Project Summary / Abstract The primary objective of this proposal is to expand on our current R01 project (parent award R01AA029258), which investigates astrocyte-neuron interaction in the dorsal striatum during ethanol seeking behaviors. Our laboratory previously demonstrated that heightened astrocyte activity in the Dorsal Medial Striatum (DMS) contributes to the transition from habitual behaviors to goal-directed behaviors. This discovery suggests a potential method to reverse maladjusted reward-seeking behavior patters observed in various psychopathologies, including addition. Within the scope of parent R01 award, our proposal aims to explore the prelimbic and orbital frontal cortices (PL, OFC). These regions are pivotal in decision making and reward economics, respectively, providing the majority of glutamatergic input into the DMS. By targeting these areas, we aim to increase DMS astrocyte activity, and consequently rescue behavior. However, whether increased activity in these pathways, specifically targeting the DMS, leads to upregulated activity in DMS astrocytes remains unexplored. Based on our findings, we anticipate that by enhancing cortical-striatal pathway activity, we can promote the shift from habitual to goal-directed behaviors. In line with the parent award’s focus on examining astrocyte-neuron interactions in ethanol seeking behaviors, we propose two aims. First (Aim 1), we will assess if activation of PL or OFC neurons projecting specifically to the DMS leads to increased DMS astrocyte calcium dynamics and alters ethanol consumption. Next (Aim 2) we will examine cortical neuron populations projecting specifically to the DMS during reward learning to determine when these regions are uniquely necessary. Finally, we will once again increase activity from either the PL or OFC to the DMS during reward devaluation to examine whether upregulated activity facilitates the transition from habitual to goal- seeking behaviors. To foster development and training for Dr. Mathew Lopez who is eligible for diversity supplement support, he will receive guidance and support from Dr. Choi. In addition, a mentoring advisory board comprising esteemed scientist and physician-scientist from the Mayo Clinic will provide structured career development and scientific advice as detailed in the mentoring plan. Matthew will participate in career development workshops, present at scientific conferences and local seminars, with an expectation of two publications per year. This work aims to pave the way for Matthew’s future NIH extramural funding, targeting K99/R00.