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Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

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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Fig. 1: An expanded neurocircuitry of post-traumatic stress disorder.
Fig. 2: A map of post-traumatic stress disorder neurocircuits in humans and rodent models.
Fig. 3: Amygdala microcircuits implicated in fear conditioning.

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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 Mental Health, the Howard Hughes Medical Institute, the National Alliance for Research on Schizophrenia & Depression and the Burroughs Wellcome Foundation.

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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 content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Kerry J. Ressler or Junghyup Suh.

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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.

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Glossary

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

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.

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) signalling

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

Memory fragmentation

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).

Long-term potentiation

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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Fenster, R.J., Lebois, L.A.M., Ressler, K. et al. Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci 19, 535–551 (2018). https://doi.org/10.1038/s41583-018-0039-7

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