Deconstructing brainstem circuits for visceral senses

解构内脏感觉的脑干回路

• 批准号: 10591627
• 负责人: Chen Ran
• 金额: $ 12.58万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591627
• 关键词: Anatomy; Animals; Anorexia; Atlases; Behavior; Behavior Control; Behavioral; Brain; Brain Stem; Brain region; Calcium; Cardiovascular Physiology; Cardiovascular system; Categories; Cell Nucleus; Code; Complex; Cues; Data; Desire for food; Diabetes Mellitus; Digestive Physiology; Disease; Eating; Eating Disorders; Efferent Pathways; Emetics; Energy Metabolism; Feedback; Feeding behaviors; Food; Gastrointestinal tract structure; Genetic; Goals; Health; Homeostasis; Hormones; Hunger; Hypothalamic structure; Image; Individual; Inflammatory; Ingestion; Intestines; Irritants; Label; Logic; Manuscripts; Maps; Mediating; Metabolic; Metabolic Control; Metabolism; Monitor; Motor Neurons; Mus; Nature; Nausea; Nervous System; Neuroanatomy; Neurons; Nucleus solitarius; Nutrient; Obesity; Organ; Pathway interactions; Pattern; Peer Review; Perception; Physiological; Physiology; Play; Population; Postdoctoral Fellow; Process; Property; Research; Respiratory System; Respiratory physiology; Role; Satiation; Scientist; Sensory; Signal Transduction; Sorting; Specificity; Stimulus; Stomach; System; Taste aversion; Therapeutic; Time; Toxin; Vagus nerve structure; Viral; Visceral; Visceral pain; Water consumption; Work; cell type; conditioned place preference; detection platform; experimental study; feeding; flyer; gastrointestinal; gastrointestinal system; genetic approach; imaging platform; in vivo; in vivo calcium imaging; insight; mechanical signal; nerve supply; neural; neural circuit; neuroregulation; neurotransmission; novel; optogenetics; paraventricular nucleus; respiratory; response; segregation; sensory system; tool; transmission process; two-photon; virus genetics

PROJECT SUMMARY/ABSTRACT The ability to tightly control metabolic homeostasis is critical for animal survival. The internal sensory nervous system monitors the status of organs, providing feedback signals that enable the brain to maintain homeostasis by executing behavioral and physiological responses. For example, the system detects and encodes gastrointestinal cues signaling the quality and quantity of food ingested during a meal to control feeding behavior, digestive physiology, and whole-body metabolism. Dysregulation of internal sensory systems that monitor the digestive system can lead to various diseases, including obesity, diabetes, and anorexia. The internal sensory gateway in the brainstem, the nucleus of the solitary tract (NTS), receives inputs from the gastrointestinal, respiratory, and cardiovascular systems through the vagus nerve and other neural/humoral pathways. In turn, the NTS projects to diverse higher-order brain regions to generate our perceptions of satiety, hunger, nausea, and visceral pain. Despite the importance of internal sensory systems in health and disease, how neural circuits process visceral signals to regulate behavior and physiology is vastly understudied. Disentangling the highly interconnected brainstem neurons requires a comprehensive analysis of the anatomy, sensory coding, and function of the NTS network to understand the circuit components that mediate individual visceral senses. In Dr. Stephen Liberles’ lab, my initial postdoctoral work deciphered the sensory representations of bodily cues in the NTS. In this proposal, the goal is to determine how internal sensory information, after being processed in the NTS, is sorted into downstream brain regions to control specific aspects of behavior and physiology. First, the neuroanatomical logic by which NTS projections are organized will be investigated (Aim 1). Second, visceral cues transmitted by each projection will be determined using in vivo calcium imaging of NTS projection neurons (Aim 2). Last, the functional roles of NTS projections in controlling behavior and autonomic physiology will be established, with the focus on pathways that mediate physiological satiation (Aim 3). Research in this proposal will be conducted under the guidance of Dr. Stephen Liberles, who pioneered the study of viscerosensory neurons in the vagus nerve using genetic approaches, Dr. Clifford Saper, a leading scientist in the neuroanatomy of the viscerosensory system, and Drs. Bradford Lowell and Eleftheria Maratos-Flier, experts in neural control of appetite and energy metabolism. This proposal will establish a functional atlas of NTS projection neurons in visceral senses, providing insights into our understanding of the neuro-circuitry underlying metabolic homeostasis and strategies to develop targeted treatments for metabolic and viscerosensory disorders.

项目概要/摘要 严格控制代谢稳态的能力对于动物的生存至关重要。 系统监测器官的状态，提供反馈信号，使大脑维持体内平衡 例如，系统通过执行行为和生理反应来检测和编码。 胃肠道信号指示进餐期间摄入食物的质量和数量，以控制进食行为， 消化生理学和监测全身代谢的内部感觉系统失调。 消化系统可导致多种疾病，包括肥胖、糖尿病、厌食症等。 脑干中的网关，孤束核（NTS），接收来自胃肠道的输入， 反过来，通过迷走神经和其他神经/体液通路影响呼吸和心血管系统。 NTS 投射到不同的高阶大脑区域，以产生我们对饱腹感、饥饿感、恶心感、 尽管内部感觉系统在健康和疾病中很重要，但神经回路如何发挥作用？ 处理内脏信号来调节行为和生理学的研究还很少。 相互连接的脑干神经元需要对解剖学、感觉编码和神经元进行全面分析。 NTS 网络的功能是为了了解调节个体内脏感觉的电路组件。 在斯蒂芬·利伯莱斯的实验室，我最初的博士后工作破译了身体线索的感官表征 在该提案中，目标是确定内部感觉信息在处理后如何进行。 NTS，被分类为下游大脑区域来控制行为和生理的特定方面。 将研究组织 NTS 投射的神经解剖学逻辑（目标 1）。 每个投射传递的线索将使用 NTS 投射神经元的体内钙成像来确定 （目标 2）最后，NTS 预测在控制行为和自主生理学中的功能作用是 建立，重点关注介导生理饱足感的途径（本提案中的研究目标 3）。 将在 Stephen Liberles 博士的指导下进行，他是内脏感觉研究的先驱 神经解剖学领域的顶尖科学家 Clifford Saper 博士使用遗传方法研究迷走神经中的神经元 内脏感觉系统专家 Bradford Lowell 和 Eleftheria Maratos-Flier 博士是神经控制领域的专家 该提案将建立 NTS 投射神经元的功能图谱。 内脏感觉，为我们对代谢基础神经回路的理解提供了见解 体内平衡和开发针对代谢和内脏感觉疾病的靶向治疗的策略。