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，他们的 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。大脑皮层儿茶酚胺和前额叶(PFC)多巴胺 受体是认知灵活性和目标导向行为的有力调节器。除了……之外 在这些皮质机制中，纹状体多巴胺是动机行为所必需的(Yen等人， 然而，PFC预测的细胞、分子和特定于投影的异质性 PFC儿茶酚胺对基底节的影响，以及它们如何调节纹状体 多巴胺和动机行为，目前还不清楚。通过以下方式更好地理解这些机制 PFC和PFC儿茶酚胺信号调节皮质-基底节回路可能导致 提供新的治疗方法，以解决神经和精神疾病患者的认知功能障碍 精神障碍。我们的中心假设是皮质去甲肾上腺素和多巴胺起作用 PFC D2R在调节纹状体多巴胺动态和动机行为中的不同作用 和D1R子电路。我们的目标是使用交叉化学遗传学，纤维光度学和 解释网络和皮层儿茶酚胺在动机调节中的作用的行为 行为和纹状体多巴胺动态。我们将使用以下三种方法来验证我们的假设 目的：1)确定去甲肾上腺素转运体对认知灵活性和 纹状体多巴胺动态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 D2R锥体神经元亚群与纹状体多巴胺和认知灵活性有关。 R01提案的结果将提供一个完善的分子和解剖学框架 描述单个PFC儿茶酚胺在调节PFC D1/D2R中的功能作用 环路、纹状体多巴胺动态和动机行为。鉴于儿茶酚胺 功能障碍是痴呆、神经性和神经精神病症认知病理的核心 疾病，我们的结果可能揭示发展分子和 针对这些疾病的基于电路的疗法。

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.