Modulating the shift from goal-directed to habitual behaviors by manipulation of dopaminergic striatonigral loops

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Cortico-basal ganglia circuits (CBGs) are essential for the learning and automatization of behaviours. CBGs are topographically organized, interact dynamically during learning and share dopamine as a key neurotransmitter. A canonical hypothesis is that reward and behaviours are bridged by dopaminergic neurons that receive input from the reward-mediating ventral striatum and project to the behavior-mediating dorsal striatum. This central hypothesis of spiraling striatal-nigro-striatal loops is plausible and backed up by neuroanatomical and behavioral data. However, it has so far not been addressed at a functional or molecular level. Here, we propose to combine automated operant learning paradigms, optogenetics and single-cell RNA-sequencing to explore this hypothesis at a functional and molecular level.Using our high throughput operant conditioning chambers, we will first measure the dynamics of goal-directed acquisition and stimulus-response based habit formation in a cue-reward contingency task in wildtype mice. We will then use targeted virus-based vectors to optogenetically modulate dopaminergic neurons projecting from the ventral tegmental area (VTA) to the dorsal striatum. The behaviorally assessed mice will then be used to identify the associated molecular changes and cellular identities by analyzing hundreds of samples from relevant brain regions using highly cost-efficient bulk RNA-seq library preparations. Further characterization will be done using single-cell RNA-seq profiles and bulk ATAC-seq profiles from the relevant regions. Finally, we propose to extend these experimental procedures to genetically modified mice that carry humanized or non-functional alleles of Foxp2, a transcription factor associated with speech development and speech evolution. As mice humanized for Foxp2 have been shown to be affected in CBG-dependent learning and automatization, our study will shed light on the function of dopaminergic loops in CBGs as well as their potential role in the evolution and development of human speech.