Mapping the neuronal circuitry underlying indirect striatal to hypothalamic connectivity and its role in feeding

绘制间接纹状体与下丘脑连接的神经元回路及其在进食中的作用

• 批准号: 10426513
• 负责人: Miriam E. Bocarsly
• 金额: $ 24.9万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426513
• 关键词: Address; Automobile Driving; Autopsy; Behavior; Behavioral; Brain region; Cells; Complex; Corpus striatum structure; Data; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Eating; Energy Intake; Feeding behaviors; Food Intake Regulation; Globus Pallidus; Glutamates; Hypothalamic structure; LH Cell; Lateral; Lesion; Link; Literature; Maps; Mediating; Methods; Motivation; Neurons; Nucleus Accumbens; Obesity; Pathway interactions; Pharmacology; Phenotype; Population; Positioning Attribute; Regulation; Research; Rewards; Role; Synapses; Techniques; Testing; Tissues; Training; Transgenic Mice; Ventral Striatum; Viral; behavioral study; brain pathway; career; cell type; designer receptors exclusively activated by designer drugs; energy balance; experience; feeding; food consumption; gamma-Aminobutyric Acid; hedonic; hypocretin; melanin-concentrating hormone; nerve supply; neuronal circuitry

Food consumption is fundamental to species survival and understanding the neuronal circuitry underlying feeding behaviors is of the utmost importance. Amassing evidence supports the idea that control of caloric intake is complex and involves calculations of hedonic value, reward and motivation. Thus, it requires interactions between brain regions classically implemented in feeding (such as the lateral hypothalamus; LH) and the regions modulating reward (such as the ventral striatum). While the intersection of these regions has been suggested, the cell-type specific circuitry linking these pathways is poorly understood. The objective of this proposal is to further elucidate the cell-type specific circuitry underlying striatal-to-lateral hypothalamic connections and determine its role in feeding, while gaining training in new neuronal circuitry mapping techniques. There is evidence that the striatum exerts its control over feeding behaviors by interfacing with the LH. Previous research indicates that the ventral striatum, and specifically the nucleus accumbens shell (NAcS), and the LH are connected via a direct pathway. However, rudimentary tracing and behavioral studies have suggested a second, indirect pathway, with the NAcS projecting to the ventral pallidum (VP), which in turn projects to the LH. However, despite this initial evidence, cell-type specific, neuronal circuitry in this indirect pathway remains unknown. Using viral tracing methods and chemogenetic approaches I will determine the cell-types implicated in each component of this three-part circuitry, and how they mediate feeding behaviors. I hypothesize that GABAergic striatal projection neurons expressing the dopamine D2 receptor in the NAcS preferentially innervate GABAergic cells in the VP, which in turn disinhibit LH GABA neurons to facilitate feeding. Furthermore, in understanding the brain pathways and connectivity underlying food intake behaviors, this project will ultimately allow us to better understand perturbations that occur in disease states such as obesity.

食物消耗是物种生存和了解基础神经元电路的基础 喂养行为至关重要。积累证据支持控制热量的想法 摄入量很复杂，涉及享乐价值，奖励和动机的计算。因此，它需要 在喂养中经典实施的大脑区域之间的相互作用（例如下丘脑侧; LH） 以及调节奖励的区域（例如腹侧纹状体）。而这些地区的交集有 提出，连接这些途径的细胞类型特异性电路对这些途径的了解很少。目的 该提议是为了进一步阐明纹状体到侧面下丘脑的细胞类型特异性电路 连接并确定其在进食中的作用，同时在新的神经元电路映射中进行培训 技术。 有证据表明，纹状体通过与LH接口对喂养行为产生了控制。 先前的研究表明，腹侧纹状体，特别是伏隔核（NACS），， LH通过直接途径连接。但是，基本的追踪和行为研究具有 建议使用第二个间接途径，NACS投射到腹侧颗粒（VP），又 向LH的项目。然而，尽管有这些初步证据，但在此间接中，细胞类型的特异性神经元回路 途径仍然未知。使用病毒追踪方法和化学发生方法，我将确定 细胞类型与该三部分电路的每个组成部分有关，以及它们如何介导喂养行为。我 假设表达NAC中表达多巴胺D2受体的GABA能纹状体投影神经元 优先在VP中支配GABA能细胞，而VP又可以抑制LH GABA神经元以促进 进食。 此外，在了解食物摄入行为的大脑通路和连通性时， 项目最终将使我们能够更好地理解肥胖症等疾病状态中发生的扰动。