Abstract 4364768: Functional Roles of Chronic Psychosocial Stress in Brain-Heart Interactions and Cardiac Autonomic Control in Male and Female Mice

Abstract

Introduction: Chronic psychosocial stress (CPSS) is a well-known risk factor for depression and anxiety disorders and a significant risk factor for cardiovascular disease. CPSS has been linked to the development of atrial fibrillation, coronary heart disease, and sudden cardiac death. However, the mechanisms of CPSS on cardiac dysfunction and arrhythmias remain less understood. Hypothesis: We hypothesize that CPSS triggers secretion of stress hormones resulting in an autonomic imbalance that impacts cardiac excitability. We aim to test the structural and functional remodeling of the brain by CPSS, and determine the mechanisms underpinning brain-heart interactions and cardiac autonomic control. Methods: We used a multi-hit CPSS mouse model by chronically exposing mice to noise, overcrowding, and sleep-deprivation for 8 hours/day over 3 months. c-Fos staining and whole-brain 3-D mapping were used to identify the neuronal activity, and serum corticosterone was measured. ECG telemetry and heart rate variability (HRV) analysis were performed to assess cardiac excitability and autonomic control. Results: To study brain-heart interactions, we established a carotid artery perfusion technique to fix brain in situ, allowing for the concurrent harvest of unfixed heart from the same experimental animal. We identified increased neuronal activities in brain regions associated with CPSS including cortical amygdala, paraventricular hypothalamic nucleus, cerebral cortex, and auditory cortex. Serum corticosterone levels were elevated by CPSS exposure indicating the activation of hypothalamic–pituitary–adrenocortical axis. ECG telemetry recordings and HRV analysis demonstrated exposure time-dependent alterations in heart rates and HRV parameters, suggesting the remodeling of sinoatrial node and autonomic imbalance. Moreover, the effects of CPSS showed significant differences between male and female mice, with greater increase in serum corticosterone levels in female mice. Conclusion: CPSS altered brain-heart interactions through activation of amygdala and hypothalamus resulting in stress hormone release. The shift in autonomic balance caused significant changes in cardiac rhythm and HRV parameters with significant sex differences, consistent with the increased vulnerability to CPSS in females compared to males. Additionally, carotid artery perfusion technique provided a useful tool for concurrent collection of fixed brain and other unfixed organs from preclinical animals.