Role of cortical catecholamines in regulating motivated behavior and striatal dopamine

皮质儿茶酚胺在动机行为和纹状体神经元调节中的作用 多巴胺 摘要 认知灵活性和目标导向行为对正常功能至关重要， 功能障碍是多种神经精神疾病的核心，包括与 神经退行性疾病皮质儿茶酚胺和前额叶皮质（PFC）多巴胺 受体是认知灵活性和目标导向行为的有效调节剂。除了 在这些皮质机制中，纹状体多巴胺是动机行为所必需的（Yin等人， 2005年）;然而，PFC预测的细胞、分子和特定预测的异质性 对基底神经节的影响，个别PFC儿茶酚胺的影响，以及它们如何调节纹状体 多巴胺和动机行为的关系尚不清楚。更好地理解机制， PFC和PFC儿茶酚胺信号调节皮质-基底神经节回路可能导致 本发明涉及用于解决神经和神经系统疾病中的认知功能障碍的新的治疗方法， 精神疾病我们的核心假设是皮质去甲肾上腺素和多巴胺 通过PFC D2 R+在调节纹状体多巴胺动力学和动机行为中的不同作用 和D1 R+子电路。我们的目标是使用交叉化学遗传学，纤维光度学， 行为，以破译NET和皮质儿茶酚胺在调节动机性行为中的作用。 行为和纹状体多巴胺动力学。我们将使用以下三种方法来检验我们的假设 目的：1）确定去甲肾上腺素转运蛋白对认知灵活性的贡献， 纹状体多巴胺动力学。2）确定去甲肾上腺素与多巴胺对 认知灵活性和纹状体多巴胺动力学。3)确定PFC D1+的贡献 和D2 R+锥体神经元亚群对纹状体多巴胺和认知灵活性的影响。 R 01提案的结果将提供一个精确的分子和解剖框架 描述单个PFC儿茶酚胺在调节PFC D1/D2 R+中的功能作用 电路，纹状体多巴胺动力学和动机行为。考虑到儿茶酚胺 功能障碍是痴呆、神经学和神经精神学的认知病理学的中心 疾病，我们的研究结果可能揭示新的机制策略，发展分子和 基于回路的治疗方法。

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.