Understanding the role of striatal cholinergic interneurons in reward and motivation processing

The dopaminergic striatal circuit is a key hub for processing reward and motivation in the brain. The main cell types of this circuit are the medial spiny neurons (MSNs), which are dynamically controlled by the interneurons of the region. Among these, the cholinergic interneurons (CINs) represent only 1-3% of the total neurons of the striatum but potentially exert a fundamental role in controlling the activity of the MSNs and local dopamine release. The overarching objective of this study is to assess the role of CINs in modulating striatal dynamics. Considering their striatal localization and their unique transcriptomic pattern (Chen et al., 2021), CINs represent an appealing cellular target. However, their role in modulating striatal dopamine-dependent functions and reward-related behaviors is not completely understood. In this study, we established a mouse behavioral task (adapted from Yang et al., 2019) sensitive to pharmacological modulation by both dopamine enhancement (GBR12909) and dopamine depletion (Tetrabenazine) to evaluate reward-related behaviors. In addition, we investigated the role of chemogenetic modulation of CINs on this task. Moreover, using fiber photometry, we will investigate the effects of these manipulations on local acetylcholine and dopamine release and their relationship with the behavioral readouts. Next, we will study the impact of knocking down molecular targets enriched in CINs to evaluate if this neuronal subtype can be targeted to develop novel therapeutics for treating reward processing deficits in patients suffering from disorders such as major depression and schizophrenia.