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

项目摘要 我们建议的主要目的是研究星形胶质细胞在背侧纹状体(DS)中的作用，这是 调节小鼠的目标导向和习惯性的奖赏行为。DS在以下方面发挥了关键作用 塑造目标导向和习惯性行为，这是奖励依赖型的主要决定因素 决策过程。星形细胞突起靠近突触周围的透明谷氨酸， 它能保护神经元免受兴奋性毒性。我们最近的研究表明，细胞的化学生成激活 背内侧纹状体(DMS)星形胶质细胞增强间接中棘神经元(IMSN)的活动， 但不是DMS中的DMSN。众所周知，DMS将目标导向的行为调节为损伤或失活 的DMS使行为习惯性，而不是目标导向。相反，背外侧纹状体(DLS) 对于习惯性行为是必要的，如损害或暂时停用DLS偏向目标的行为- 定向操作。由于GABA能iMSN投射到苍白球外区(GPE)，我们还观察了 星形胶质细胞在GPE中的作用。有趣的是，DMS和GPE的星形胶质细胞的化学发生激活 促进从习惯性的酒精寻觅行为向目标导向的行为转变。然而，它的确切作用是 星形胶质细胞在调节习惯性酒精寻求行为的DMS-GPE或DLS-GPE回路中没有 已经被探索过了。根据我们的发现，我们假设星形胶质细胞的活动对MSN有不同的调节作用。 DMS和DLS中的活动，从而决定了目标导向和习惯性的酒精寻求行为。至 考察这一假说，我们提出了三个目标。首先，我们将确定星形胶质细胞的激活 不同活性对酒精诱导的大鼠脑内谷氨酸和GABA能信号的调节作用 DMS和DLS。第二，我们计划研究DMS和DLS星形胶质细胞激活在Goal- 定向的或习惯性的酒精寻觅行为。最后，我们将研究DMS的消融效果。 GPE和DLS-GPE在目标导向或习惯性寻求酒精行为中的回路。我们的研究将阐明 编码目标导向和习惯性含酒精奖赏行为的神经机制。 为开发治疗AUD的新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.