Neurobehavioral Control of Body Fluid Balance in Mouse

描述（由申请人提供）：体液稳态取决于调节肾水和钠损失速率的反射以及摄食行为（即，口渴和盐的食欲），纠正体内平衡的缺陷。尽管肾脏机制减缓了液体损失，但血管容积的恢复取决于水和溶质的摄入（例如，钠）。细胞外容量的维持需要中枢神经系统（CNS）接收和处理有关身体水和钠状态的信息。几个内脏感觉系统提供这种传入输入，但对中枢神经系统如何处理这些信息的了解非常有限。目前的建议建立在我们以前的研究，已被定向在定义的性质的传入信号参与体液和心血管稳态的相互作用，并在了解这种传入信息的中枢神经系统的处理机制。最近，我们使用小鼠来研究与体液和心血管稳态相关的几个问题。使用这种物种是由于操纵小鼠基因组获得的新实验模型的潜力。我们的一些初步研究已经适应和验证了许多用于研究大鼠口渴和盐食欲的常规实验操作。结果表明，小鼠和其他实验物种之间有许多重要的相似之处，也有挑衅性的差异。我们建议在正常小鼠中进行研究，使我们能够澄清对该物种口渴和盐食欲控制的理解。此外，我们还提出了利用现有小鼠模型的研究，以产生有关口渴和盐食欲的基本神经生物学的重要新信息。具体来说，我们将研究系统和大脑的肾素-血管紧张素-醛固酮系统和血压的相互作用，在控制他们的行为，有助于体液稳态。最初的研究将采用来自研究野生型小鼠的方法和知识，以进一步了解身体和大脑的肾素-血管紧张素系统在体液平衡的行为控制中的作用。其他研究将利用爱荷华州大学开发的小鼠转基因模型，该模型在大脑和感觉室周器官神经元中过度表达血管紧张素1型受体。从这些研究中产生的信息将与暴露于生理（例如，锻炼）和环境（例如，热）的挑战。这些研究对于了解高血压和充血性心力衰竭等病理条件下的机制尤其重要，这些疾病中已经记录了过度口渴和钠摄入。

DESCRIPTION (provided by applicant): Body fluid homeostasis depends on reflexes that modulate the rate of renal water and sodium loss and on ingestive behaviors (i.e., thirst and salt appetite) that correct homeostatic deficits. Although renal mechanisms slow fluid loss, the restoration of vascular volume depends on the ingestion of water and solute (e.g., sodium). The maintenance of extracellular volume requires that the central nervous system (CNS) receives and processes information about the status of body water and sodium. Several visceral sensory systems provide this afferent input, but there is only a very limited understanding about how this information is handled by the CNS. The present proposal builds upon our prior studies that have been directed at defining the nature of interactions of afferent signals involved in body fluid and cardiovascular homeostasis and at understanding the CNS processing mechanisms of such afferent information. Recently, we have used the mouse to investigate several issues related to body fluid and cardiovascular homeostasis. Use of this species was prompted by the potential of new experimental models derived by manipulation of the mouse genome. Several of our initial studies have adapted and validated many of the conventional experimental manipulations used to study thirst and salt appetite in rat. The results indicate that there are many important similarities between mouse and other experimental species, and also provocative differences. We propose studies in normal mice that allow us to clarify understanding of the control of thirst and salt appetite in this species. In addition we propose studies that take advantage of currently available mouse models to generate important new information about the basic neurobiology of thirst and salt appetite. Specifically, we will study the interaction of the systemic and brain renin-angiotensin-aldosterone systems and blood pressure in the control of their behaviors that contribute to body fluid homeostasis. Initial studies will employ methods and knowledge derived from studying wild type mice to further understanding of the role of body and brain renin-angiotensin systems in the behavioral control of body fluid balance. Other studies will make use of a mouse transgenic model developed at the University of Iowa that over-expresses angiotensin type 1 receptors in brain and in sensory circumventricular organ neurons. Information generated from these studies will be relevant to the well-being of normal individuals exposed to physiological (e.g., exercise) and environmental (e.g., heat) challenges. These studies will be especially important for understanding mechanisms underlying pathological conditions such as hypertension and congestive heart failure where excess thirst and sodium intake have been documented.