Date of Award
Summer 2021
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Biological Sciences
First Advisor
Evans, Jennifer
Second Advisor
Blackmore, Murray
Third Advisor
Gasser, Paul
Abstract
Daily rhythms in behavior and physiology are programmed by the circadian system, which is a collection of endogenous biological clocks that allow organisms to anticipate recurring daily environmental events relevant for survival. The suprachiasmatic nucleus (SCN) acts as the central clock coordinating downstream tissues to the environment, and SCN signaling is critical for circadian timekeeping. Arginine vasopressin (AVP) is produced by a subset of SCN neurons, which is transduced by the V1A and V1B receptors. V1A and V1B are expressed in the SCN itself, suggesting AVP signaling modulates central clock function through mechanisms that remain unclear. To gain deeper insight into the role of AVP signaling in the central clock, here I tested that AVP is necessary and sufficient to modulate SCN function using pharmacological and genetic approaches. First, I used V1 antagonists to test that AVP signaling modulates SCN molecular rhythms in vitro. V1 antagonism lengthened period and altered phase relationships among SCN neurons in a region-specific manner, suggesting differential roles for V1A and V1B receptors. Second, I used an AVP deficient mouse model to test how AVP signaling modulates circadian rhythms in locomotor behavior. Loss of AVP signaling increased the period, imprecision, and plasticity of behavioral rhythms in a manner influenced by sex, indicating that AVP circuits are sexually dimorphic. Last, I used V1 receptor agonists to test that AVP signaling is sufficient to reset the SCN clock in vitro. V1 agonists reset the SCN molecular clock, with larger responses in females. Further, I found that both Gαq and Gαs signaling are necessary for the V1-induced SCN resetting, which indicates that AVP interacts with other SCN neuropeptides to modulate central clock function. Overall, this work provides novel insights by revealing AVP signaling alters SCN period, phase, and precision by interacting with other signals in a manner that varies by sex.