Neurobehavioral Control of Body Fluid Balance in Mouse

描述(由申请人提供)：体液平衡依赖于调节肾脏水分和钠流失速率的反射，以及纠正体内平衡缺陷的摄食行为(即口渴和食盐)。虽然肾脏机制减缓液体丢失，但血管容量的恢复依赖于水和溶质(如钠)的摄取。维持细胞外容量需要中枢神经系统(CNS)接收和处理有关体内水和钠状态的信息。有几个内脏感觉系统提供了这种传入输入，但对于中枢神经系统如何处理这些信息，人们只有非常有限的了解。目前的建议建立在我们先前的研究基础上，这些研究旨在确定涉及体液和心血管内稳态的传入信号相互作用的性质，并了解此类传入信息的中枢神经系统处理机制。最近，我们用小鼠研究了几个与体液和心血管动态平衡有关的问题。这种物种的使用受到了通过操纵小鼠基因组而衍生的新实验模型的潜力的推动。我们最初的几项研究已经调整和验证了许多用于研究大鼠口渴和食盐胃口的传统实验操作。结果表明，小鼠与其他实验物种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身上进行研究，以澄清对该物种口渴和食盐量控制的理解。此外，我们建议进行研究，利用目前可用的小鼠模型来产生关于口渴和食盐的基本神经生物学的重要新信息。具体地说，我们将研究全身和大脑肾素-血管紧张素-醛固酮系统和血压之间的相互作用，以控制它们有助于体液稳态的行为。最初的研究将使用从研究野生型小鼠中获得的方法和知识，以进一步了解身体和大脑肾素-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大学开发的小鼠转基因模型，该模型在大脑和感觉周脑室器官神经元中过度表达血管紧张素1型受体。这些研究产生的信息将与暴露在生理(例如运动)和环境(例如高温)挑战中的正常个人的幸福感相关。这些研究对于了解高血压和充血性心力衰竭等病理疾病的潜在机制尤其重要，在这些疾病中，过度口渴和钠摄入量已被记录在案。

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.