Astrocyte-Neuron Interaction in the Dorsal Striatum and Ethanol-Seeking Behaviors

项目摘要 我们的主要目标是研究星形胶质细胞在背侧纹状体（DS）中的作用， 调节小鼠的目标导向和习惯性奖励寻求行为。DS在以下方面发挥着关键作用： 形成目标导向和习惯性行为，这是奖励依赖的主要决定因素 决策过程靠近突触环境的星形胶质细胞突起清除谷氨酸， 保护神经元免受兴奋性毒性的伤害我们最近的研究表明， 背内侧纹状体（DMS）星形胶质细胞增强间接中型棘神经元（iMSN）的活性， 而不是DMS中的dMSN。已知DMS调节目标导向的行为，如损伤或失活 的DMS呈现行为习惯，而不是目标导向。相反，背外侧纹状体（DLS）是 作为损伤或DLS暂时失活的习惯性行为所必需的目标偏差行为- 指导行动。由于GABA能iMSNs投射到外部苍白球（GPe），我们还检查了 星形胶质细胞在GPe中的作用。有趣的是，DMS和GPe的化学发生性星形胶质细胞活化 促进从习惯性到目标导向的乙醇寻求行为的转变。然而， DMS-GPe或DLS-GPe回路中的星形胶质细胞在调节习惯性乙醇寻求行为中没有 被探索。基于我们的发现，我们假设星形胶质细胞的活动差异调节MSN DMS和DLS中的活动，从而决定目标导向和习惯性乙醇寻求行为。到 研究这个假设，我们提出三个目标。首先，我们将确定星形胶质细胞的激活 活动差异调节酒精诱导的谷氨酸能和GABA能信号转导的变化， DMS和DLS。其次，我们计划研究DMS和DLS星形胶质细胞激活在目标- 定向的或习惯性的乙醇寻求行为。最后，我们将研究消融DMS的效果- GPe和DLS-GPe回路在目标导向或习惯性乙醇寻求行为中的作用我们的研究将阐明 编码目标导向和习惯性含乙醇奖励寻求行为的神经机制。 我们将为开发治疗AUD的新治疗方法提供一条合理的途径。

Project Summary The main goal of our proposal is to investigate the role of astrocytes in the dorsal striatum (DS), which regulates goal-directed and habitual reward-seeking behaviors in mice. The DS has a critical role in shaping goal-directed and habitual actions, which are the main determinants for the reward-dependent decision-making process. Astrocytic processes in close proximity to the synaptic milieu clear glutamate, which protects neurons from excitotoxicity. Our recent studies revealed that chemogenetic activation of dorsomedial striatum (DMS) astrocyte enhances the activities of indirect medium spiny neurons (iMSNs), but not dMSNs in the DMS. The DMS is known to regulate goal-directed actions as lesions or inactivation of DMS render actions habitual instead of goal-directed. Conversely, the dorsolateral striatum (DLS) is necessary for habitual actions as lesions or temporary inactivation of DLS bias behavior towards goal- directed actions. Since GABAergic iMSNs project to external globus pallidus (GPe), we also examined the role of astrocyte in the GPe. Interestingly, both chemogenetic astrocyte activation of DMS and GPe promotes transition from habitual to goal-directed ethanol-seeking behaviors. However, the precise role of astrocytes in the DMS-GPe or DLS-GPe circuits in regulating habitual ethanol seeking behavior has not been explored. Based on our findings, we hypothesize that astrocyte activities differentially regulate MSNs activities in the DMS and DLS, thereby determine goal-directed and habitual ethanol-seeking behaviors. To investigate this hypothesis, we propose three aims. First, we will determine how activation of astrocyte activities differentially regulates the alcohol-induced changes in glutamatergic and GABAergic signaling of the DMS and DLS. Second, we plan to examine the role of DMS and DLS astrocyte activation in goal- directed or habitual ethanol-seeking behaviors. Finally, we will investigate the effect of ablation of DMS- GPe and DLS-GPe circuits in goal-directed or habitual ethanol-seeking behaviors. Our study will elucidate the neural mechanisms encoding goal-directed and habitual ethanol-containing reward-seeking behaviors. We will provide a rational path for the development of new therapeutic methods for the treatment of AUD.