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交换氧气和葡萄糖等物质，但阻止包括激素和信号分子在内的大多数其他物质的交换。然而，被称为感觉周脑室器官(CVO)的专门区域毛细血管泄漏，缺乏血脑屏障。感觉性CVO包含专门的神经元，用于检测循环中的激素、血浆中离子的浓度(如Na+)和大量代谢物。然后，这些信息被传输到其他大脑中心，最终调节体内平衡。 我的研究重点是大脑的穹隆下器(SFO)，这是一种感觉性CVO，在调节口渴、食盐食欲、心血管功能和能量平衡方面发挥着广泛的作用。这项拟议研究的目标是更好地了解SFO神经元的基本调节以及它们的电特性是如何受到激素调节的。 我之前的发现赠款促成的一项调查是对大鼠SFO的转录分析。在进行这项工作的过程中，我和我的受训人员能够构建一份SFO表达的所有离子通道和受体的列表。通过检测表达的离子通道和受体的补充性，我们已经开始更好地了解SFO神经元的生理作用。目前的应用有三个研究目标：(1)研究一种名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)研究一组特定的离子通道(称为钙通道)在塑造SFO神经元电特性中的作用。我的目标是为4名研究生和10名本科HQP提供培训。 意义：SFO已被作为大脑中心进行了深入的研究，它对调节多种内环境平衡功能至关重要。神经降压素是一种激素，它在许多与SFO相同的体内平衡过程中汇聚。有人提出，在SFO对电信息的处理或在检测激素方面的错误可能导致动态平衡的偏离，例如摄食和/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是一个以前没有描述过的神经降压素的作用部位。这项研究将提供神经降压素在SFO中的详细细胞和分子作用机制，并提供整个动物生理学水平的生理学背景。这项工作对于那些对中枢神经系统、感觉环室器官和神经降压素调节基本稳态功能感兴趣的人来说将是重要的。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.