Role of cortical catecholamines in regulating motivated behavior and striatal dopamine

点击翻译按钮获取中文摘要

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.