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

表达多巴胺受体的皮质投射电路在认知灵活性中的作用

基本信息

批准号：
10451272
负责人：
Nikhil Urs
金额：
$ 19.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-10 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451272
关键词：
Behavior Behavioral Biology Brain Brain Diseases Cell Nucleus Central Nervous System Diseases Cognition Cognitive Corpus striatum structure DRD2 gene Data Dopamine Dopamine Receptor Drug Addiction Fiber Foundations Functional disorder Future GTP-Binding Protein alpha Subunits, Gs Glutamates Goals Impairment Individual Medial Mediating Mental disorders Midbrain structure Modeling Molecular Molecular Profiling Neuromodulator Neurons Nucleus Accumbens Obsessive-Compulsive Disorder Outcome Pathologic Pattern Pharmacology Photometry Play Prefrontal Cortex Regulation Reversal Learning Role Schizophrenia Specificity Substance Use Disorder Substantia nigra structure Testing Therapeutic Time Work Yin base behavioral impairment cell type cognitive reappraisal combinatorial dalton designer receptors exclusively activated by designer drugs flexibility hippocampal pyramidal neuron innovation interdisciplinary approach neuroregulation new therapeutic target novel strategies pars compacta

项目摘要

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.

表达多巴胺受体的皮质投射电路在认知灵活性中的作用抽象的多巴胺是认知灵活性的重要神经调节剂，这对于日常活动至关重要，并高效地实现目标。多巴胺功能障碍会导致灵活性受损，这是与许多中枢神经系统疾病有关，例如精神分裂症、强迫症和毒瘾。前额叶皮层（PFC）锥体神经元及其向纹状体的投射对于调节至关重要认知灵活性。 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以前未被重视的地形表达 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。在这个建议，我们将使用跨学科的方法（药理学、神经元追踪、行为和纤维光度测定）来测试中心假设，即不同的地形组织 D2R+ 或 D1R+ PFC 子电路差异性地调节认知灵活性和纹状体多巴胺。在目标 1，使用交叉化学遗传学方法，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，使用交叉化学遗传学方法，我们将操纵 D2R+ 子投射到不同皮层下目标的电路，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增进我们对当地和全球的理解皮质多巴胺和多巴胺受体的回路效应，并了解它们在正常情况下的作用和认知灵活性的病理调节。我们的研究也将提供强有力的理由以便未来的研究更好地针对皮质纹状体回路来治疗认知不灵活性。