Neuroendocrine Mechanisms Regulating Drinking Behavior in Females

Maintaining adequate body fluid levels is essential for life. Mammals experience continual water and electrolyte loss through urine and the evaporation of fluids during sweating and breathing. To replace these lost fluids, water and electrolyte consumption is necessary. Therefore, understanding the neural controls of fluid intake is critical to understand how animals survive. Importantly, there is overwhelming evidence that estradiol regulates fluid intake in female mammals. It was first demonstrated in the late 1970s that both overnight and stimulated fluid intake is decreased during behavioral estrus. Follow up studies demonstrated that estradiol inhibits both water and saline intake. From an ultimate perspective, this inhibitory role of estradiol on fluid intake may be advantageous to allow for females to spend more time finding a mate and less time searching for fluids during times of fertility. From a proximate point of view, however, the underlying mechanisms by which estradiol inhibits fluid intake are unknown. Recent work by the PI has demonstrated that different estrogen receptor (ER) subtypes have specific effects on fluid intake, specifically intake stimulated by the hormone angiotensin II. The goal of this proposal is to test the overarching hypothesis that estradiol signaling in the brain decreases water and saline intake through distinct actions of ERα, ERβ, and G-protein estrogen receptor 1 (GPER-1) in female rats using multiple levels of analysis by investigating gene expression up to behavior. Aim 1 will determine which areas of the brain and estrogen receptor subtypes are necessary and sufficient for estradiol's inhibitory effect on drinking. Aim 2 will determine if estrogen receptor subtypes differentially influence angiotensin type 1 receptor intracellular signaling in areas of the brain that control fluid intake. Aim 3 will determine if estradiol modulates excitatory and/or inhibitory cells in fluid-relevant brain areas to inhibit water and saline intake. The approach taken in this proposal is novel because it combines a variety of techniques from gene analysis up to behavioral analysis of fluid intake to understand how estradiol via its receptor subtypes acts at multiple levels of brain organization (nuclei, genes, cells) to alter a basic and fundamental behavior. Furthermore, the outcomes from this proposal will serve as a starting point in understanding how fluid intake, and in turn fluid balance, is regulated across the female lifespan. During the reproductive years the demand for fluid changes dramatically during both pregnancy and lactation, a time when estradiol levels are also dynamic. Once we begin to understand the mechanisms by which estradiol inhibits fluid intake in adult, non-pregnant animals we can begin to study how these interactions may be modified during gestation and lactation.