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Posttraumatic stress disorder can be viewed as a disorder of fear dysregulation. An abundance of research suggests that the prefrontal cortex is central to fear processing—that is, how fears are acquired and strategies to regulate or diminish fear responses. The current review covers foundational research on threat or fear acquisition and extinction in nonhuman animals, healthy humans, and patients with posttraumatic stress disorder, through the lens of the involvement of the prefrontal cortex in these processes. Research harnessing advances in technology to further probe the role of the prefrontal cortex in these processes, such as the use of optogenetics in rodents and brain stimulation in humans, will be highlighted, as well other fear regulation approaches that are relevant to the treatment of posttraumatic stress disorder and involve the prefrontal cortex, namely cognitive regulation and avoidance/active coping. Despite the large body of translational research, many questions remain unanswered and posttraumatic stress disorder remains difficult to treat. We conclude by outlining future research directions related to the role of the prefrontal cortex in fear processing and implications for the treatment of posttraumatic stress disorder.

The study of inflammation in fear- and anxiety-based disorders has gained interest as growing literature indicates that pro-inflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear- and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear- and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro-inflammatory signaling in the maintenance of these unique psychiatric conditions.

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.

In this review, the authors highlight recent progress made in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to understanding, treatment, and possible prevention of fear disorders in the clinic. Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.

Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder, characterized by re-experiencing, avoidance, negative emotions and thoughts, and hyperarousal in the months and years following exposure to severe trauma. PTSD has a prevalence of approximately 6–8% in the general population, although this can increase to 25% among groups who have experienced severe psychological trauma, such as combat veterans, refugees and victims of assault. The risk of developing PTSD in the aftermath of severe trauma is determined by multiple factors, including genetics — at least 30–40% of the risk of PTSD is heritable — and past history, for example, prior adult and childhood trauma. Many of the primary symptoms of PTSD, including hyperarousal and sleep dysregulation, are increasingly understood through translational neuroscience. In addition, a large amount of evidence suggests that PTSD can be viewed, at least in part, as a disorder that involves dysregulation of normal fear processes. The neural circuitry underlying fear and threat-related behaviour and learning in mammals, including the amygdala–hippocampus–medial prefrontal cortex circuit, is among the most well-understood in behavioural neuroscience. Furthermore, the study of threat-responding and its underlying circuitry has led to rapid progress in understanding learning and memory processes. By combining molecular–genetic approaches with a translational, mechanistic knowledge of fear circuitry, transformational advances in the conceptual framework, diagnosis and treatment of PTSD are possible. In this Review, we describe the clinical features and current treatments for PTSD, examine the neurobiology of symptom domains, highlight genomic advances and discuss translational approaches to understanding mechanisms and identifying new treatments and interventions for this devastating syndrome.Post-traumatic stress disorder (PTSD) is one of the few neuropsychiatric disorders for which the timing and cause of onset are understood, facilitating research into the underlying mechanisms. In this Review, Ressler and colleagues examine the neurobiology of PTSD, highlighting new insights from omics studies and discussing future directions of research.

Recent decades have witnessed tremendous advances in the neuroscience of emotion, learning and memory, and in animal models for understanding depression and anxiety. This review focuses on new rationally designed psychiatric treatments derived from preclinical human and animal studies. Nonpharmacological treatments that affect disrupted emotion circuits include vagal nerve stimulation, rapid transcranial magnetic stimulation and deep brain stimulation, all borrowed from neurological interventions that attempt to target known pathological foci. Other approaches include drugs that are given in relation to specific learning events to enhance or disrupt endogenous emotional learning processes. Imaging data suggest that common regions of brain activation are targeted with pharmacological and somatic treatments as well as with the emotional learning in psychotherapy. Although many of these approaches are experimental, the rapidly developing understanding of emotional circuit regulation is likely to provide exciting and powerful future treatments for debilitating mood and anxiety disorders.

Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of a sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS–US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediate either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS–US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression.Pairing an odor conditioned stimulus (CS) with an unconditioned stimulus (US) induces memory formation. Vetere et al. replace the real CS and US with direct optogenetic stimulation of the brain and create a fully artificial odor memory in mice.

Depression is a common condition, but current treatments are only effective in a subset of individuals. To identify new treatment targets, we integrated depression genome-wide association study (GWAS) results ( N  = 500,199) with human brain proteomes ( N  = 376) to perform a proteome-wide association study of depression followed by Mendelian randomization. We identified 19 genes that were consistent with being causal in depression, acting via their respective cis -regulated brain protein abundance. We replicated nine of these genes using an independent depression GWAS ( N  = 307,353) and another human brain proteomic dataset ( N  = 152). Eleven of the 19 genes also had cis -regulated mRNA levels that were associated with depression, based on integration of the depression GWAS with human brain transcriptomes ( N  = 888). Meta-analysis of the discovery and replication proteome-wide association study analyses identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously implicated in depression by GWAS. Together, these findings provide promising brain protein targets for further mechanistic and therapeutic studies. Wingo et al. integrate depression GWAS results with human brain proteomes to perform proteome-wide association studies followed by Mendelian randomization. They identify 25 proteins as potential causal mediators of depression, of which 20 are new.

Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.