Differential Activation of Neurons of the Paraventricular Nucleus of the Hypothalamus in Response to Chronic Social Defeat Stress in Male Mice
Authors: Eikenberry Sophia , Scott Karen , Krause Eric , de Kloet Annette 
Published: May 2023

Social adversity is a major contributor to chronic illnesses such as hypertension, obesity, and type-2 diabetes. Populations associated with lower social status are disproportionately affected by such illnesses, possibly due to recurrent exposure to social stress and adversity. Previous studies from our group and others have revealed that Chronic Social Defeat Stress (CSDS) in mice, which models the effects of low social status, results in anxiety-like behavior, endocrine abnormalities and cardiovascular perturbations. In this paradigm, intruder male C57BL/6J mice are placed in the home cage of larger, more aggressive Cd-1 male mice, and allowed to interact until the intruder is defeated and/or exhibits submissive behavior. The intruder is then housed within the resident cage for 24 hours, separated by a polycarbonate divider allowing for continuous sensory contact; this process is then repeated on a daily basis for several days. Of particular relevance, we have found that, over time, deleterious cardiovascular effects of CSDS are heightened, such that mice subjected to CSDS exhibit hypertension that increases in severity over time. Furthermore, corticosterone responses to the defeat session demonstrate plasticity with repeated exposure to social stress. Here, we hypothesized that activity within the paraventricular nucleus of the hypothalamus (PVN) may mediate altered physiological responses to defeat over time. The PVN contains neuroendocrine and pre-autonomic populations of neurons that produce oxytocin (OT), vasopressin (AVP), and corticotropin releasing hormone (CRH). Additionally, this region contains neurons which express the angiotensin type-1 receptor (AT1R) and increase blood pressure, at least in part, through release of CRH. To evaluate the impact of CSDS on neural activity within these specific PVN neuronal phenotypes, adult male C57BL/6J wild type mice or mice that expressed a variant of red fluorescent protein in cells that express (AT1R-tdTomato) were subjected to one or ten daily defeat sessions. Controls were handled similarly to defeated mice, but were not subjected to defeat. Ninety minutes after the initiation of the first or tenth defeat session, mice were euthanized and brains were processed to evaluate expression of c-Fos, a neuronal activation marker, in OT, AVP, and AT1R/CRH neurons, using a combination of immunohistochemistry and in situ hybridization. Compared to controls, one session of defeat resulted in elevated activation of OT and AVP neurons, as well as activation of AT1R/CRH neurons. Ten sessions of defeat robustly activated both OT and AT1R/CRH neurons compared to control conditions, while resulting in decreased activation of AVP neurons compared to one session of defeat. Collectively, these data suggest that mobilization of the PVN in response to social defeat stress may drive altered sympathetic and endocrine activity, contributing to cardiometabolic pathology.

R01HL136595, R35HL150750, R01HL145028, R00HL125805, Florida Education Fund McKnight Fellowship

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.