UC Davis

Social Anxiety Disorder (SAD) is one of the most prevalent and debilitating stress-related affective disorders across nations. Despite its high prevalence, current treatments, such as selective serotonin reuptake inhibitor and cognitive behavioral therapy, only work in about half of the patients. Thus, there is a strong need for novel therapeutics that address the underlying biological mechanisms of SAD. This dissertation explores the roles of neuropeptides oxytocin and hypocretin in social behaviors and stress responses, highlighting their potential as treatment targets for SAD.Chapter 1 examines the anxiogenic effects of oxytocin receptor (OTR) signaling. We find that OTR-Gq signaling in the bed nucleus of the stria terminalis (BNST) promotes social avoidance and social vigilance behaviors in female and male California mice. Chapter 1 also provides analyses of published BNST and nucleus accumbens (NAc) single cell RNA-seq data and reveals a diverse expression pattern of OTRs across numerous cell types. Chapter 2 broadens the scope to include the hypocretin (Hcrt) system, typically associated with arousal and wakefulness, but also implicated in stress responses. This chapter presents a comprehensive review of how Hcrt may contribute to individual differences in stress coping strategies, especially in response to social stress. We propose that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and cell types. Chapter 3 focuses on understanding sex differences in SAD since women are twice as likely to be diagnosed with an anxiety disorder. Experimental findings from the study of California mice demonstrate that the effects of Hcrt on social behaviors are anatomically and sex specific. In female but not male mice, the Hcrt receptor signaling regulates social approach and vigilance in the NAcshell but not anterodorsalBNST.