Neural mechanisms of taste and metabolic state integration in the brainstem

脑干味觉和代谢状态整合的神经机制

• 批准号: 10524319
• 负责人: Nilay Yapici
• 金额: $ 71.87万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524319
• 关键词: Acute; Affect; Animals; Area; Behavior; Biology; Brain; Brain Stem; Brain imaging; Brain region; Cell Nucleus; Cerebellum; Code; Collaborations; Consumption; Cranial Nerves; Data Set; Detection; Eating; Evaluation; Feeding behaviors; Food; Homeostasis; Hunger; Hypothalamic structure; Image; Ingestion; Insula of Reil; Knowledge; Lead; Location; Mammals; Mediating; Metabolic; Monitor; Mus; Nerve Fibers; Neurons; Nucleus solitarius; Operative Surgical Procedures; Optics; Organ; Organism; Palate; Pathway interactions; Perception; Peripheral; Pharyngeal structure; Photons; Population; Positioning Attribute; Regulation; Research; Research Personnel; Resolution; Resource Sharing; Sensory; Signal Transduction; Somatostatin; Source; Taste Perception; TimeLine; Tongue; Ventral Tegmental Area; awake; base; behavior measurement; calretinin; design; experimental study; food consumption; food resource; implantation; in vivo calcium imaging; indexing; lens; microendoscope; microendoscopy; neuromechanism; neuronal circuitry; novel; optogenetics; relating to nervous system; response; sugar

ABSTRACT The taste of food is a critical factor that determines whether an organism will accept or reject a food source. In addition, the sensory perception of food taste changes significantly depending on the metabolic state of animals. Despite the significant progress in understanding the homeostatic biology of food intake in the mammalian brain, how metabolic states (e.g., how hungry an animal is) alter the perception of food taste at the level of specific neuronal circuits remains poorly understood. Here, we assembled a team of investigators that will use quantitative measurements of behavior, cutting edge 3P microendoscopy, and optogenetic manipulation of neural activity to study how taste representations in the brainstem are modulated with metabolic state, and how the state dependent activity of brainstem taste circuits contributes to the regulation of ingestive behaviors in mice. Specifically, this new team of investigators will probe the functions and the state dependent activity of two distinct populations of neurons, sugar sensitive calbindin 2- neurons (Calb2) and bitter sensitive somatostatin- neurons (Sst), in the rostral nucleus solitary tract (rNTS), the first central relay station of the taste pathway. In Aim 1 the investigators will develop and optimize a state of the art 3-photon (3P) microendoscope that will allow optical access to Calb2 and Sst neurons in the rNTS at cellular resolution. In Aim 2, the 3P microendoscope will be used to examine the taste responses of Calb2 and Sst neurons in hungry and sated mice to investigate whether sugar or bitter responses are modulated in response to changes in metabolic state. In Aim 3, the investigators will investigate whether acute changes in the hunger state of mice affect the taste representations in the rNTS by artificially modulating the activity of hunger promoting AgRP neurons in the hypothalamus. More specifically, they will record the activity of Calb2 or Sst neurons using the 3P microendoscope, while optogenetically activating or inhibiting AgRP neurons of sated or hungry mice that are offered a sugar solution or sugar plus bitter mixture. The proposed study will provide critical information for understanding a core mechanism of taste and metabolic state integration in the brainstem. It will also allow the team to investigate whether taste coding is modulated in the brainstem based on metabolic state before the information is sent to higher-order gustatory nuclei and to the insula cortex in a feed-forward fashion. Together, the proposed experiments will generate novel knowledge and provide necessary technical and conceptual advances to lay the groundwork for a subsequent Targeted BRAIN Circuits R01 with the same team of investigators aiming to further investigate how brainstem taste circuits communicate with other central gustatory nuclei in a metabolic state dependent manner to control ingestive behaviors in mice.

摘要 食物的味道是决定生物体是否接受或拒绝食物来源的关键因素。在 此外，食物味道的感官感知会根据动物的代谢状态而发生显著变化。 尽管在了解哺乳动物大脑食物摄入的稳态生物学方面取得了重大进展， 代谢状态（例如，动物的饥饿程度）在特定的水平上改变食物味道的感知。 神经回路仍然知之甚少。在这里，我们组建了一个调查小组， 行为的定量测量、尖端3 P显微内窥镜检查和光遗传学操作， 神经活动，研究脑干中的味觉表征如何与代谢状态调制，以及如何 脑干味觉回路的状态依赖性活动有助于调节摄食行为， 小鼠具体来说，这个新的研究小组将探讨两个功能和状态依赖活动， 不同的神经元群体，糖敏感的钙结合蛋白2-神经元（Calb 2）和苦敏感的生长抑素- 神经元（Sst），在嘴侧核孤束（rNTS），味觉通路的第一个中央中继站。在 目的1研究人员将开发和优化最先进的3光子（3 P）显微内窥镜， 以细胞分辨率对rNTS中的Calb 2和Sst神经元进行光学访问。在目标2中，3 P显微内窥镜将 用于检测饥饿和饱足小鼠中Calb 2和Sst神经元的味觉反应，以研究 糖或苦的反应是否响应于代谢状态的变化而被调节。在目标3中， 研究人员将调查小鼠饥饿状态的急性变化是否会影响味觉表征， 在rNTS中通过人工调节下丘脑中促进饥饿的AgRP神经元的活性。更 具体来说，他们将使用3 P显微内窥镜记录Calb 2或Sst神经元的活动， 光遗传学地激活或抑制提供糖溶液的饱足或饥饿小鼠的AgRP神经元 或糖加苦味的混合物。拟议的研究将提供关键信息，以了解一个核心 味觉和脑干代谢状态整合的机制。这也将使小组能够调查 在信息被发送到脑干之前，基于代谢状态，味觉编码是否在脑干中被调制。 高级味觉核团并以前馈的方式传递到大脑皮层。在一起，拟议的 实验将产生新的知识，并提供必要的技术和概念的进步，奠定 为随后的靶向脑回路R 01奠定基础，同一研究团队旨在进一步 研究脑干味觉回路在代谢状态下如何与其他中枢味觉核团通信 依赖性方式控制小鼠摄食行为。