BRAIN Initiative K99 Project

BRAIN Initiative K99 项目

• 批准号: 10268063
• 负责人: Veronica A Alvarez
• 金额: $ 5.4万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268063
• 关键词: BRAIN initiative; Behavior; Brain region; Cells; Complex; Corpus striatum structure; Disease; Dopamine D2 Receptor; Eating; Energy Intake; Feeding behaviors; Food Intake Regulation; Globus Pallidus; Hypothalamic structure; Lateral; Link; Mediating; Methods; Motivation; Neurons; Nucleus Accumbens; Obesity; Pathway interactions; Research; Rewards; Role; Techniques; Training; Ventral Striatum; Viral; behavioral study; brain pathway; cell type; energy balance; feeding; food consumption; gamma-Aminobutyric Acid; hedonic; 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 implicated 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，了解摄食行为背后的神经回路是至关重要的。越来越多的证据支持这样一种观点，即控制卡路里摄入量是复杂的，涉及到享乐主义价值、奖励和动机的计算。因此，它需要大脑中典型的与摄食有关的区域(如下丘脑外侧核)和调节奖赏的区域(如腹侧纹状体)之间的相互作用。虽然已经提出了这些区域的交叉点，但连接这些通路的细胞类型特定电路却知之甚少。这项建议的目的是进一步阐明纹状体到下丘脑外侧连接的细胞类型特定回路，并确定其在进食中的作用，同时获得新的神经元回路映射技术的培训。 有证据表明，纹状体通过与黄体生成素的相互作用来控制取食行为。以前的研究表明，腹侧纹状体，特别是伏隔核壳(NACS)和黄体生成素(LHs)是通过直接通路连接的。然而，初步的追踪和行为学研究已经提出了第二种间接通路，NACS投射到腹侧苍白球(VP)，后者投射到LH区。然而，尽管有这一初步证据，但这种间接途径中的特定细胞类型的神经元回路仍然未知。使用病毒追踪法和化学遗传学方法，我将确定在这个三部分电路的每个组件中所涉及的细胞类型，以及它们如何调节摄食行为。我推测在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内的GABA能细胞，进而抑制LHGABA神经元以便于摄食。 此外，在了解大脑通路和食物摄入行为背后的连接时，这个项目最终将使我们能够更好地了解在肥胖等疾病状态下发生的扰动。