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的基础，也是理解其背后的神经回路的基础。 摄食行为是最重要的。大量的证据支持这样的观点， 摄入是复杂的，涉及到享乐价值、奖励和动机的计算。因此，它要求 进食过程中典型脑区之间的相互作用（如外侧下丘脑; LH） 以及调节奖赏的区域（如腹侧纹状体）。虽然这些区域的交叉点 尽管已经有人提出，但连接这些通路的细胞类型特异性电路却知之甚少。的目标 本研究旨在进一步阐明下丘脑纹状体至外侧核的细胞类型特异性回路， 连接，并确定其在喂养中的作用，同时获得新的神经元回路映射的培训 技术. 有证据表明，纹状体通过与LH相互作用来控制进食行为。 先前的研究表明，腹侧纹状体，特别是核壳（NAcS）， 和LH通过直接通路连接。然而，基本的追踪和行为研究 提出了第二个间接途径，NAcS投射到腹侧苍白球（VP）， 项目到LH。然而，尽管有这一初步证据，细胞类型特异性，神经元回路在这一间接 路径仍然未知。使用病毒追踪方法和化学遗传学方法，我将确定 涉及这三部分电路的每个组件的细胞类型，以及它们如何介导进食行为。我 假设在NAcS中表达多巴胺D2受体的GABA能纹状体投射神经元 优先支配VP中的GABA能细胞，这反过来又解除LH GABA神经元的抑制，以促进 喂食 此外，在理解食物摄入行为背后的大脑通路和连通性时， 该项目最终将使我们能够更好地了解在肥胖等疾病状态中发生的扰动。