Author ORCID Identifier

0000-0002-6315-8628

Date of Award

5-1-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Aras Petrulis

Abstract

Dysfunction in social communication is a prominent aspect of many psychopathologies and social disorders including autism, schizophrenia, and social anxiety. Consequently, development of clinical treatment for these disorders requires an understanding of neural circuitry underlying social communication. Sex differences are a persistent feature of social disorders, where autism is more prevalent in males, while social anxiety occurs more frequently in females. A critical gap in knowledge exists in understanding the role of sex-differences in the control of social behavior and communication. A reasonable hypothesis is that differences in neural circuitry underlie sex-differentiated dysfunctions in social behavior and communication. A well-studied circuit in this regard is the sexually dimorphic expression of the neuropeptide arginine vasopressin (AVP). AVP in the nervous system originates from several distinct sources which are, in turn, regulated by different inputs and regulatory factors. Using modern molecular approaches, we can begin to define the specific role of AVP cell populations in social behavior. We demonstrate a behavioral function for the sexually dimorphic AVP neurons in the bed nucleus of the stria terminalis (BNST) and in the paraventricular nucleus of the hypothalamus (PVN). Collectively, our results indicate that AVP cell groups appear to play opposite roles in social investigation by males and females, as BNST-AVP cell ablations and BNST AVP knockdown reduced male social approach, while PVN-AVP cell ablations increased female social approach. We next utilized circuit level tracing techniques to map the inputs and outputs of BNST and medial amygdala (MeA) AVP cells, which are the major source of sexually dimorphic AVP expression. Finally, we tested the function of several sexually dimorphic BNST-AVP projection areas, such as, the lateral septum (LS), lateral habenula (LHb), and dorsal raphe (DR). In male mice, but not female mice, optogenetic stimulation of the BNST AVP terminals in the LS increased their social investigation and anxiety-like behavior in the elevated-zero maze. Antagonism of V1aR in the LS blocked optogenetic-mediated increases in male social investigation and anxiety-like behavior. Therefore, activation of a distinct BNST-LS AVP circuit modulates sex-specific social approach and anxiety-like behavior, which is mediated by V1aR within the LS. This work suggests that sex differences in the neurochemical underpinnings of social behavior may contribute to sex differences in disorders of social behavior and communication.

DOI

https://doi.org/10.57709/35399428

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