Role of cortical catecholamines in regulating motivated behavior and striatal dopamine

皮质儿茶酚胺在调节动机行为和纹状体多巴胺中的作用

基本信息

批准号：
10659716
负责人：
Nikhil Urs
金额：
$ 35.8万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659716
关键词：
Address Affect Anatomy Basal Ganglia Behavior Biology Brain Catecholamines Cognition Cognitive Corpus striatum structure DRD2 gene Data Dementia Disease Dopamine Dopamine Receptor Exhibits Fiber Functional disorder Ganglia Genetic Goals Heterogeneity Impaired cognition Incentives Individual Knock-out Knockout Mice Lateral Learning Lesion Literature LoxP-flanked allele Medial Mental disorders Midbrain structure Molecular Motivation Mus Neurodegenerative Disorders Neuromodulator Neurons Noise Norepinephrine Nose Outcome Oxidopamine Pathology Pattern Performance Photometry Play Prefrontal Cortex Regulation Reversal Learning Role Signal Transduction Testing Therapeutic Time Yin cognitive enhancement cognitive reappraisal cortical catecholamine dalton designer receptors exclusively activated by designer drugs extracellular flexibility hippocampal pyramidal neuron innovation motivated behavior nervous system disorder neuropsychiatric disorder neuropsychiatry new therapeutic target noradrenaline transporter novel novel therapeutic intervention pharmacologic

项目摘要

Role of cortical catecholamines in regulating motivated behavior and striatal dopamine Abstract Cognitive flexibility and goal-directed behavior are critical for normal functioning, and their dysfunction is central to multiple neuropsychiatric conditions, including dementias associated with neurodegenerative disease. Cortical catecholamines and prefrontal cortical (PFC) dopamine receptors are potent regulators of cognitive flexibility and goal-directed behavior. In addition to these cortical mechanisms, striatal dopamine is necessary for motivated behavior (Yin et al., 2005); however, the cellular, molecular, and projection-specific heterogeneity of PFC projections to the basal ganglia, the impact of individual PFC catecholamines, and how they regulate striatal dopamine and motivated behavior, are not clear. A better understanding of the mechanisms by which PFC and PFC catecholamine signaling regulate cortico-basal ganglia circuitry could lead to novel therapeutic approaches for addressing cognitive dysfunction in neurological and psychiatric disorders. Our central hypothesis is that cortical norepinephrine and dopamine play distinct roles in regulating striatal dopamine dynamics and motivated behavior through PFC D2R+ and D1R+ sub-circuits. Our goal is to use intersectional chemogenetics, fiber photometry and behavior to decipher the roles of NET and cortical catecholamines in the regulation of motivated behavior and striatal dopamine dynamics. We will test our hypothesis using the following three aims: 1) Determine the contributions of the norepinephrine transporter to cognitive flexibility and striatal dopamine dynamics.2) Determine the contributions of norepinephrine vs. dopamine to cognitive flexibility and striatal dopamine dynamics. 3) Determine the contributions of PFC D1+ and D2R+ pyramidal neuron subpopulations to striatal dopamine and cognitive flexibility. The outcomes of this R01 proposal will provide a refined molecular and anatomical framework describing the functional roles of individual PFC catecholamines in regulating PFC D1/D2R+ circuits, striatal dopamine dynamics and motivated behavior. Given that catecholamine dysfunction is central to cognitive pathology of dementias, neurological and neuropsychiatric diseases, our results may reveal novel mechanistic strategies for developing molecular- and circuit-based therapeutics for these disorders.

皮质儿茶酚胺在调节动机行为和纹状体中的作用多巴胺抽象的认知灵活性和目标导向行为对于正常功能至关重要，它们的功能障碍是多种神经精神疾病的核心，包括与以下疾病相关的痴呆：神经退行性疾病。皮质儿茶酚胺和前额皮质 (PFC) 多巴胺受体是认知灵活性和目标导向行为的有效调节器。此外在这些皮质机制中，纹状体多巴胺对于动机行为是必需的（Yin 等人， 2005）；然而，PFC 预测的细胞、分子和预测特异性异质性个别 PFC 儿茶酚胺对基底神经节的影响，以及它们如何调节纹状体多巴胺和动机行为之间的关系尚不清楚。更好地理解机制 PFC 和 PFC 儿茶酚胺信号传导调节皮质基底节电路可能导致解决神经系统和认知功能障碍的新治疗方法精神疾病。我们的中心假设是皮质去甲肾上腺素和多巴胺发挥作用通过 PFC D2R+ 在调节纹状体多巴胺动力学和动机行为中发挥独特作用和D1R+子电路。我们的目标是利用交叉化学遗传学、纤维光度测定法和行为破译 NET 和皮质儿茶酚胺在动机调节中的作用行为和纹状体多巴胺动力学。我们将使用以下三个方法来检验我们的假设目标： 1) 确定去甲肾上腺素转运蛋白对认知灵活性和认知灵活性的贡献纹状体多巴胺动力学。2) 确定去甲肾上腺素与多巴胺对纹状体多巴胺的贡献认知灵活性和纹状体多巴胺动力学。 3) 确定PFC D1+的贡献和 D2R+ 锥体神经元亚群对纹状体多巴胺和认知灵活性的影响。 R01提案的成果将提供一个完善的分子和解剖框架描述各个 PFC 儿茶酚胺在调节 PFC D1/D2R+ 中的功能作用电路、纹状体多巴胺动力学和动机行为。鉴于儿茶酚胺功能障碍是痴呆症、神经病学和神经精神病学认知病理学的核心疾病，我们的结果可能揭示开发分子和疾病的新机制策略针对这些疾病的基于回路的疗法。