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

多巴胺受体表达的皮层投射回路在认知灵活性中的作用 摘要 多巴胺是认知灵活性的关键神经调节器，认知灵活性对日常活动至关重要， 并高效地实现目标。多巴胺功能障碍会导致灵活性的破坏，这是 与许多中枢神经系统疾病有关，如精神分裂症、强迫症和药物成瘾。前额叶 皮层(PFC)锥体神经元及其向纹状体的投射在调节 认知灵活性。PFC神经元上的多巴胺和多巴胺受体也在 调节认知灵活性。我们最近的发现显示了一种以前未被认识到的地形 表达PFC锥体神经元和回路的多巴胺受体的组织。然而， 这些PFC多巴胺受体回路对认知灵活性的影响尚不清楚。我们的目标是 剖析这些不同的多巴胺受体皮质纹状体回路的功能作用。在这 建议，我们将使用跨学科的方法(药理学、神经元追踪、行为和纤维 光度学)，以检验不同地形组织的D2R+或D2R+或 D1R+PFC亚通路对认知灵活性和纹状体多巴胺有不同的调节作用。在……里面 目标1，使用交叉化学发生方法，我们将操纵D1R+子电路 投射到不同的皮质下目标，并测试它们对行为灵活性和纹状体的影响 多巴胺。在目标2中，使用交叉化学发生方法，我们将操纵D2R+亚基 投射到不同的皮质下靶点的回路，并测试它们对行为灵活性和 纹状体多巴胺。我们的研究将极大地促进我们对当地和全球 大脑皮层多巴胺和多巴胺受体的回路效应及其在正常大脑中的作用 以及认知灵活性的病理性调节。我们的研究也将提供一个强有力的理论基础 在未来的研究中，更好地针对皮质-纹状体环路治疗认知障碍。

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.