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Dissecting contributions of different D2R populations to activity and appetite

剖析不同 D2R 群体对活动和食欲的贡献

基本信息

批准号：
9514560
负责人：
JEFF A. BEELER
金额：
$ 46.2万
依托单位：
QUEENS COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514560
关键词：
Adaptive Behaviors Appetitive Behavior Attention Autoreceptors Basic Science Behavior Behavioral Cells Compulsive Behavior Corpus striatum structure DRD2 gene Data Desire for food Development Diet Disease Dopamine Dopamine D2 Receptor Drug usage Energy Metabolism Enterobacteria phage P1 Cre recombinase Functional disorder Future Genetic Glutamates Grant Health Hyperphagia Income Indirect Calorimetry Interneurons Knowledge LoxP-flanked allele Mediating Mental Depression Motivation Mus Neurons Obesity Parkinson Disease Pathologic Pathway interactions Periodicity Pharmaceutical Preparations Phenotype Play Population Publishing Receptor Signaling Regulation Rodent Role Running Scanning Schizophrenia Synapses Testing Thinness Tissues Work addiction behavioral study cell type cholinergic cholinergic neuron clinical practice dopaminergic neuron energy balance increased appetite insight knock-down metabolic rate neglect neuropsychiatric disorder new therapeutic target postsynaptic presynaptic receptor expression relating to nervous system therapeutic development tool

项目摘要

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.

项目总结/摘要多巴胺D2受体（D2 R）被认为在多种正常的、适应性的神经系统中起核心作用。行为及其失调被认为在许多神经精神疾病中起作用，包括成瘾、肥胖、精神分裂症和帕金森病。然而，由于它在不同的细胞群，在大多数神经基质中发挥不同的功能作用，很难分离不同的D2 R人群并确定其对健康的确切贡献，疾病有证据表明，成瘾和肥胖症患者的D2 R表达减少，因此它已被接受作为一个调解强迫行为的候选人而受到广泛关注。然而，这项工作的大部分忽视了纳入和评估D2 R信号对活动和行为能量消耗的影响，导致对D2 R及其在行为调节和能量平衡中的作用的有限认识。拟议研究中，我们重点关注D2 R在调节自愿活动和食欲动机和使用中的作用小鼠遗传工具来选择性地操纵纹状体微电路内不同细胞群上的D2 R。我们将单独检查以下各项的相对贡献：（i）间接途径上表达的突触后D2 R 中棘神经元，（ii）胆碱能神经元上的D2 R，（iii）多巴胺细胞D2 R自身受体和（iv）突触前D2 Rs在传入的多巴胺能皮质传入神经上表达。我们将评估诱发的多巴胺释放使用快速扫描循环伏安法，在自身受体操作中使用间接量热法，评估多巴胺介导的代谢率改变。拟议的工作将提供详细的，细胞特异性的见解，目前缺乏的机制， D2 R调节活动和食欲动机。正如我们最近发表的研究所表明的那样， D2 R的减少不成比例地改变了活动的调节，而不是食欲动机，这项工作可能有助于发展一个更好的概念框架，调节随意活动，这是多巴胺在健康和疾病中功能的一个相对未充分研究的方面。最后，通过确定D2 R特定群体的贡献，拟议的工作可能会开辟新的探索和开发针对行为能量消耗的新疗法的途径，也可能与许多神经精神疾病有关，如精神分裂症和抑郁症，肥胖和能量平衡。