MPFC→ BNST→ PVN CIRCUITS MEDIATE EMOTIONAL AND CARDIAC DYSFUNCTION INDUCED BY SOCIAL ISOLATION IN ADOLESCENT MICE

Abstract Background Social and demographic changes have led to an increased prevalence of loneliness and social isolation in modern society, which increase the risk of mental illness such as anxiety, depression and sleep disorders (Brooks et al., 2020, Lee et al., 2021). Population-based studies have demonstrated that social isolation and loneliness are correlated with a higher risk of mortality and both are risk factors for cardiovascular disease (Xia and Li, 2018). Adolescence is a sensitive period of development and negative social experiences during adolescence are central features for several stress-related mental illnesses (Burke et al., 2017). Medial prefrontal cortex (mPFC) is known to play important roles in social behaviors and paraventricular nucleus of the hypothalamus (PVN) are central players in the stress response which integrating both external and visceral stress-relevant information (Duman and Aghajanian, 2012). The mPFC has been strongly implicated in control of PVN response to stress (Jiang et al., 2019). As a node of information integration and coordination, bed nucleus of stria terminalis (BNST) transmits the information encoded by the corticolimbic system to the downstream neuroendocrine and autonomic nervous center PVN, thereby regulating the behavioral response to stress and autonomic nervous response (Radley et al., 2009, Spencer et al., 2005). However, the mechanism of mPFC→ BNST→ PVN circuits in emotional and cardiac dysfunction induced by social isolation stress remains unclear. Aims & Objectives We aim to reveal the effects of different modes of social isolation stress in adolescence on emotional and cardiovascular function and its long-term effects, and to explore the neuronal activity changes of mPFC, BNST, PVN and other sub-regions after social isolation stress and mechanism of mPFC→ BNST→ PVN neural circuits in emotional and cardiac dysfunction induced by social isolation stress. Method Adolescent mice (three-week-old) were subjected to social isolation stress (2 or 6 weeks). Open field test, elevated plus maze and novelty suppressed feeding test were used to evaluate the anxiety behavior of mice. Forced swimming test and tail suspension test were used to evaluate the depressive behavior of mice. Three-chamber social test was used to evaluate social ability of mice. Immunofluorescence was used to detect the activation and type of neurons in mPFC, BNST and PVN. The cardiac function indexes of mice were detected by echocardiography. The mPFC→ BNST→ PVN neural circuit was identified by retrograde tract-tracing, and this circuit was regulated by chemogenetics or optogenetics. Results Adolescent mice subjected to social isolation stress for 6 weeks increased depression, anxiety and social dysfunction, aggravated cardiac dysfunction. Social isolation stress decreased mPFC and BNST neuronal activity and increased PVN neuronal activity. Chemogenetic regulation of mPFC→ BNST→ PVN neural circuits could rescue behavioral abnormalities caused by social isolation stress. Discussion & Conclusion Adolescent social isolation stress can lead to functional impairment of brain stress and emotion-related brain areas such as mPFC and BNST, and regulate cardiovascular function by acting on autonomic nervous centers such as PVN. The mPFC→ BNST→ PVN circuit plays an important role in emotional and social impairment and cardiac dysfunction caused by social isolation stress in adolescent mice. References 1.BROOKS, S. K., WEBSTER, R. K., SMITH, L. E., WOODLAND, L., WESSELY, S., GREENBERG, N. & RUBIN, G. J. 2020. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet, 395, 912-920. 2.BURKE, A. R., MCCORMICK, C. M., PELLIS, S. M. & LUKKES, J. L. 2017. Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses. Neurosci Biobehav Rev, 76, 280-300. 3.DUMAN, R. S. & AGHAJANIAN, G. K. 2012. Synaptic dysfunction in depression: potential therapeutic targets. Science, 338, 68-72. 4.JIANG, Z., RAJAMANICKAM, S. & JUSTICE, N. J. 2019. CRF signaling between neurons in the paraventricular nucleus of the hypothalamus (PVN) coordinates stress responses. Neurobiol Stress, 11, 100192. 5.LEE, C. R., CHEN, A. & TYE, K. M. 2021. The neural circuitry of social homeostasis: Consequences of acute versus chronic social isolation. Cell, 184, 2794-2795. 6.RADLEY, J. J., GOSSELINK, K. L. & SAWCHENKO, P. E. 2009. A discrete GABAergic relay mediates medial prefrontal cortical inhibition of the neuroendocrine stress response. J Neurosci, 29, 7330-40. 7.SPENCER, S. J., BULLER, K. M. & DAY, T. A. 2005. Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J Comp Neurol, 481, 363-76. 8.XIA, N. & LI, H. 2018. Loneliness, Social Isolation, and Cardiovascular Health. Antioxid Redox Signal, 28, 837-851.