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Dissecting contributions of different D2R populations to activity and appetite

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PROJECT SUMMARY/ABSTRACT The dopamine D2 receptor (D2R) is recognized to play a central role in a variety of normal, adaptive behaviors and its dysregulation is thought to play a role in a number of neuropsychiatric disorders, including addiction, obesity, schizophrenia and Parkinson's disease. However, because it is ubiquitously expressed on different cell populations, playing different functional roles across most neural substrates, it has historically been difficult to isolate different populations of D2R and determine their precise contribution to health and disease. As evidence suggests that D2R expression is reduced in addiction and obesity, it has received widespread attention as a candidate for mediating compulsive behavior. Much of this work, however, has neglected to incorporate and assess effects of D2R signaling on activity and behavioral energy expenditure, resulting in a limited view of D2R and its role in behavioral regulation and energy balance. In the proposed studies, we focus on the role of D2R in the regulation of voluntary activity and appetitive motivation and use mouse genetic tools to selectively manipulate D2R on different populations of cells within striatal microcircuits. We will separately examine the relative contribution of: (i) postsynaptic D2R expressed on indirect pathway medium spiny neurons, (ii) D2R on cholinergic neurons, (iii) dopamine cell D2R autoreceptors and (iv) presynaptic D2Rs expressed on incoming glutamatergic cortical afferents. We will assess evoked dopamine release using fast-scan cyclic voltammetry and in autoreceptor manipulations use indirect calorimetry to assess for dopamine mediated alterations in metabolic rate. The proposed work will provide detailed, cell-specific insight that is currently lacking on mechanisms of D2R regulation of activity and appetitive motivation. As our recently published work has demonstrated that reduction of D2R disproportionately alters regulation of activity rather than appetitive motivation, the proposed work will likely contribute to the development of a better conceptual framework for examining dopaminergic regulation of voluntary activity, a relatively understudied aspect of dopamine function in health and disease. Finally, by identifying the contribution of specific populations of D2R, the proposed work may open up new avenues for the exploration and development of novel therapeutics targeting behavioral energy expenditure, potentially relevant to a number of neuropsychiatric disorders, such as schizophrenia and depression, as well as obesity and energy balance.
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