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.

项目摘要/摘要多巴胺D2受体（D2R）被认为在多种正常的适应性中起着核心作用行为及其失调被认为在许多神经精神疾病中发挥作用，包括成瘾，肥胖，精神分裂症和帕金森氏病。但是，因为它无处不在不同的细胞群体，在大多数神经底物中扮演不同的功能角色，它具有历史很难隔离不同的D2R人群，并确定其对健康的精确贡献疾病。正如证据表明，D2R表达在成瘾和肥胖症中降低，已收到作为介导强迫行为的候选者的广泛关注。但是，这项工作的大部分被忽略的是合并和评估D2R信号对活动和行为能量消耗的影响，导致对D2R的有限观点及其在行为调节和能量平衡中的作用。在提议中研究，我们专注于D2R在调节自愿活动和食用动机和使用中的作用小鼠遗传工具可在纹状体微电路中选择性地操纵D2R的D2R。我们将分别检查：（i）在间接途径上表达的突触后D2R的相对贡献中刺神经元，（ii）D2R在胆碱能神经元上，（iii）多巴胺细胞D2R自身受体和（iv）在传入的谷氨酸能皮质传入中表达的突触前D2R。我们将评估诱发的多巴胺使用快速扫描的循环伏安法释放，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，特定于细胞的见解，目前缺乏有关机制 D2R活动和食欲动机的调节。正如我们最近发表的工作表明 D2R的减少不成比例地改变了活动的调节，而不是食欲动机，该提议工作可能有助于开发更好的概念框架来检查多巴胺能自愿活动的调节，这是健康和疾病中多巴胺功能的相对研究。最后，通过确定D2R的特定人群的贡献，拟议的工作可能会打开新的针对行为能量消耗的新型治疗学探索和开发的途径，可能与许多神经精神疾病有关，例如精神分裂症和抑郁症作为肥胖和能量平衡。