The role of orexin neurotransmission in stress-induced cardiorespiratory and metabolic disturbances
Authors: Gagnon Marianne , Fournier Stéphanie , Marcouiller François , Ambrozio-Marques Danuzia , Joseph Vincent , Michael Natalie , Kinkead Richard 
Published: May 2023

Social isolation (SI) is a form of chronic stress that increases the risk for disease (hypertension, obesity, depression) and the COVID-19 pandemic has brought the entire world to appreciate its impact on mental and physical health. However, there is limited information pertaining to the neurobiological mechanisms underlying the deleterious impacts of SI. Within the hypothalamus, orexin-producing neurons (ORX) contribute to the regulation of arousal states, stress response, cardiorespiratory and metabolic homeostasis. Because these functions are all affected by SI, we hypothesised that SI disrupts ORX neurotransmission in rats.The experiments were carried out on two groups of adult female and male Sprague Dawley rats: controls (2/cage, n = 7), and socially isolated (SI; 1/cage, 3 weeks, n = 10). At the end of the isolation protocol, cardiovascular measurements were obtained by the tail cuff method. Rats were deeply anesthetised, and terminal blood samples were taken by cardiac puncture for multiplex assay. The brain was extracted after transcardiac perfusion 4% PFA/borax between 11.00 h and 13.00 h. Fos-B is a transcription factor indicative of neuronal activity; its expression was quantified in the paraventricular nucleus of the hypothalamus (PVN) and in the nucleus of the solitary tract (NTS), which are essential regions in the regulation of the stress response and cardiorespiratory function, respectively. Double immunostaining was performed with Fos-B on ORX neurons.In SI males, the elevated plasma corticosterone levels and increased number of Fos-B expressing neurons in the PVN compared to controls confirm that SI activates the stress pathways. Preliminary results in females indicate no stress activation. Mean arterial pressure of SI rats was higher than controls (+14mmHg); this stress effect was less important in females (+4mmHg). In males, SI reduced the number of ORX-labeled cells by 20% but increased the proportion of cells co-expressing Fos-B by 60%. SI also increased Fos-B expression in the NTS of males compared to controls.We conclude that SI activates the stress pathways in a sex-specific manner. This effect, along with enhanced activation of the NTS and ORX neurons likely play an important role in the etiology of hypertension and metabolic dysfunction. Completion of ongoing analyses in females will determine if the effects of SI on ORX neurotransmission is sex-specific. This research is supported by operating grants from the Canadian Institutes of Health Research (CIRH, RK and VJ). N.J.M. was supported by a Sentinel North Partnered Research Chair in Sleep Pharmacometabolism and a Fonds de Recherche du Quebec Sante (FRQS) Research Scholar J1 award. MG is the recipient of a doctoral scholarship from the FRQS. 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.