Role of Dopamine receptor-expressing cortical projection circuits in cognitive flexibility

多巴胺受体表达皮层投射回路在认知灵活性中的作用

Role of Dopamine receptor-expressing cortical projection circuits in cognitive flexibility Abstract Dopamine is a crucial neuromodulator of cognitive flexibility, which is essential for daily activities, and achieving goals efficiently. Dopamine dysfunction leads to disruption in flexibility, which is implicated in many CNS disorders such as schizophrenia, OCD, and drug addiction. Prefrontal cortex (PFC) pyramidal neurons and their projections to the striatum are critical in regulating cognitive flexibility. Dopamine and dopamine receptors on PFC neurons also play a critical role in regulating cognitive flexibility. Our recent findings show a previously unappreciated topographical organization of dopamine receptor expressing PFC pyramidal neurons and circuits. However, the effects of these PFC dopamine receptor circuits on cognitive flexibility is not known. Our goal is to dissect the functional role of these distinct dopamine receptor cortico-striatal circuits. In this proposal, we will use an interdisciplinary approach (pharmacology, neuron tracing, behavior and fiber photometry) to test the central hypothesis that distinct topographically-organized D2R+ or D1R+ PFC subcircuits differentially regulate cognitive flexibility and striatal dopamine. In Aim 1, using intersectional chemogenetic approaches, we will manipulate D1R+ sub-circuits that project to distinct subcortical targets, and test their effects on behavioral flexibility and striatal dopamine. In Aim 2, using intersectional chemogenetic approaches, we will manipulate D2R+ sub- circuits that project to distinct subcortical targets, and test their effects on behavioral flexibility and striatal dopamine. Our studies will significantly advance our understanding of the local and global circuit effects of cortical dopamine and dopamine receptors, and understand their role in normal and pathological regulation of cognitive flexibility. Our studies will also provide a strong rationale for future studies to better target cortico-striatal circuits in the treatment of cognitive inflexibility.