Defining the functional organization of cerebellar output circuits that control feeding behavior

定义控制进食行为的小脑输出电路的功能组织

• 批准号: 10352402
• 负责人: John Nicholas Betley
• 金额: $ 55.79万
• 依托单位: SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352402
• 关键词: Address; Anatomy; Appetite Stimulants; Behavior; Behavior Therapy; Behavioral; Biological Assay; Body Weight; Brain; Brain imaging; Brain region; Cerebellar Nuclei; Cerebellum; Cerebral cortex; Cognitive; Complex; Consumption; Data; Development; Eating; Eating Disorders; Feeding behaviors; Food; Functional Magnetic Resonance Imaging; Functional disorder; Gastrointestinal tract structure; Genetic; Goals; Hunger; Hypothalamic structure; Image; Infusion procedures; Lateral; Link; Logic; Maps; Measures; Mediating; Metabolic; Metabolism; Methods; Molecular; Molecular Genetics; Motivation; Motor; Motor Pathways; Mus; Nervous System Trauma; Neurons; Nutrient; Obesity; Output; Pathway interactions; Pattern; Physiological; Population; Prevalence; Process; Property; Public Health; Publishing; Rabies virus; Rewards; Rodent; Role; Satiation; Signal Transduction; Stomach; Structure; Structure of nucleus infundibularis hypothalami; Synapses; Testing; Thalamic structure; Therapeutic; Viral; Weight maintenance regimen; base; calcium indicator; cerebellar lesion; classical conditioning; drug efficacy; drug modification; experimental study; feeding; food consumption; insight; limb movement; motivational processes; motor control; nervous system disorder; novel; obese patients; optogenetics; paraventricular nucleus; rabies viral tracing; reduced food intake; relating to nervous system; reward processing; satiety center; therapeutically effective; tool; treatment strategy; zona incerta

Project Summary In addition to motor and classical conditioning functions, the cerebellum contributes to motivation and reward processes that underlie complex behaviors. To influence non-motor processes, such as feeding and food- seeking behaviors, it is thought that the cerebellum modulates cortical and subcortical feeding centers. The only path through which the cerebellum can influence feeding control is through cerebellar output circuits in the deep cerebellar nuclei (DCN). Yet little is known about how DCN circuits are organized and whether distinct pathways are dedicated to feeding and food-seeking behaviors. The recent identification of discrete subsets of DCN neurons that project to thalamic, subthalamic and hypothalamic brain regions indicates the existence of neural subtype organization to cerebellar output. Based on published and preliminary data, the primary hypotheses of this proposal are that: 1) distinct DCN-mediated pathways project to known feeding centers to influence food intake; and 2) these features identify distinct DCN circuits essential for feeding and/or metabolism; and finally, 3) dedicated DCN-mediated pathways are engaged during feeding, and influence the neural activity of specific neuronal subtypes in key feeding centers. This proposal will test these hypotheses through three aims. Aim 1 delineates distinctions in target selectivity of specific DCN circuits. We will employ conditional viral tracing, and genetic fate-mapping methods to define the output connectivity of DCN subpopulations to feeding centers (paraventricular nucleus, lateral hypothalamus, arcuate nucleus and zona incerta), which we hypothesize influence feeding behavior. Additionally, we will determine if major subclasses of arcuate neurons (e.g. POMC or AgRP) are linked to the DCN with specific Cre-lines and trans-synaptic rabies virus. In Aim 2, we will define the role of DCN circuits in feeding control through optogenetic activation and silencing of discrete neuronal subpopulations in the DCN. Specifically, we will examine how selective neural manipulation of anatomically- defined DCN pathways influences food intake and metabolism, and dissociate output pathways for motor control. Finally, the experiments in Aim 3 will determine the activity profile of discrete DCN neuronal subpopulations, and how activity in these subpopulations changes neural activity of known feeding circuits in freely moving mice during food intake using deep-brain imaging. By defining the anatomical and functional organization of cerebellar output pathways, and their activity dynamics involved in feeding behavior, these aims provide insight into more general mechanisms of how cerebellum controls motivation and reward circuits, and establish a framework for exploring the more enigmatic cognitive roles of the cerebellum. A more comprehensive understanding of cerebellar function will provide greater insight into how neurological disorders and injuries disrupt food intake, and lay the groundwork for development of novel treatment strategies for obesity and eating disorders.

项目摘要 除了运动和经典的条件反射功能，小脑有助于动机和奖励 复杂行为背后的过程影响非运动过程，比如进食和食物- 寻找行为，小脑被认为调节皮层和皮层下的摄食中心。唯一的 小脑影响进食控制的途径是通过深部的小脑输出回路 小脑核（DCN）。然而，关于DCN回路是如何组织的以及不同的通路是否 专门负责觅食和觅食行为。DCN离散子集的最新识别 投射到丘脑、底丘脑和下丘脑脑区的神经元表明神经元的存在。 小脑输出的亚型组织。根据已发表的和初步的数据， 这一建议是：1）不同的DCN介导的途径投射到已知的摄食中心，以影响食物 摄入量;以及2）这些特征识别对于进食和/或代谢必不可少的不同DCN回路;以及最后， 3)专门的DCN介导的通路在进食过程中参与，并影响特定的神经活动。 神经元亚型的关键喂养中心。本提案将通过三个目标来检验这些假设。要求1 描述了特定DCN电路的目标选择性的区别。我们将采用条件病毒追踪， 确定DCN亚群到饲养中心的输出连接性的遗传命运作图方法 （室旁核，外侧下丘脑，弓状核和齿状回），我们假设 影响进食行为。此外，我们将确定弓状神经元的主要亚类（例如POMC） 或AgRP）通过特异性Cre-lines和跨突触狂犬病病毒与DCN连接。在目标2中，我们定义 DCN回路通过离散神经元光遗传学激活和沉默在摄食控制中的作用 DCN中的亚群。具体来说，我们将研究如何选择性神经操纵解剖- 定义的DCN通路影响食物摄入和代谢，并分离用于运动控制的输出通路。 最后，目标3中的实验将确定离散的DCN神经元亚群的活性谱，并且 这些亚群的活动如何改变自由活动小鼠中已知进食回路的神经活动 在食物摄入过程中使用脑深部成像。通过定义小脑的解剖和功能组织， 输出途径，以及它们参与摄食行为的活动动力学，这些目标提供了更多的洞察力。 小脑如何控制动机和奖励回路的一般机制，并建立一个框架， 探索小脑更神秘的认知作用。更全面地了解 小脑功能将为神经系统疾病和损伤如何破坏食物摄入提供更深入的了解， 并为肥胖和饮食失调的新治疗策略的发展奠定基础。