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

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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.