The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the identification and treatment of stress-related psychiatric disorders.

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Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in trauma susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we hypothesized that susceptibility to develop PTSD-like symptoms following trauma will be underpinned by aberrant DG structure and function. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD-like symptomatology following recovery. In four independent experiments, DG neuronal morphology, synaptic protein gene and protein expression, and neuronal activity during trauma encoding and recall were assessed. Behaviorally, trauma-susceptible animals displayed increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of trauma susceptible vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer1b/c gene and protein, a larger population of neurons active during trauma encoding, and a greater presence of somatostatin neurons. In contrast, the dorsal DG of trauma-susceptible animals did not differ in terms of spine density or gene expression but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. Collectively, we here report on specific structural and functional changes in the ventral DG in trauma susceptible male mice.

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Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in PTSD susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we investigated the association between deviant DG structure and function and susceptibility to develop PTSD-like symptoms following trauma. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD symptomatology following recovery. In three independent experiments, DG neuronal morphology, synaptic protein gene expression and neuronal activity during trauma encoding and recall were assessed. Behaviorally, PTSD-like animals displayed some increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of PTSD-like vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer 1b/c gene, a larger population of neurons active during trauma encoding and a greater presence of somatostatin neurons to be associated with PTSD susceptibility. In contrast, the dorsal DG of PTSD-like animals did not differ in terms of spine density or gene expression, but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. These data propose a critical role for -mainly the ventral-DG in establishing symptomatology addressed in this PTSD model.

Adaptive responding to severe stress or trauma requires an optimized reconfiguration in the activity of large-scale neural networks. In vulnerable individuals, this response can go awry, inducing long-term consequences on mental health, such as posttraumatic stress disorder (PTSD). Improved understanding of the neurobiological mechanisms underlying this maladaptive neural response to trauma might benefit early intervention (i.e., secondary prevention) options in stress-related psychopathology. Yet, because of obvious ethical limitations these acute responses to trauma are inaccessible in humans. Therefore, we here used a mouse model for PTSD to investigate adaptive vs. maladaptive neural responding to trauma, the latter leading to long-term behavioral consequences mimicking symptoms observed in PTSD patients. By using transgenic mice, we were able to fluorescently label all activated neurons during trauma exposure, and relate these activation patterns to later PTSD-like symptomatology. We observed increased neuronal activity in sensory-processing and memory-related areas of mice vulnerable to the long-term consequences of trauma exposure, compared to resilient mice. Moreover, vulnerable mice displayed increased functional connectivity between the default mode network and lateral cortical network (a proxy for the central executive network in humans) during trauma processing relative to resilient mice. As such, these findings provide first insight in how a maladaptive neural response to trauma can result in later symptoms of psychopathology. Disclosure No significant relationships.