Molecular and circuit mechanisms of nausea-associated behaviors

项目总结 恶心是一种内脏不适的不适感觉，通常伴随着一种不由自主的呕吐冲动。 对毒素摄入和感染的恶心反应是进化上有益的生存行为， 避免或排出可能导致周围组织损伤的毒素。然而，恶心的感觉可以 也是不适应的，因为许多治疗癌症、糖尿病和其他疾病的方法都会导致恶心 副作用大，而目前的止吐药物疗效有限。被称为 “化学感受器触发区”用于恶心，最后区是脑室周围感觉器官 对恶心和呕吐很重要。最后区的神经元在解剖上占有独特的位置 有缺陷的血脑屏障，可通过体液途径和 胃肠道。然而，关于最后区神经元如何参与 恶心及其相关厌恶行为的机制。使用单核RNA测序 结合遗传和行为研究，我们最近发现了该地区的一个种群 后丘神经元对呕吐提示的反应，在大脑中诱发与恶心相关的厌恶行为 老鼠。在这里，我提出了一种多层次的方法，基于这些初步发现，来调查 体液和迷走神经传入最后区的化学感觉回路及其如何参与 恶心。首先，我将找出通过后厌恶感促进区起作用的幽默线索 通过测试一组引起恶心或厌食性体液刺激的兴奋性神经元类型(目标1)。 接下来，我将映射和识别迷走神经输入到遗传定义的后部兴奋性神经元类型 使用病毒追踪和视紫红质辅助的电路标测技术(目标2)。这些 实验将揭示迷走神经输入和体液暗示如何调节该区域的功能。 介导恶心相关厌恶行为的最后神经元。在这次培训之后，我将成为 准备过渡到我职业生涯的R00阶段，并建立一个独特的独立研究计划 在呕吐动物模型中纳入有针对性的细胞型操作(目标3)。这些研究将 阐明恶心的细胞和神经机制，指导新型止吐剂的设计 治疗。这项提议的核心是对内科专家斯蒂芬·利伯勒斯博士的指导 Sensations，功能电路图谱专家Brad Lowell博士，肠道专家Frank Reimann博士 荷尔蒙信号，血脑屏障机制的领导者顾成华博士和查尔斯·霍恩博士， 呕吐模型和恶心生理学方面的专家。他们会为我提供职业指导和帮助 完成我的训练目标。在我的申请中，我概述了一个全面的收购计划 使我能够过渡到独立研究的概念、技术和专业技能 位置。

Project summary Nausea is an unpleasant sensation of visceral malaise often accompanied by an involuntary urge to vomit. Nausea responses to toxin ingestion and infection are evolutionarily beneficial survival behaviors that avoid or expel toxins which may cause peripheral tissue damage. However, the sensation of nausea can also be maladaptive, as many treatments for cancer, diabetes, and other illnesses induce nausea as a major side effect, while current anti-emetic drugs have only limited efficacy. Known as the “chemoreceptors trigger zone” for nausea, the area postrema is a brain circumventricular sensory organ critical for nausea and vomiting. Neurons in the area postrema occupy a unique anatomical location with a deficient blood-brain barrier, and can be regulated by inputs from both the humoral routes and the gastrointestinal tract. However, little is known about how area postrema neurons contribute to the mechanisms of nausea and its related aversive behaviors. Using single-nucleus RNA-sequencing combined with genetic and behavioral studies, we have recently discovered a population of the area postrema neurons that, in response to emetic cues, induce nausea-associated aversive behaviors in mice. Here, I propose a multi-tiered approach, based on these preliminary findings, to investigate the humoral and vagal inputs to the chemosensory circuit of the area postrema and how they contribute to nausea. First, I will identify humoral cues that act through the area postrema aversion-promoting excitatory neuron types by testing a panel of nausea-inducing or anorexigenic humoral stimuli (Aim 1). Next, I will map and identify vagal inputs to the genetically defined area postrema excitatory neuron types using viral tracing and channelrhodopsin-assisted circuit mapping techniques (Aim 2). These experiments will reveal how vagal inputs and humoral cues can regulate the functions of the area postrema neurons which mediate nausea-associated aversive behaviors. Following this training, I will be poised to transition to the R00 phase of my career and establish a unique independent research program incorporating targeted cell-type manipulation in vomiting animal models (Aim 3). These studies will elucidate the cellular and neural mechanisms nausea and may guide the design of novel anti-emetic therapies. Central to this proposal is the mentorship of Dr. Stephen Liberles, an expert in internal sensations, Dr. Brad Lowell, an expert in functional circuit mapping, Dr. Frank Reimann, an expert in gut hormone signaling, Dr. Chenghua Gu, a leader in blood-brain barrier mechanisms, and Dr. Charles Horn, an expert in vomiting models and nausea physiology. They will provide career guidance and help me achieve my training goals. In my application I have outlined a comprehensive plan for acquiring the conceptual, technical, and professional skills that will enable my transition to an independent research position.