Neural Basis for Regulation of Vasopressin Secretion by Presystemic Anticipated Disturbances in Osmolality, and by Hypoglycemia

Abstract

Vasopressin (AVP), released by magnocellular AVP neurons of the hypothalamus, is a multifaceted hormone. AVP regulates many physiological processes including blood osmolality, blood glucose, and blood pressure. In this dissertation, I present two independent studies investigating the neural mechanism for role of AVP in fluid and glucose homeostasis. In regards to regulating water excretion and hence blood osmolality, magnocellular AVP neurons are regulated by two temporally distinct signals: 1) slow systemic signals that convey systemic osmolality information, and 2) rapid ‘presystemic’ signals that anticipate future osmotic challenges. Magnocellular AVP neurons show bidirectional presystemic responses to feeding and drinking. In our first study, we identified and characterized the neural circuits mediating presystemic regulation of AVP release. Using in vivo calcium imaging and opto- and chemo-genetic approaches, we demonstrated that presystemic regulation of magnocellular AVP neurons is mediated by two functionally-distinct neural circuits that transmit information related ingestion of either water or food, which decrease or increase osmolality, respectively. We also validated a brainstem circuit mediating blood pressure information to magnocellular AVP neurons that is completely separate from water- and food-related presystemic circuits. Next, we focused on the glucoregulatory function of AVP. We adopted a wide range of in vitro and in vivo techniques in mice and human to provide a comprehensive analysis of central and peripheral pathways mediating AVP’s glucoregulatory effect. We performed the very first in vivo simultaneous real-time monitoring of blood glucose and magnocellular AVP neuron activity in mice to demonstrate robust activation of magnocellular AVP neurons by hypoglycemia. We further demonstrated that A1/C1 neurons in the brainstem mediate this activation. We showed that AVP acts on V1b subtype of AVP receptors specifically expressed on pancreatic alpha cells to stimulate glucagon release, which then stimulates hepatic glucose production. Taken together, our data shows that activity of magnocellular AVP neurons is tightly regulated by multiple functionally-distinct neural circuits. We propose that proper regulation of AVP release is crucial for homeostasis of multiple physiological processes, and dysregulation of AVP release might underlie certain diseases with impaired water and glucose balance.