Hippocampal Trauma Memory Processing Conveying Susceptibility to Traumatic Stress.

While the majority of the population is ever exposed to a traumatic event during their lifetime, only a fraction develops posttraumatic stress disorder (PTSD). Disrupted trauma memory processing has been proposed as a core factor underlying PTSD symptomatology. We used transgenic Targeted-Recombination-in-Active-Populations (TRAP) mice to investigate potential alterations in trauma-related hippocampal memory engrams associated with the development of PTSD-like symptomatology. Mice were exposed to a stress-enhanced fear learning paradigm, in which prior exposure to a stressor affects the learning of a subsequent fearful event (contextual fear conditioning using foot shocks), during which neuronal activity was labeled. One week later, mice were behaviorally phenotyped to identify mice resilient and susceptible to developing PTSD-like symptomatology. Three weeks post-learning, mice were re-exposed to the conditioning context to induce remote fear memory recall, and associated hippocampal neuronal activity was assessed. While no differences in the size of the hippocampal neuronal ensemble activated during fear learning were observed between groups, susceptible mice displayed a smaller ensemble activated upon remote fear memory recall in the ventral CA1, higher regional hippocampal parvalbuminneuronal density and a relatively lower activity of parvalbumininterneurons upon recall. Investigation of potential epigenetic regulators of the engram revealed rather generic (rather than engram-specific) differences between groups, with susceptible mice displaying lower hippocampal histone deacetylase 2 expression, and higher methylation and hydroxymethylation levels. These finding implicate variation in epigenetic regulation within the hippocampus, as well as reduced regional hippocampal activity during remote fear memory recall in interindividual differences in susceptibility to traumatic stress.

Aberrant ventral dentate gyrus structure and function in trauma susceptible mice.

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.

Longitudinal assessment of amygdala activity in mice susceptible to trauma.

Resilience to consequences of trauma exposure contains relevant information about the processes that contribute to the maintenance of mental health in the face of adversity; information that is essential to improve treatment success of stress-related mental diseases. Prior literature has implicated aberrant amygdala (re)activity as potential factor contributing to trauma susceptibility. However, it remains to be resolved which amygdalar subregions and neuronal subclasses are involved, and when - i.e., pre-, peri- or post-trauma exposure - and under what conditions changes in amygdala (re)activity manifest themselves. Here, we implemented a preclinical rodent model for PTSD that entailed exposure to a traumatic event (severe, unpredictable foot shock) followed by a trigger (mild, predictable foot shock). Using behavioral phenotyping, trauma susceptible vs. resilient mice were identified and pre-, peri- or post-trauma amygdala activity was compared. Neuronal activity was tagged in living mice by the use of the ArcTRAP transgenic mouse line, labeling all activated (i.e., Arc-expressing) neurons by a systemic injection of tamoxifen. Furthermore, we assessed amygdala responses during fear memory recall, induced by either (re-)exposure to the trauma, trigger, or a novel, yet similar context, and analyzed behavioral fear responses under these conditions, as well as basal anxiety in the mice. Results revealed no major differences dissociating susceptible vs. resilient mice prior to trauma exposure, but exaggerated activity in specifically the basolateral amygdala (BLA) peri-trauma that predicted susceptibility to later PTSD-like symptoms. Post-trauma, susceptible mice did not display altered basal amygdala activity, but BLA hyperreactivity in response to trigger context re-exposure, and BLA hyporesponsivity in response to the trauma context. Exposure to the novel, similar context evoked a differential temporal pattern of freezing behavior in susceptible mice and an increased activity of amygdalar somatostatin-expressing neurons specifically. As such, these results for the first time show that deviant BLA activity during fear learning predicts susceptibility to its long-term consequences and that aberrant subsequent BLA responses to stressful contexts depend on the exact context.