Sex differences in BNST prepronociceptin-expressing neurons in modulating chronic stress-induced depressive-like behaviour in mice

ongoing

Major Depressive Disorder (MDD) is a highly prevalent and disabling condition experienced by ~6% of the population worldwide. Interestingly, women are twice as likely as men to suffer from MDD, and the specific mechanisms contributing to such difference are only starting to be elucidated. Chronic mild stress has been shown to reproduce in rodents some of the main traits of MDD, such as anhedonia or anxiety-like behaviour. Chronic stress has been shown to interfere with prepronociceptin (Pnoc) expression in the anterior BNST (amBNST) in rodents. Interestingly, it has been established a functional antagonistic role of Pnoc neurons over corticotropin-releasing hormone (CRH)-expressing neurons, which mediate the stress response in mammals. Moreover, amBNSTPnoc neurons have been shown to support rapid arousal responses toward motivationally salient stimuli in mice. Preliminary data has demonstrated sex differences in amBNSTPnoc distribution across compartments, indicating possible sex-dependent effects of stress on amBNSTPnoc function. We aim to explore sex differences in amBNSTPnoc neurons in rapid arousal responses upon sucrose presentation and its relationship with chronic stress-driven anhedonia. To that end, rapid arousal responses in male and female mice will be studied after chronic stress in mice, and related to anhedonic-like behaviour, and Pnoc and CRH expression in compartments of the BNST. To further understand the effects of chronic stress in Pnoc neurons, calcium transients using 2-photon calcium imaging in amBNSTPnoc neurons will be studied before and after chronic stress. Chemogenetic activation of amBNSTPnoc after stress will be used to functionally test that low Pnoc expression drives hypoarousal states related to anhedonic behavior. The proposal aims to elucidate sex differences in the pathophysiology of chronic stress-driven depressive-like behaviour and provide new perspectives and ideas on the higher prevalence and treatment resistance in females.