Repeated unpredictable stress and social isolation induce chronic HPA axis dysfunction and persistent abnormal fear memory.

The lack of progress in the psychopharmacological treatment of stress-related disorders such as PTSD is an ongoing crisis due to its negative socioeconomic implications. Current PTSD pharmacotherapy relies on a few FDA approved medications used primarily for depression which offer only symptomatic relief and show limited efficacy. As the population of PTSD patients is growing, the identification of effective etiology-based treatments for the condition is a high priority. This requires an in-depth understanding of the neurobiological and behavioral outcomes of stress in translationally relevant animal models. In this study, we use neuroendocrine, biochemical and behavioral measures to assess the HPA axis function and fear-memory deficits in a mouse model of chronic stress. The chronic stress procedures involved exposure to 21 days of repeated unpredictable stress (RUS), including predator stress, restraint and foot shock, followed by chronic social isolation. We show that mice exposed to our stress paradigm demonstrate exaggerated fear memory recall and blunted HPA axis functionality at one month after RUS. Our neuroendocrinal testing suggests that the attenuated stress response in our model may be related to an alteration in the adrenal MC2 receptor reactivity. While there was no noticeable change in pituitary negative feedback regulation mechanisms, CRH and phosphorylated Glucocorticoid receptors levels were altered in the hypothalamus. We also show that chronic supplementation with a peripheral glucocorticoid receptor agonist (low-dose dexamethasone) after RUS partially restores a number of stress-related behavioral deficits in the RUS model. This suggests a direct relationship between HPA axis function and behavior in our model. Our findings emphasize the importance of the adrenal receptors as a target for HPA axis dysfunction in stress and fear-related disorders.

Impact of Repetitive Mild Traumatic Brain Injury on Behavioral and Hippocampal Deficits in a Mouse Model of Chronic Stress.

Clinical studies examining the interaction between traumatic brain injury (TBI) and stress-related disorders (e.g., post-traumatic stress disorder) are often complicated by methodological constraints, such as heterogeneity in injury type and severity, time post-trauma, and predisposing risk factors. Developing relevant animal models whereby many variables can be efficiently controlled is thus essential to understanding this elusive relationship. Here, we use our repeated unpredictable stress (RUS) paradigm, in combination with our established mouse model of repetitive mild TBI (r-mTBI), to assess the impact of repeated exposures to these paradigms on behavioral and neurobiological measures. C57BL/6J male mice were exposed to RUS and r-mTBI at 3 and 6 months of age followed by batteries of behavioral testing. Mice were euthanized 10 days and 3 months post-exposure, with brain and plasma samples collected for molecular profiling. The RUS paradigm involved exposure to a predator odor (trimethylthiazoline; TMT) while under restraint, daily unstable social housing, five inescapable footshocks on separate days, and chronic social isolation. Animals receiving r-mTBI ( × 5) and stress were exposed to a single closed-head injury 1 h after each footshock. Stress-alone mice showed significant weight loss, recall of traumatic memories, and anxiety-like and passive stress-coping behavior when compared with control mice. However, in stress+r-mTBI animals, the changes in cued fear memory, anxiety, and stress-coping tests were diminished, possibly due to TBI-induced hyperactivity. We also report complex brain molecular and neuropathological findings. Stress and r-mTBI, either individually or comorbidly, were associated with a chronic reduction in dendritic spine GluN2A/GluN2B ratio in the hippocampus. While stress augmented the r-mTBI-dependent astrogliosis in the corpus callosum, it mitigated r-mTBI-induced increases in hippocampal pro-brain-derived neurotrophic factor. We anticipate that our model will be a good platform to untangle the complex comorbid pathophysiology in stress disorders and r-mTBI.