes to the
functional connectivity between the left vmPFC and the amygdala in individuals with
PTSD43. Given that vmPFC-mediated inhibition of the amygdala is thought to be necessary
for fear extinction31, these changes could offer a mechanistic basis for the decrements in
extinction retention observed in PTSD subjects. There is also some evidence to support the
idea that patients with PTSD might exhibit an increased capacity for fear conditioning
itself44 or a greater propensity for increased fear generalization45–47; however, there have
been no longitudinal studies of these traits in patients at risk of developing PTSD, making it
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unclear whether these characteristics are a cause or an effect of developing PTSD.

Animal models of fear conditioning and fear extinction have highlighted the importance of
the relation ship between the vmPFC and the amygdala in both the expression and extinction
of fear behaviours (BOX 3). Although there is some debate among comparative
neuroanatomists regarding the precise homologies of the human and rodent prefrontal cortex
(PFC), projection patterns and cytoarchitecture suggest that the vmPFC in rodents is
composed of the prelimbic and infralimbic cortices48,49. Pharmacological or electrolytic
inhibition of the prelimbic cortex prevents expression of conditioned fear behaviours,
whereas inhibition of the infralimbic cortex impairs retrieval of fear extinction50,51.

Experiments using optogenetics have confirmed and refined this dichotomy. These studies
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have shown that, in mice, optogenetic inhibition of prelimbic cortex projection neurons
inhibits the expression of fear behaviours52, whereas the release of prelimbic cortex
projection neuron firing through optogenetic inhibition of parvalbumin-expressing
interneurons drives expression of fear behaviours53. Silencing infralimbic projection neurons
during extinction training prevents the retention of fear extinction memories, and protein
synthesis within the infralimbic cortex is necessary for retention of fear extinction54,55.
Interestingly, silencing infralimbic projection neurons after extinction has occurred has no
impact on extinction retrieval, suggesting that these neurons are crucial for formation, but

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not retention, of extinction memories54. A recent study may explain this phenomenon by
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suggesting that it is the activation of basolateral amygdala (BLA) inputs within the
infralimbic cortex that facilitates fear extinction retention rather than the activation of
infralimbic neuronal somata56. It is not currently known whether prelimbic and infralimbic
projection neuron cell types are molecularly distinct or whether there is heterogeneity
among these neurons. The identification of genetic markers for neurons that project from the
infralimbic cortex to the BLA could lead to pharmacological targets for increasing the
encoding of fear extinction memories.

Avoidance
Criterion C of the DSM-5 framework encapsulates persistent, effortful avoidance of
distressing trauma-related stimuli11, which can include thoughts, feelings and environmental
cues (including people, places, conversations, activities, objects and situations). Theoretical
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commentary has suggested that an imbalance in approach versus avoidance behavioural

responses is at the centre of PTSD dysfunction57; however, the neurobiological
underpinnings of trauma-cue avoidance are surprisingly understudied in human-based PTSD
research.

A study using a symptom provocation paradigm found that the experience of actively
avoiding trauma-related thoughts or feelings was associated with decreased activity in
multiple regions of the anterior cingulate cortex (ACC) and inferior frontal cortex and with
increased activity in the superior temporal cortex32. Avoidance has also been examined in
the context of fear conditioning. In a recent fear conditioning study, the severity of
interview-assessed PTSD avoidance symptoms within the past month was shown to be
positively associated with hippocampal responses to context cues and conditioned stimuli in
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the acquisition phase of a fear conditioning paradigm and to amygdala, hippocampus and
insula activity during the extinction phase58. These findings suggest that avoidance
symptoms and fear circuit activation are closely linked and that avoidance is central to the
fear extinction deficits reported in PTSD (see above). By definition, a cue or context that is
avoided cannot be extinguished in a normal fashion; thus, many behavioural therapy
approaches to the treatment of PTSD focus on decreasing such avoidance behaviours.

A growing literature describes the brain circuits involved in determining whether an animal
will respond to a threat-associated stimulus with passive avoidance (freezing; see also the
dissociative subtype of PTSD, Box 2) or more active avoidance strategies (such as running
towards a safe chamber)59. Both strategies can be maladaptive if used excessively or in a
fashion in which the individual has no control; however, there is evidence to suggest that
active avoidance strategies can dampen responses to subsequent stressors60. For example, a
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recent human study with a clever yoked-subject design showed a decreased skin
conductance response in non-psychiatric control participants who were given access to an
active avoidance strategy to prevent electrical shock compared with those who were not61.
This decreased skin conductance was observed both for subsequent presentations of the
extinguished conditioned stimulus and for presentation of a novel conditioned stimulus. In
this case, active avoidance was shown to be associated with changes in striatal blood-
oxygen-level-dependent (BoLD) signalling.

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In rodents, avoidance behaviours are often studied using a shuttlebox learning paradigm. In
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this test, rodents first undergo Pavlovian threat conditioning, in which a previously
innocuous conditioned stimulus becomes paired with an aversive unconditioned stimulus. In
an inescapable chamber, rodents will respond by freezing when the conditioned stimulus is
subsequently presented. In a second phase of the task, the rodents learn that if they run into a
second compartment when presented with the conditioned stimulus within the testing
chamber, they can avoid receiving the unconditioned stimulus. Rodents will thus learn to run
from the context in which the conditioned and unconditioned stimuli were paired (active
avoidance) instead of passively freezing. The propensity to pursue active avoidance
strategies is heterogeneous in rodent populations and as such is thought to be a possible
model for resilience62.

Several lesion studies in rodents have shown that passive freezing responses are mediated by
signals transmitted from neurons within the lateral amygdala to the central amygdala and
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then to neurons within the periaqueductal grey (PAG)63,64 (FIG. 3). Active avoidance
strategies appear to require signalling from the lateral amygdala to the basal amygdala and
then to the shell of the nucleus accumbens65. The infralimbic cortex is also critical for active
avoidance66. Active avoidance and freezing appear to be mutually inhibitory, as lesions of
the central amygdala increase active avoidance, whereas lesions of the infralimbic cortex,
which releases central amygdala inhibition, create increases in freezing66. Furthermore,
recent experiments have shown that, within the central amygdala, there are microcircuits of
mutually inhibitory corticotropin-releasing hormone (CRH)-expressing and somatostatin-
expressing neuronal subpopulations that mediate active avoidance and freezing,
respectively67.

Avoidance behaviour may also be conceptualized more generally. When interacting with an
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uncertain environment, an organism must make decisions about whether to approach or

avoid external stimuli. A recent hypothesis proposed by several groups reconceptualizes
amygdala function as the gating of decisions about ‘behavioural engagement’; that is, the
decisions that an organism makes when approaching its environment68,69. This hypothesis
stems from work that has shown that amygdala lesions can affect risk-taking behaviour in
rats in a food foraging paradigm70 as well as the identification of populations of neurons
within the BLA that respond to movement during a risk-taking behavioural task rather than
to the presence of a threat per se71. This finding brings the rodent literature more in line with
the widespread changes in activation patterns seen in the human neuroimaging literature.
Deficits in a ‘behavioural engagement’ circuit may align more closely with the functional
impairments seen in individuals with PTSD than do the deficits pre dicted by the more
traditional model that theorizes that the amygdala acts only as a locus for conditioned fear72.
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Altered cognition and mood

Criterion D of the DSM-5 PTSD diagnosis describes negative alterations in cognition and
mood that begin or worsen after a traumatic event11. This criterion includes memory deficits,
distorted beliefs, persistent negative emotions, diminished interest in previously rewarding
activities, constricted emotional experience and social detachment symptoms11. Many of
these symptoms are nonspecific and highly overlapping with the symptoms of depression.

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For the most part, the neurobiological understanding of these symptoms is still preliminary;
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however, emerging evidence again points towards potential aberrations in regions that are
part of limbic circuits (particularly the hippocampus and amygdala) and their relationship
with top-down prefrontal cortical control.

Dissociative amnesia and memory deficits.

In addition to the maladaptive enhancement of emotional memories described above, some
forms of memory can be impaired in PTSD. A marked inability to recall key features of the
traumatic event is a common occurrence in PTSD and is frequently referred to as
dissociative or psychogenic amnesia. This amnesia often occurs in the realm of declarative
memory — that is, memory that can be explicitly recalled, such as semantic or episodic
memory73 — whereas nondeclarative and/or implicit memory is preserved. Individuals with
PTSD also report the experience of memory fragmentation11. These declarative memory
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deficits have been proposed to be the result of impaired encoding or retrieval mechanisms, or
a combination thereof.

A PTSD-specific neurobiological model focusing on the hippocampus has been proposed to

account for these memory deficits74. The hippocampus is crucial for memory and learning
processes and in particular for declarative memory73. The hippocampus is involved in the
initial storage of this type of memory and in integrating aspects of memory during retrieval.
A sizeable literature demonstrates that there is reduced hippocampal volume in individuals
with PTSD75. This observation has been established in studies of different types of trauma
and different sample populations and was supported by the recent findings of the largest
brain imaging study of PTSD to date76. However, whether trauma leads to hippocampal
atrophy in individuals who develop PTSD or whether having small hippocampi predisposes
an individual to PTSD remains controversial77. In positron emission tomography and
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functional MRI (fMRI) studies, individuals with PTSD have been demonstrated to exhibit
decreased hippocampal activity while taking part in a declarative memory task, when
compared with trauma-exposed controls without PTSD78, as well as decreased hippocampal
activity and a failure to recall extinction learning when taking part in a fear conditioning
paradigm35. It remains to be determined whether reduced hippocampal activity is caused by
the reduced size or vice versa and whether reduced activity and/or size affects the capacity to
encode or store memories.

Extensive research also documents deficits in a number of executive function tasks in

individuals with PTSD when compared with trauma-exposed controls79. However, there is
also evidence to suggest that there are subtle deficits in these functions that exist before the
trauma exposure in PTSD cohorts, suggesting that individuals with executive function
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deficits have a heightened risk of developing PTSD after trauma exposure80. It is thought
that these deficits would then be further exacerbated after trauma exposure and may
contribute to lack of recovery80. Evidence of changes to neural circuitry that may explain
this finding is varied; however, most evidence suggests that there are changes in PFC
engagement81–83. Individuals with PTSD have increased prefrontal activity during sustained
attention tasks, and decreased prefrontal involvement when participating in more taxing
inhibition-related tasks, when compared with those without PTSD81–83. This pattern could

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be a by-product of attentional hypervigilance associated with PTSD and an inability to

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inhibit this pattern of activation during more demanding tasks. Alternatively, it could reflect
a compensatory mechanism for maintaining focus during sustained attention tasks that stops
working with more difficult inhibition tasks80. Another interpretation is that this pattern of
activity reflects a decreased ability to regulate midline cortical self-referential processing
activity during attentional tasks84. It is yet to be determined how these changes in PFC
engagement might also alter the hippocampal-related declarative memory processes
discussed above.

Studies that have used animal models have given us more information on the cellular-level
changes in the hippocampus that may drive PTSD memory deficits. In rodent models, both
acute and chronic corticosterone secretion occur in response to traumatic experiences85 and
can induce profound molecular changes in the hippocampus. These changes include
decreased brain-derived neurotrophic factor (BDNF) and cAMP-responsive element-binding
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protein 1 (CREB1) expression in the dentate gyrus, impaired neurogenesis in the dentate
gyrus, decreased long-term potentiation in the CA1 region and dendritic retraction in CA3
(REFs86–88). The loss of dendritic complexity observed in rodents after stress suggests a
mechanism for the hippocampal atrophy observed in patients with PTSD. There are likely to
be many more molecular pathways that are involved in adaptations to both acute and chronic
stress. Indeed, a recent study showed that there are hundreds of gene expression changes
within CA3 neurons after rodents are exposed to either acute forced swim stress or chronic
restraint stress; however, the gene expression signatures observed in these two conditions
were almost completely non-overlapping89.

Research with rodents and nonhuman primates also demonstrates that exposure to an acute,
uncontrollable stress impairs performance in cognitive and memory tasks that depend
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heavily on the PFC90. For example, restraint-stressed rats display impaired performance in a
delayed spatial alternation task, a rodent behavioural test of spatial working memory91. The
stressed animals made more perseverative errors on the task, suggesting a lack of attention
and short-term memory as well as cognitive and/or behavioural inflexibility91. Interestingly,
correlated neural activity in the PFC and hippocampus is believed to be important for
successful performance on this task: hippocampal theta oscillations have been shown to be
phase-locked with both theta and single-unit activity in the PFC during the performance of a
similar task92. Furthermore, a genetic mouse model of schizophrenia in which this
hippocampus-PFC synchrony is disrupted also shows impairments in the acquisition of
spatial working memory, and a recent study in which optogenetic manipulation was
combined with a spatial working memory paradigm confirmed that gamma activity in the
pathway from the ventral hippocampus to the PFC is crucial for encoding task-relevant
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cues93. These findings suggest that deficits in memory processes in patients with PTSD are
caused by atypical coordination of neural synchronization in large-scale networks including
the PFC.

Persistent negative emotions.

Criterion D of the DSM-5 PTSD diagnosis also includes the experience of enduring negative
trauma-related emotions such as fear, horror, anger, guilt or shame11. Constructivist views of

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emotion suggest that our emotional experience is generated through a dynamic interaction of
more basic processes in memory, perception and attention94,95. Consistent with this idea, a
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broad network of cortical and subcortical regions is associated with our experience of
emotion96. In particular, recent neuroimaging evidence has associated fluctuating valence
experience with activity in the orbitofrontal cortex and arousal with amygdala activation
across different emotions (such as fear, sadness and happiness)97.

A key characteristic of the negative emotional experiences of individuals with PTSD is that
they seem to persist despite interfering with the day-to-day functioning of the individual.
The persistence of these negative emotions is often described as a failure of emotion
regulation — that is, the ability to exert ‘voluntary control’ over one’s emotional
responses98. For example, individuals with PTSD were shown to have poorer ability to
down-regulate emotional reactions to negative pictures than trauma-exposed and non-
trauma-exposed controls, and this was associated with decreased PFC activity99. Similarly,
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the experience of negatively valenced (but not traumatic) memories elicited emotions of
sadness and anxiety in individuals with PTSD and was associated with decreased ACC and
thalamus activity — patterns of activity analogous to those seen when personally triggering
trauma cues are presented100. Likewise, viewing of negatively valenced pictures was
associated with lower vmPFC activity in individuals with PTSD than it was in trauma and
non-trauma-exposed controls34. The vmPFC and ACC are regions that are often associated
with emotion regulation101.

There is some evidence to suggest that processing of emotional valence itself is altered in
PTSD, in particular for individuals who have suffered childhood maltreatment102–103. Given
our desire to understand the basic neuroscience of negative emotions, there has been
considerable recent effort made to use modern optogenetic and chemogenetic tools to
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understand the coding of valence in the mouse brain subpopulations of neurons in the
BLA104, central amygdala105, nucleus accumbens106 and ventral tegmental area (VTA)107,
and other regions appear to respond to the appetitive or aversive qualities of a stimulus,
independent of its sensory features10. However, it is not yet known whether these neurons
can be defined by their molecular properties, projection targets or some combination of these
characteristics10. It is also not yet known to what extent these valence-encoding neurons are
fixed in the nature of their response (that is, whether they always respond to either positive
or negative cues) or exhibit plasticity. There is some evidence to suggest that such plasticity
depends on brain region: an experiment that attempted to ‘flip’ the responses of appetitive
and aversive neuronal populations was successful in the dentate gyrus but not in the BLA108.
There is also evidence to suggest that the ‘tunable range’ of valences to which these neurons
respond depends on the emotional state of the animal: the valence tuning of neurons in the
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nucleus accumbens changes during stress109. Given that these valence-coding neurons are
likely to influence affective behaviours, these findings suggest that a stressful context can
influence the range of such behaviours available to an organism. A similar mechanism may
help to explain how trauma can alter the range of affective experience available to
individuals with PTSD.

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Constricted affect and interest.

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Individuals with PTSD frequently exhibit markedly diminished interest in activities that
were important to them before the trauma, demonstrate constricted affect and have a
persistent inability to experience positive emotions (anhedonia11). Dysfunction in reward
processing is thought to be one of the mechanisms underlying these experiences110,111.
Reward processing can be divided into different components: an approach phase, in which
rewarding stimuli are sought out, and a consumption phase, in which hedonic pleasure is
experienced once the reward is acquired111. Evidence points towards potential dysfunction
in both components of this process in PTSD112. The brain’s reward circuitry includes
regions responsible for evaluating a stimulus as rewarding and regions involved in acting to
acquire the reward (including the VTA, amygdala, orbitofrontal cortex, anterior insula, ACC,
dorsomedial prefrontal cortex (dmPFC), striatum and motor cortex)110,113. There is evidence
of hypoactivity in both the striatum and PFC in response to rewarding stimuli for individuals
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with PTSD in comparison to controls114,115. Furthermore, one study found that less activity
in the striatum in the reward paradigm was associated with motivational and social deficits
per self-report114. These studies imply that reduced activity in these regions leads to altered
reward processing in PTSD.

One human neuroimaging study has focused on the experience of a restricted range of affect
— also termed ‘emotional numbing’116 — in individuals with PTSD. In this study,
decreased dmPFC activity was associated with experiences of being emotionally numb in
both positive and negative scenarios designed to elicit emotional imagery117. Alexithymia
describes the condition of having difficulty recognizing and naming emotional states and is
considered to be closely related to (or perhaps a result of) anhedonia and emotional
numbing. Specifically, in participants with PTSD, alexithymia has been associated with
decreased vmPFC, anterior insula and inferior frontal gyrus activity during paradigms
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designed to trigger PTSD symptoms116. These are areas associated with a visceral sense of
emotion, self and emotion regulation.

In rodents, chronic stress protocols are commonly used to induce anhedonia-like states,
which are then assayed with behavioural paradigms such as the sucrose preference test. In
this paradigm, the loss of a rodent’s natural preference to seek out a rewarding sweet
solution is used as a surrogate for anhedonia symptoms. These models are typically
discussed with respect to depression; however, they may also be applicable to our
understanding of PTSD given that the inability to experience positive emotions can also
occur in this disorder. Studies in which optogenetic manipulations have been focused on
dopaminergic neurons in the VTA have provided valuable insight into dysfunctions in
subcortical circuits that are related to anhedonia-like symptoms. Specifically, phasic
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activation of VTA dopaminergic neurons can promote sucrose preference following

subthreshold social defeat stress118. Interestingly, in a parallel study, optogenetic activation
of nucleus accumbens-projecting VTA dopaminergic neurons following longer chronic mild
stress also alleviated sucrose preference deficits119. This finding suggests that there are more
complex long-term neuronal adaptations within the dopaminergic systems after stress
exposure that may also occur in more chronic forms of PTSD.

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In addition to the subcortical dopaminergic circuits, the PFC and its projections have also
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been targeted using optogenetics. High-frequency stimulation of PFC terminals in the

nucleus accumbens was found to reduce sucrose preference in mice following chronic social
defeat stress120. Moreover, a recent study that used a combination of local optogenetic
stimulation and global brain-wide fMRI in rats highlighted an inhibitory influence of the
PFC on reward-related behaviour and anhedonia121. This study demonstrated that
hyperexcitability in the PFC led to a reduction in sucrose preference through top-down
suppression of striatal responses to dopamine release and by driving dynamic interactions in
corticolimbic areas. This study is of particular interest for translational work because it
demonstrates how microcircuit-based manipulations can be related to larger changes in brain
activity and offers a template for ways in which we may move forward in our understanding
of how larger changes in brain BOLD activity may relate to the firing patterns of artificially
activated neuronal populations.
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Altered arousal and reactivity

PTSD criterion E in DSM-5 includes alterations in arousal and reactivity that started or were
exacerbated after the traumatic event11. Arousal and reactivity changes can include any
combination of hypervigilant, irritable, aggressive, self-destructive or reckless behaviours,
exaggerated startle responses, problems with concentration or sleep disturbances11. This
cluster has traditionally been the most well studied of the PTSD symptoms and is in some
ways the most easily translatable to nonhuman animal subjects. Evidence from these studies
suggests that both heightened salience detection and dysfunctional emotion or arousal
regulation underlie symptoms in this cluster6,122. The overarching theory emerging from
human and animal subject experiments is that symptoms from this cluster are generally
likely to arise owing to decreased activity in the mPFC and ventral hippocampus and
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hyperactivity in the amygdala and the bed nucleus of the stria terminalis (BNST)122,
although investigation into the microcircuitry that produces these global regional effects is
ongoing.

Hypervigilance.
For a long time, neuroimaging stud ies of PTSD focused upon the role of the amygdala in
mediating symptoms of hypervigilance. Across paradigms and sample populations,
individuals with PTSD typically display increased amygdala activity123. Even at rest, there
is evidence that the salience network, which includes the amygdala, ‘dominates’ processing
in individuals with PTSD rather than the more typical default-mode network activity
observed in controls124. Interestingly, however, individuals with Urbach-Wiethe disease, a
rare genetic disorder that presents with focal damage to the BLA, are hypervigilant to fear
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cues, suggesting that the BLA plays a role in inhibiting hypervigilant monitoring125. The
discrepancies between these findings may relate to differences in the activity of amygdala
subnuclei, and literature from rodent studies has begun to elucidate many layers of
complexity within amygdala microcircuitry.

In mice, there have been a number of studies that suggest that different subpopulations of
neurons in the BLA can either trigger or inhibit anxiogenic responses in mice. Optogenetic

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activation of all cell bodies within the BLA leads to anxiogenic responses, whereas selective
activation of BLA terminals in the central amygdala triggers anxiolysis126. The projection-
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specific modulation of threat responses by the BLA seems to be mediated by distinct

molecularly defined sub populations of ‘fear on’ and ‘fear off’ neurons within the
BLA127,128 and the central amygdala129–130. Given the functional heterogeneity of neurons
within these regions, it may be difficult to interpret human neuroimaging studies that lack
the resolution to observe activity at a cellular level.

Both human and animal data implicate the BNST in the production of hypervigilant states,
although the BNST is difficult to precisely and reliably delineate with current human
neuroimaging methods, and results should be interpreted cautiously. That said, human
neuroimaging studies of healthy participants show that the BNST, along with the insula, is
activated during threat monitoring tasks131,132. To our knowledge, the BNST has not
emerged as a key area of differential activation in individuals with PTSD. However, research
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in rodent models suggests that it is a key structure for future investigations.

Studies using optogenetics have renewed interest in the role of the BNST in producing
rodent anxiety-like behaviours133. Recent work suggests that the complicated subnuclear
structure of the BNST can be roughly divided into two functional subregions: the oval
BNST, which has been shown to control anxiogenic features of mouse behaviour, and the
anterodorsal BNST, which mediates anxiolysis134. Another group found that a behavioural
rodent model of PTSD, in which mice were exposed to a trauma (sustained, inescapable foot
shock) followed the next day by a trigger (shorter duration foot shocks), demonstrated
features of hypervigilant behaviour135. They observed decreased risk assessment in a light-
dark paradigm, lower pre-pulse inhibition and higher light-phase locomotion, some of which
were blocked by the optogenetic inhibition of a subpopulation of BNST neurons that express
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CRH receptor 2 (CRHR2)135,136. These data, although incomplete, implicate alterations in

both amygdala and BNST circuits in the production of behaviours associated with
hyperarousal and hypervigilance.

Aggressive behaviour.
Individuals with PTSD will frequently demonstrate reactive aggression to perceived threat.
Our understanding of the neural circuits mediating aggression is still preliminary.
Neuroimaging studies implicate the amygdala and PAG in threat detection, and activation in
some of these regions is altered in individuals with PTSD137. Other studies have found that
activation of the locus coeruleus, an important structure in the hormone cascade associated
with the autonomic stress response, is linked specifically to aggression138,139. It is
hypothesized that locus coeruleus activity helps to orient attention to salient information and
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that changes to activity within this region may alter threat reactivity140.

Perhaps more importantly, aggressive and/or impulsive behaviour is also related to a failure
of top-down control of these circuits. Some studies have found that medial PFC structures
regulate threat detection and help us to select an appropriate behavioural response given the
broader context141,142. For example, the vmPFC is implicated in the regulation of emotion,
including aggression143,144, and angry rumination is associated with dorsal ACC activity and
individual differences in aggression145. Orbitofrontal cortex and BLA circuitry are also

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 Fenster et al. Page 13

important in the regulation and maintenance of emotional responses142. Orbitofrontal cortex

dysfunction in particular has been linked to aggressive and/or impulsive behaviour146–148.
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Specifically, in PTSD there is empirical evidence of differential activity in the orbitofrontal

cortex, vmPFC and locus coeruleus in anger-related paradigms140,142.

In animal models, we currently have limited understanding at a cellular level of how circuits
related to fear conditioning may influence subsequent development of aggressive
behaviours: there have been some studies implicating the medial amygdala and ventromedial
hypothalamus in rodent aggression149–151. A population of neurons within the central
amygdala has recently been shown to mediate mouse predatory behaviour152. However, as in
the other limbic regions discussed above, parallel, opposing pathways that mediate
antithetical behavioural responses are likely to exist within both of these regions.
Optogenetic and chemogenetic manipulations have demonstrated the existence of these
intermingled pathways150,153, but we have limited understanding of the extent of these
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circuits and how they change their firing patterns in response to stress.

Unifying themes and future directions

A few overarching theoretical ideas have emerged from the recent advances in PTSD
research outlined above. The studies discussed above demonstrate the existence of parallel,
mutually inhibitory pathways within the larger brain regions that are implicated in PTSD.
These ‘push-and-pull’ circuits, which have a long history in our understanding of the
functioning of the striatum154, have now been identified in the rodent BLA127,128, central
amygdala129 and BNST134 in addition to the midline mPFC51. The existence of these
anatomically intermixed opposing pathways complicates our interpretation of the human
PTSD neuroimaging literature, which lacks the spatial resolution to parse these opposing
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pathways and necessitates a deeper understanding of the molecular fingerprints of the

neuronal cell types that define these pathways to more directly target potential therapeutics.

At the same time that our knowledge of microcircuitry has deepened, our understanding of
the functional roles of larger brain regions has evolved, both implicating novel brain regions
in the pathogenesis of PTSD (such as the BNST) and challenging traditional dogma about
regions long understood to contribute to PTSD pathogenesis (such as the amygdala). The
reconceptualization of amygdala function, from playing a restricted role in conditioned fear
learning to a model in which it helps to detect salience and coordinate behavioural
engagement, helps to explain how a deficit in amygdala circuitry might affect multiple
domains of PTSD symptoms, including avoidance, re-experiencing and the altered
perception of valence.
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As we illustrate above, preclinical and clinical research has begun to elucidate the
neurocircuitry of PTSD, and there are areas of convergence between the two approaches.
The stunning growth in our understanding of the microcircuits governing threat processing,
avoidance, reward and arousal have been made possible by circuit-altering technological
breakthroughs. However, there remains a need within animal model research for improved
technologies to allow monitoring of neuronal activity with cellular resolution throughout the
entire brain rather than in only certain regions of interest. The production of brain-wide

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 Fenster et al. Page 14

quantitative data sets will offer unbiased insights into how neural dynamics change during
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different cognitive demands and how these demands are affected by stress and by brain
disorders.

Within human neuroimaging research, the need exists for the development of imaging
technologies that can offer spatial resolution at the cellular level and temporal resolution at
the millisecond level. However, until such a technology becomes available, we need to invest
further in strategies to translate regional changes in BOLD signal activation into putative
models of microcircuit alteration. The technique of optogenetic fMRI offers one possible
path forward in this endeavour155,156. By mapping BOLD changes observed from
optogenetic manipulations, it may enable the development of a library of BOLD signal
changes created by manipulation of certain neuronal populations and the ability to more
closely target the circuits creating dysfunction in PTSD and other neuropsychiatric
disorders.
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Given the advances in our understanding of the neurocircuits in PTSD, it is natural to ask
whether these discoveries offer therapeutic hope. There is currently some effort underway to
develop transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)
interventions for PTSD157–161. Although the invasiveness of DBS is likely to mean that such
treatments would be reserved for only the most intractable of cases, the use of TMS has been
steadily increasing as a therapeutic tool in psychiatry. The mechanisms by which TMS
might exert its effects to mediate symptom improvement in PTSD remain unclear; however,
the concurrent combination of TMS with electroencephalography (EEG) or fMRI is
becoming a powerful technology for identifying pathological changes in brain functional
network connectivity and predicting the efficacy of the treatment161,162. The hope of using
more targeted methodologies to modulate circuits remains. Nevertheless, these ideas are
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currently largely theoretical and are limited by our understanding of the neural circuitry,
which lends urgency to the development of technological innovation in this area163.

Understanding whether the differences in neural activity related to PTSD are risk factors for
developing PTSD or whether they are a product of the trauma exposure and/or the disorder
itself is key to developing targeted methodologies to modulate circuits. Current evidence
from PTSD samples and twin studies suggests that increased amygdala and dorsal ACC
activity in fear learning contexts is a vulnerability that pre disposes an individual to the
development of PTSD, whereas brain changes related to reduced capacities to extinguish
fear (such as the reduced functional connectivity between the mPFC and hippocampus) are
an acquired dysfunction164,165. More research, in particular from neuroimaging genetic twin
studies and prospective longitudinal work, is needed to better understand the relationship
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between risk-related and acquired differences in PTSD.

Molecular neuroscience has lagged behind in the study of PTSD. There has been some
dissection of the molecular properties of subtypes of neurons within the amygdala, but our
understanding of the molecular fingerprints of the neuronal subpopulations in the mPFC,
BNST, hippocampus and PAG and the transcriptional changes that occur within these cell
types after stress and fear conditioning remains underdeveloped. These studies may be ‘low-
hanging fruit’ in the identification of novel therapeutic drug targets for PTSD. The

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availability of genetic, projection-specific and activity-dependent means of cell-type-specific

translational profiling166 in mouse models and the application of single-cell sequencing
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technologies such as Drop-seq167 to human post-mortem brain samples will allow this work
to proceed in the near future. These approaches offer the promise of identifying unique
receptor profiles for cell types of specific valence and function within the complex
microcircuitry described. Such an approach could lead to targeted multidrug
pharmacotherapy, based on understanding specific clusters of quantitative symptoms, with
drugs targeting known symptom-related circuits.

Conclusion
Although our treatments for PTSD have yet to change, our understanding of the genetics,
neural circuitry and behaviour related to the disorder and its component symptoms and
intermediate phenotypes has advanced considerably in recent years. Furthermore,
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technological progress in preclinical models has moved rapidly in advancing our

understanding of the neural circuitry underlying basic behaviours such as fear and threat
processing, fear extinction, avoidance behaviour and appetitive and anhedonic behaviour as
well as the effects of stress on memory and cognition. Thus, the translation of these
behaviours to human trauma and stress-related and anxiety-related disorders, such as PTSD,
is progressing rapidly and promises to soon lead to novel treatments and interventions based
upon the underlying neurobiology.

Acknowledgements
The work was supported by US National Institutes of Health (NIH) grants R01MH108665, R01MH094757 and
R21MH112956 to K.J.R., NIH fellowship grant F32MH109274 to L.A.M.L. and the Frazier Foundation Grant for
Mood and Anxiety Research to K.J.R. K.J.R. has received research funding from the US National Institute of
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Mental Health, the Howard Hughes Medical Institute, the National Alliance for Research on Schizophrenia &
Depression and the Burroughs Wellcome Foundation.

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Genome-wide association studies

(GWAS). Studies in which statistical associations between genetic variants and a disease
or trait of interest are identified by genotyping individuals with disease and healthy
controls for a set of single-nucleotide polymorphisms that capture variation across the
entire genome.

Optogenetics
The use of genetically encoded light-activated proteins (for example, ion channels) to
control the functional parameters (for example, membrane potential) of targeted neuronal
populations

Chemogenetics
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The use of exogenous macromolecules to manipulate activity of genetically encoded

receptors with no endogenous ligands (that is, designer receptors exclusively activated by
designer drugs).

Fibre photometry
Technology that utilizes an optical fibre for monitoring of activity of neuronal ensembles
through genetically encoded activity indicators.

Valence
The appetitive or aversive nature of a stimulus.

Gene by environmental risk

The interaction between a genotype and environmental variation.
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Symptom provocation studies

Studies designed to elicit PTsD symptoms by exposing participants to their own trauma
narratives.

Fear generalization
Describes a situation in which conditioned fear responses are elicited in response to
stimuli related to the conditioned stimulus.

Blood-oxygen-level-dependent (BOLD) signaling

An index of brain activation based on detecting changes in blood oxygenation with fMRi.

Memory fragmentation
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Trauma memory retrieval that is experienced as only portions of various sensory and
emotional representations and that lacks an integrative personal narrative.

Executive function
A set of top-down cognitive control processes including inhibition (resisting habits,
temptations or distractions), working memory (mentally holding and using information)
and cognitive flexibility (adjusting to change).

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Long-term potentiation
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A long-lasting (hours or days) increase in the response of neurons to stimulation of their

afferents following a brief patterned stimulus (for example, a 100 Hz stimulus).

Salience detection
The detection of information relevant to basic biological drives and psychological needs
(for example, potential threats).

Default-mode network
A large-scale brain network that is more active when individuals are not directing
attention to the external environment.
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Genomic influences on post-traumatic stress disorder circuits

Although a large proportion of people (estimates range from 50% to 85%) are exposed to
major traumatic events during their lifetimes, only a small fraction subsequently develop
persistent symptoms of post-traumatic stress disorder (PTsD)168. This observation has led
to investigations of the mechanisms underlying PTsD risk and resilience. Twin studies,
which allow for an estimate of the heritability of disorders by comparing their prevalence
in monozygotic and dizygotic twins, suggest heritability in the range of 40–50% for
PTSD (although this number varies depending on the type of trauma and the sample in
the survey)169. The remaining risk is thought to arise owing to environmental factors,
possibly mediated through epigenetic mechanisms (which we here define in the broadest
sense to include mechanisms of persistent cellular memory and reprogramming)170.

The investigation of the genetic basis for PTSD remains in its early stages, in part owing
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to the highly polygenic nature of the genetic risk, the heterogeneity of trauma exposures
and the heterogeneity among methodologies employed, which has made meta-analysis
difficult4, 171. The basic design of genetic studies within PTSD is to apply a case–control
approach, in which alleles of interest are tested for their association with individuals in
which PTsD has developed compared with trauma-exposed controls. Initially, such
studies relied upon a candidate gene approach, in which hypotheses generated from
existing knowledge of genes involved in stress and threat processing were tested for
association with PTSD risk. Unfortunately, the genetic hits from gene candidate studies
largely failed to replicate robustly across cohorts172.

However, there may be some exceptions to this rule. For example, FKBP5, encoding a
molecular chaperone and regulator of the glucocorticoid receptor, has been shown across
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multiple studies to mediate gene by environmental risk of both depression and PTSD173.
FKBP5 risk alleles have been associated with increased amygdala activation, altered
hippocampal function, decreased hippocampal size and decreased cingulum bundle white
matter integrity174. Similarly, the genes encoding pituitary adenylyl cyclase-activating
polypeptide (PACAP) and its receptor, PAC1, showed a modest significant association
with PTSD risk in a recent meta-analysis175 and have also been associated with increased
amygdala activation in humans and rodent studies43, 176. Ongoing larger scale genetic
studies are clearly required to know with certainty the genetic underpinnings of PTSD.

Thus, studies investigating the genetics of PTSD risk have largely moved to an unbiased
genome-wide association study (GWAS) model, which seeks to determine whether
associations exist between single-nucleotide polymorphisms (SNPs) distributed across
the entire genome and PTSD risk. There have been a number of small GWAS studies
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published on PTSD risk177–180; however, genes surviving tests for multiple-testing

correction have not yet replicated across studies. Promising gene candidates that have
emerged from these studies include those encoding the nuclear receptor ROR-a (RORA),
neuroligin 1 (NLGN1), tolloid-like protein 1 (TLL1), protein cordon-bleu (COBL),
ankyrin repeat domain-containing protein 55 (ANKRD55) and cGMP-dependent protein
kinase 1 (PRKG1)4,177–187. COBL risk alleles were associated with decreased white
matter integrity in the uncinate cortex, part of the medial prefrontal cortex, suggesting

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that decreased connectivity between this region and the amygdala contributes to PTSD
risk185. NLGN1 is strongly expressed in the cortex and hippocampus and plays an
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important role in the proper development and maintenance of excitatory synapses188.

PRKG1 has been shown to regulate nitric oxide signalling and to be necessary for the
encoding of auditory cue fear memory in the mouse189. Results from GWAS approaches
for other psychiatric disorders suggest that, with increasing sample sizes, SNPs that have
a small effect with genome-wide significance will be found; however, these SNPs may
reside in either coding or non-coding regions of the genome, and the underlying
biological function of the association may take some time to elucidate.
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Post-traumatic stress disorder dissociative subtype

Traumatic dissociation encompasses a range of distinct, yet clinically interrelated,
symptoms, including depersonalization, derealization, amnesia, numbing, intrusive
flashbacks, passive influence phenomena and identity disturbances190,191. The Diagnostic
and Statistical Manual of Mental Disorders, fifth edition (DsM-5), recognized a
dissociative subtype of post-traumatic stress disorder (PTsD), characterizing individuals
who, in addition to the criteria explicated in this article, experience dissociative feelings
of detachment from their body, thoughts and surroundings. It is estimated that 13–30% of
individuals with PTSD meet the criteria for the dissociative subtype18.

Evidence from studies that have used symptom provocation paradigms in individuals
with PTSD has implicated differential patterns of brain activity and bodily arousal in
those with high versus low levels of dissociative symptoms192–196. In such paradigms,
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PTSD symptoms are elicited by exposing participants to reminders of their past traumatic
events197,198. During this exposure, participants with low levels of dissociation reported
classic re-experiencing symptoms associated with hyperarousal, whereas those with high
levels of dissociation reported entering into a state characterized predominantly by
feelings of detachment and numbness. These symptoms were reflected in differential
patterns of neural activity in regions related to emotion regulation and inhibition of
limbic regions (ventromedial prefrontal cortex (vmPFC)), emotional expression, conflict
monitoring, integration of threat information (dorsal anterior mid-cingulate cortex
(daMCC)195,199,200) and salience detection (amygdala201). Specifically, the low-
dissociation group exhibited the ‘classic’ PTSD neural signatures of decreased vmPFC
activity, increased amygdala and insula activity and increased heart rate in response to
trauma cues (see the figure). By contrast, the high-dissociation group exhibited the
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opposite pattern — increased vmPFC and daMCC activity, decreased amygdala and
insula activity and no change in, or decrease in, heart rate. Resting-state functional
connectivity analyses also supported this pattern: both the basolateral amygdala (BLA)
and centromedial amygdala subregions demonstrated increased connectivity with
prefrontal structures in the dissociative subtype of PTSD compared with classic PTSD202.
The BLA also exhibited increased connectivity with subregions of the insula203, and the
ventrolateral periaqueductal grey exhibited increased functional connectivity with brain
regions linked to passive responses to threat in individuals with the dissociative subtype,
when compared with those with classic PTSD204.

Subsequent studies in individuals with dissociative identity disorder (DID) have built on
these PTSD studies. According to predominant theories, DID is a type of developmental
post-traumatic adaptation typically associated with chronic childhood trauma205. In
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addition to depersonalization and derealization symptoms, individuals with DID

experience amnesia and identity disturbances in which their own thoughts, emotions,
bodily sensations and sense of self sometimes feel like they are not their own, despite
intact reality testing, in which individuals with DID know these experiences must be their
own190,205. In a symptom provocation paradigm, individuals with DID exhibited either
classic PTSD neural signatures or dissociative PTSD neural signatures to trauma cues

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when they were feeling activated and hyperaroused or numb and detached,
respectively206,207.
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These findings are consistent with a ‘top-down’ overmodulation hypothesis of the

dissociative subtype of PTSD. This theory suggests that, in individuals with high levels of
dissociation, top-down cortical activation overmodulates limbic activity, inhibiting
sympathetic bodily arousal and upregulating parasympathetic activity192,199. The daMCC
in particular may also be highly involved in the appraisal and expression of negative
emotion in these paradigms and may drive the increased top-down modulation of the
amygdala by the vmPFC199,208. The existence of the dissociative subtype may have
implications for treatment. Given evidence that dissociation affects emotional
learning209, individuals with this type of PTSD may have a differential response to
current cognitive behavioural therapies; evidence is currently mixed on this front210–219.
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Classic PTSD Dissociative identity disorder PTSD dissociative subtype

Responses to tra urn a- Responses to trauma-related cues Responses to trauma-related cues
related cues characterized by fluctuate between classic and characterized by
dissociative subtype
neurobiological patterns
• intrusive re-experiencing • symptoms of detachment and
symptoms numbness
• behavioural activation
• increased physiological • behavioural deactivation
arousal
• increased amygdala and • decreased and/or maintained
insula activation physiological arousal
• decreased vmPFC • decreased amygdala and insula
activation activation
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• increased vmPFC activation

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Animal models of post-traumatic stress disorder

The sprawling set of symptoms, many of which can be defined only in a subjective
manner, that characterize post-traumatic stress disorder (PTsD) in the Diagnostic and
Statistical Manual of Mental Disorders, fifth edition (DsM-5), make it challenging to
develop suitable animal models of the disorder. Moreover, the lack of identified alleles
with high genetic penetrance for increasing PTsD risk makes it difficult to create PTsD
animal models with high construct validity — that is, models that translate a known
biological cause in humans into a disorder in animals220. Lacking known causative
agents, the PTsD research community has therefore historically relied upon animal
models with high face validity — that is, models that recapitulate certain behavioural
features of human PTsD.

Commonly used behavioural paradigms that have been used to assess PTsD-like
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symptoms in animal models include chronic social defeat stress, inescapable foot shock,
early-life stress and stress-enhanced fear learning221,222. These tests have different
advantages and disadvantages, which have recently been reviewed221; however, they all
suffer from a lack of robustness and from low construct validity. One criticism that has
been levelled against PTsD animal models is that responses to stress are typically
measured in all animals, rather than in a select group of vulnerable animals, as happens
with human PTsD. However, it has been slowly recognized that there is still variability in
many animal models, with some animals being stress-susceptible and others stress-
resilient. For instance, one group demonstrated a predator-based psychosocial stress
paradigm that can generate groups of rats with either extreme (PTsD-like) or minimal
(resilient) responses to stress223.
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Given the current limitations in our understanding of the genetic basis of PTsD and our
rapidly growing understanding of the neural circuitry of PTsD, a promising future avenue
for developing animal models of PTsD could be to use optogenetic manipulations of
selected neuronal populations to recapitulate the dysfunctional circuit features of the
disorder. This method would effectively model the specific circuit disruption directly and
there would be less focus on interpretation of disparate and, at times, evolutionarily non-
conserved behaviours across species and more focus on the conserved neural circuits.
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Fig. 1|. An expanded neurocircuitry of post-traumatic stress disorder.

Recent work suggests that an expanded brain network is implicated in post-traumatic stress
disorder (PTSD) symptoms. This figure highlights brain regions that have been implicated in
either human imaging studies of PTSD (mid-sagittal section) or in rodent models of related
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behaviours (horizontal section). Each quadrant illustrates brain regions that have evidence
linking them to symptoms in the labelled cluster. Rodent behaviours were chosen that map
aspects of the corresponding symptom cluster: fear extinction (intrusions); active and
passive avoidance (avoidance); spatial memory, emotional valence and anhedonia (altered
cognition and mood); and aggression and arousal (altered reactivity and arousal). BLA,
basolateral amygdala; BNST, bed nucleus of the stria terminals; CeA, central amygdala;
CPu, caudate and putamen; dACC, dorsal anterior cingulate cortex; DG, dentate gyrus; IL,
infralimbic cortex; LA, lateral amygdala; LC, locus coeruleus; MeA, medial amygdala;
mPFC, medial prefrontal cortex; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PAG,
periaqueductal grey; PL, prelimbic cortex; rACC, rostral anterior cingulate cortex; vmPFC,
ventromedial prefrontal cortex; VTA, ventral tegmental area.
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Fig. 2|. A map of post-traumatic stress disorder neurocircuits in humans and rodent models.
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The schematic illustrates the brain regions currently implicated in each of the four major
post-traumatic stress disorder (PTSD) symptom clusters by experiments involving human
neuroimaging or rodent models. Red shading indicates areas for which there is evidence
linking that particular brain region to the symptom cluster or related rodent behaviour. ACC,
anterior cingulate cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria
terminals; CeA, central amygdala; dACC, dorsal anterior cingulate cortex; dmPFC,
dorsomedial prefrontal cortex; IFC, inferior frontal cortex; IL, infralimbic cortex; LA, lateral

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 Fenster et al. Page 35

amygdala; LC, locus coeruleus; LPFC, lateral prefrontal cortex; MeA, medial amygdala;
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mPFC, medial prefrontal cortex; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PAG,
periaqueductal grey; PFC, prefrontal cortex; PL, prelimbic cortex; rACC, rostral anterior
cingulate cortex; STC, superior temporal cortex; vmPFC, ventromedial prefrontal cortex;
VTA, ventral tegmental area.
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Fig. 3|. Amygdala microcircuits implicated in fear conditioning.

The schematic offers a simplified representation of the mouse amygdala microcircuits that
are currently implicated in fear conditioning. During fear conditioning, output neurons from
the central amygdala increase their responsiveness to a conditioned stimulus. This increased
responsiveness is likely to occur through the mutual interaction of two parallel ‘fear on’ and
‘fear off’ pathways that project to these neurons from the basolateral amygdala (BLA) and
lateral amygdala (LA). There is an additional pathway for the establishment of competing
fear extinction memories that is likely to originate from neurons in the infralimbic cortex
that activate intercalated cells in the amygdala (‘fear ext.’ neurons). Although our
understanding of these pathways remains incomplete, several cell types have been
demonstrated to modify the expression of fear behaviours. Excitatory connections are
indicated with arrows. Inhibitory connections are indicated with blunt arrows. Solid lines
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designate proven connections, whereas dashed lines illustrate hypothetical connections. CeL,
lateral division of the central amygdala; CeM, medial division of the central amygdala;
CRH, corticotropin-releasing hormone; FOXP2, forkhead box protein P2; GRP, gastrin-
releasing peptide; ITCd, ITCv and ITCl, intercalated cell masses dorsal, ventral and lateral,
respectively; PRKCD, protein kinase C delta type; PV, parvalbumin; SST, somatostatin;
TAC2, protachykinin 1 (also known as TAC1); THY1, Thy-1 membrane glycoprotein.

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Table 1|

Translation of DSM-5 diagnostic criteria to RDoC domains

DSM-5 H diagnostic criteria RDoC domains

Fenster et al.

Negative valence systems Positive valence systems Cognitive systems Social processes Arousal and regulatory
systems
Criterion B: intrusions
Intrusive memories Loss None Attention, declarative None Arousal
memory, perception,
cognitive control and
working memory

Distressing dreams Sustained threat None None None Arousal and sleep-wakefulness

Dissociative reactions Loss None Attention, perception, Perception and understanding None
declarative memory of self
and cognitive control

Psychological distress to trauma Potential threat and sustained None Cognitive control None None
cues threat

Marked physiological reactions Acute threat None None None Arousal

Criterion C: avoidance
Avoidance of internal reminders Acute threat, potential threat None Attention and cognitive None None
and sustained threat control

Avoidance of external reminders Acute threat, potential threat Approach motivation Attention and cognitive None None
and sustained threat control

Criterion D: negative cognitions and mood

Inability to Loss None Attention, declarative None None
remember traumatic event memory and cognitive
control

Persistent exaggerated negative Acute threat, potential threat, None Attention, declarative Perception and understanding None
beliefs sustained threat and loss memory and cognitive of self and of others

Nat Rev Neurosci. Author manuscript; available in PMC 2018 September 21.
control

Distorted cognitions Loss None None Perception and understanding None

of self and of others

Persistent negative emotional state Acute threat, potential threat None Cognitive control None None
and sustained threat

Markedly diminished interest Loss Approach motivation, initial None None None
responsiveness to reward
attainment, sustained and/or
longer-term responsiveness to
reward attainment and reward
learning
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DSM-5 H diagnostic criteria RDoC domains

Negative valence systems Positive valence systems Cognitive systems Social processes Arousal and regulatory
systems
Feelings of detachment or None None None Affiliation and attachment None
estrangement
Fenster et al.

Inability to experience positive Loss Initial responsiveness to None None None

emotions reward attainment and
sustained and/or longer-term
responsiveness to reward
attainment

Criterion E: arousal and reactivity

Irritable behaviour and angry Acute threat, potential threat, None Cognitive control None Arousal
outbursts sustained threat and frustrative
non-reward

Reckless or self-destructive None Approach motivation, initial Cognitive control Perception and understanding None
Dehaviour responsiveness to reward of self
attainment, sustained and/or
longer-term responsiveness to
reward attainment and reward
learning

Hypervigilance Sustained threat None Attention and cognitive None Arousal

control

Exaggerated startle response Acute threat, potential threat None None None Arousal
and sustained threat

Problems with concentration Sustained threat None Attention, cognitive None Arousal
control and working
memory

Sleep disturbance None None None None Arousal and sleep-wakefulness

Dissociative symptoms
Depersonalization Acute threat None Perception and Perception and understanding None
cognitive control of self

Nat Rev Neurosci. Author manuscript; available in PMC 2018 September 21.
Derealization Acute threat None Perception and Perception and understanding None
cognitive control of others

DSM-5, Diagnostic and Statistical Manual of Mental Disorders, fifth edition; RDoC, Research Domain Criteria, issued by the National Institutes of Mental Health.
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