Neuroendocrine mechanisms regulating drinking behavior in females

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Maintaining adequate body fluid levels is essential for life. Mammals, including humans, experience continual water and electrolyte loss through urine, defecation, and the evaporation of fluids during sweating and breathing. To replace these lost fluids, water and electrolyte consumption is necessary. Failure to replace lost fluids results in fatigue, headache, cognitive impairments, and ultimately will result in death. Therefore, understanding how the body controls fluid intake is critical for understanding how animals survive. Importantly, there is overwhelming evidence that the ovarian hormone estradiol regulates fluid balance, and specifically fluid intake, in females. However, how estradiol controls drinking behavior is not well understood. This project addresses this fundamental question and thereby will contribute critically to understanding of how estradiol controls fluid intake in females. This question is important also because elucidating how estradiol controls drinking is key to understanding how whole-body fluid balance is maintained in females. The demand for fluid changes dramatically across the female reproductive lifespan, both during pregnancy and lactation, and is coupled with marked fluctuations in estradiol secretion during these times. Therefore, research investigating how estradiol regulates intake is also necessary for understanding cardiovascular physiology in females. An additional part of this project is the dissemination of this work, and more generally information about research in neuroendocrinology and hydration, to the public. Toward this goal, the investigators of this project contribute to events at the University of Kentucky, such as Expanding Your Horizons and BioBonanza. Finally, inclusion of university students in this project provides training in scientific research and outreach.The goal of this project is to understand how estradiol inhibits fluid intake in female laboratory rats. Toward this goal, the investigators test the overarching hypothesis that estradiol signaling in the brain decreases angiotensin II-stimulated water and saline intake through distinct actions of various estrogen receptor (ER) subtypes. The project examines this question at multiple levels of analysis, from gene expression to behavior, to determine the roles of estrogen receptor alpha, estrogen receptor beta, and G protein estrogen receptor 1 in the regulation of fluid intake by estradiol. Aim 1 use AAV-mediated shRNA knockdown of ER subtypes and parenchymal injections of ER agonists to determine which areas of the brain and ER subtypes are necessary and sufficient for estradiol’s inhibitory effect on water and saline intake. Aim 2 quantifies gene and protein expression to determine if ER subtypes differentially influence angiotensin type 1 receptor intracellular signaling in areas of the brain that control fluid intake. Aim 3 uses immunohistochemistry to determine if estradiol modulates excitatory and/or inhibitory cells in fluid-relevant brain areas to inhibit fluid intake. In addition to identifying how estradiol controls fluid intake in females, this work will advance more generally understanding of how ovarian hormones signal in the brain and influence behavior. This project is jointly funded by the Modulation Program in the Division of Integrative Organismal Biology and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.