Evaluating Angiotensin Type 2 Receptors in the Medial Prefrontal Cortex: Implications for Post-Traumatic Stress Disorder and Associated Cardiovascular Disease
Open Access DepositedPost-traumatic stress disorder (PTSD) is a debilitating neuropsychological disorder characterized by overgeneralization of fear and highly comorbid with cardiovascular disease (CVD). Though women are more likely to develop PTSD, research has historically focused on males, resulting in a poor understanding of sex-specific fear circuitry and flawed treatment strategies. The renin-angiotensin system (RAS) has emerged as a pivotal regulator in the PTSD-CVD link, and targeting RAS receptors could provide a new avenue for therapeutic intervention. However, the neurobiological mechanisms through which RAS receptors contribute to fear memory remain unknown. Specifically, the angiotensin type 2 receptor (AT2R), which is highly expressed in the medial prefrontal cortex (mPFC) —a key region in fear learning that is dysregulated in PTSD—has not been previously examined. The mPFC is essential to top-down fear regulation, processing an array of exteroceptive (environmental), and interoceptive (heart rate and blood pressure) factors impacting fear memory. Investigation of complex fear circuits such as the mPFC alongside autonomic systems, however, is currently limited. To enhance translation of preclinical findings, there is a critical need for innovative animal behavioral paradigms that integrate neural circuitry, behavior, and environment. The goal of this dissertation is therefore to investigate the role of mPFC AT2Rs in fear learning and memory, and to develop a method for assessing the impact of chronic fear reminders considering environmental and cardioautonomic factors. The presented research does this through two specific aims: 1) to examine the sex-specific expression and function of mPFC-AT2Rs in fear extinction, and 2) to develop an innovative preclinical behavioral paradigm incorporating integrated cardioautonomic assessments and environmental factors. Here we show, for the first time, the sex-dependent functional necessity of mPFC-AT2Rs to extinction learning and their localization on somatostatin interneurons, identifying mPFC-AT2R as a novel receptor in fear-related memory. In addition, using lab-developed software for integrated cardio-behavioral analysis, we establish and validate a new behavioral paradigm to investigate the effects of chronic unpredictable threat reminders. Overall, these findings enhance our current understanding of the neurobiological mechanisms involved in fear and may have implications for maladaptive fear memory in PTSD, as well as the associated risk of comorbid CVD.
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