Regulation of Subfornical Organ Neurons by the Neuropeptide Neurotensin

脊椎动物的中枢神经系统受到血脑屏障的保护。这种屏障允许血液和神经元周围的液体之间的物质交换，如氧气和葡萄糖，但阻止大多数其他物质的交换，包括激素和信号分子。然而，被称为感觉室周器官（CVOs）的专门区域具有毛细血管渗漏，并且缺乏血脑屏障。感觉CVOs含有专门的神经元，用于检测循环激素、血浆中的离子浓度（如Na+）和许多代谢物。然后，这些信息被传递到其他大脑中心，最终调节体内平衡。 我的研究重点是大脑中一个被称为穹窿下器官（SFO）的区域，这是一种感觉CVO，在调节口渴，盐食欲，心血管功能和能量平衡方面具有良好的作用。拟议研究的目标旨在更好地了解SFO神经元的基本调节以及激素如何调节其电特性。 我之前的发现基金支持的研究之一是对大鼠SFO进行转录组学分析。在进行这项工作时，我和我的学员能够构建一个由SFO表达的所有离子通道和受体的列表。通过研究表达的离子通道和受体的互补性，我们已经开始更好地了解SFO神经元的生理作用。本申请具有三个研究目标：（1）研究称为神经降压素的激素如何改变SFO神经元的电活动;（2）确定神经降压素是否像许多其他激素一样作用于SFO以调节血压和/或心率;（3）研究称为Ca++通道的特定组的离子通道在塑造SFO神经元的电特性中的作用。我的目标是为4名研究生水平和10名本科生水平的HQP提供培训。 意义：SFO作为调节许多稳态功能的关键脑中心已被深入研究。神经降压素是一种激素，它与SFO一样，汇聚在许多相同的稳态过程中。有人提出，在SFO的电信息的处理，或在检测激素的错误可能会导致偏离稳态，如喂养和/或心血管输出的异常调节。我和我的学员已经收集了初步数据，表明SFO是神经降压素以前未描述的作用部位。这项研究将提供详细的细胞和分子机制的神经降压素在SFO的行动，并提供在整个动物生理水平的生理背景。这项工作对于那些对中枢神经系统、感觉室周器官和神经降压素调节基本稳态功能感兴趣的人来说是很重要的。这项工作对那些对能量平衡和心血管调节生物学感兴趣的人也很重要。

The central nervous system of vertebrates is protected by a blood brain barrier. This barrier allows exchange of materials such as oxygen and glucose between the blood and the fluid surrounding neurons, but prevents exchange of most other materials, including hormones and signaling molecules. Specialized areas called sensory circumventricular organs (CVOs), however, have leaky capillaries, and lack a blood brain barrier. Sensory CVOs contain specialized neurons to detect circulating hormones, concentration of ions in the plasma such as Na+, and numerous metabolites. This information is then transmitted to other brain centres which ultimately regulate homeostasis. My research focuses on an area of the brain called the subfornical organ (SFO), a sensory CVO with well-established roles in regulating thirst, salt appetite, cardiovascular function and energy balance. The goals of the proposed research aim to deliver a better understanding of the fundamental regulation of SFO neurons and how their electrical properties are modulated by hormones. One of the investigations enabled by my previous Discovery Grant was a transcriptomic analysis of rat SFO. In carrying out this work, my trainees and I were able to construct a list of all the ion channels and receptors expressed by the SFO. By examining the complement of expressed ion channels and receptors, we have begun to gain a better understanding of the physiological roles of SFO neurons. The present application has three research objectives: (1) investigate how a hormone called neurotensin alters electrical activity of SFO neurons; (2) determine if neurotensin, like many other hormones, acts at the SFO to regulate blood pressure and/or heart rate; (3) investigate the roles of a specific group of ion channels called Ca++ channels in shaping electrical properties of SFO neurons. I aim to provide training for 4 graduate-level and 10 undergraduate-level HQP. Significance: The SFO has been intensely studied as a brain centre critical to regulation of numerous homeostatic functions. Neurotensin is a hormone that converges on many of the same homeostatic processes as SFO. It has been proposed that errors in processing of electrical information at the SFO, or in detecting hormones may result in departures from homeostasis such as abnormal regulation of feeding and/or cardiovascular output. My trainees and I have gathered preliminary data to indicate that the SFO is a previously undescribed site of action for neurotensin. This research will provide detailed cellular and molecular mechanisms of action for neurotensin at the SFO, and provide physiological context at the level of whole animal physiology. The work will be of importance to those who are interested in regulation of basic homeostatic functions by the central nervous system, sensory circumventricular organs and neurotensin. The work will also be of importance to those interested in the biology of energy balance and cardiovascular regulation.