Adiponectin regulation of the mesolimbic dopamine system

脂联素对中脑边缘多巴胺系统的调节

基本信息

批准号：
8228413
负责人：
Daniel Lodge
金额：
$ 22.13万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-22 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8228413
关键词：
Address Adipose tissue Area Behavior Biological Biological Markers Blood Circulation Clinical Diabetes Mellitus Disease Dopamine Drug abuse Eating Disorders Emotional Emotions Endocrine Glands FOS gene Functional disorder Hormones Injection of therapeutic agent Knockout Mice Lead Leptin Link Measures Mediating Mental Depression Mental disorders Metabolic syndrome Microdialysis Microinjections Motivation Mus Mutant Strains Mice Neuraxis Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleus Accumbens Obesity Pathway interactions Pattern Peptides Pharmaceutical Preparations Population Process Property Regulation Rewards Role Schizophrenia Signal Transduction System Testing Transgenic Mice Ventral Tegmental Area adipokines adiponectin base dopamine system dopamine transporter dopaminergic neuron in vivo insight mesolimbic system neurochemistry neuropsychiatry novel peptide hormone receptor relating to nervous system response

项目摘要

DESCRIPTION (provided by applicant): The mesolimbic dopamine system is a major neural substrate for reward, motivation and emotion. Dysfunction of this system has been linked to several psychiatric conditions including eating disorders, drug abuse, schizophrenia and depression. Recent studies suggest adiposity status and adipose-derived hormones, termed "adipokines", modulate motivational and emotional responses. Adiponectin is the most abundant adipokine in circulation that can access the central nervous system. Our preliminary studies demonstrate that adiponectin induces activation of dopamine neurons in the ventral tegmental area (VTA) and that adiponectin receptor 1 (AdipoR1) is expressed in VTA dopamine neurons, suggesting that adiponectin functionally interacts with the mesolimbic dopamine system. The proposed studies in this project are to determine whether adiponectin regulates mesolimbic dopamine activity via interacting with AdipoR1 on dopamine neurons. To test this, we will first determine the effect of exogenous adiponectin on firing properties of VTA dopamine neurons and dopamine release in the nucleus accumbens, one of the major targets of the VTA dopamine neurons. Second, we will generate conditional knockout mice lacking AdipoR1 specifically in dopamine neurons and determine firing properties of VTA dopamine neurons as well as dopamine efflux in these mutant mice. These studies will provide novel information on the regulation of the mesolimbic dopamine pathway and new insights into dopamine-related processes in psychiatric illnesses especially those associated with metabolic syndrome such as obesity and diabetes. PUBLIC HEALTH RELEVANCE: Abnormal dopamine-related processes lead to aberrant reward, motivation and emotion in psychiatric disorders including eating disorders, drug addition, schizophrenia and depression. The proposed studies will enhance our understanding of how the mesolimbic dopamine system is regulated by the adipose-derived hormone adiponectin and will have clinical implications for psychiatric disorders associated with obesity and type 2 diabetes.

描述（由申请人提供）：中脑边缘多巴胺系统是奖励、动机和情感的主要神经基质。该系统的功能障碍与多种精神疾病有关，包括饮食失调、药物滥用、精神分裂症和抑郁症。最近的研究表明，肥胖状态和脂肪源性激素（称为“脂肪因子”）可调节动机和情绪反应。脂联素是循环中最丰富的脂肪因子，可以进入中枢神经系统。我们的初步研究表明，脂联素诱导腹侧被盖区 (VTA) 多巴胺神经元的激活，并且脂联素受体 1 (AdipoR1) 在 VTA 多巴胺神经元中表达，表明脂联素与中脑边缘多巴胺系统有功能性相互作用。该项目拟议的研究是确定脂联素是否通过与多巴胺神经元上的 AdipoR1 相互作用来调节中脑边缘多巴胺活性。为了测试这一点，我们将首先确定外源性脂联素对 VTA 多巴胺神经元的放电特性和伏核（VTA 多巴胺神经元的主要靶标之一）中多巴胺释放的影响。其次，我们将产生在多巴胺神经元中特异性缺乏 AdipoR1 的条件敲除小鼠，并确定这些突变小鼠中 VTA 多巴胺神经元的放电特性以及多巴胺流出。这些研究将提供有关中脑边缘多巴胺通路调节的新信息，以及对精神疾病中多巴胺相关过程的新见解，特别是与肥胖和糖尿病等代谢综合征相关的疾病。公共卫生相关性：异常的多巴胺相关过程会导致精神疾病（包括饮食失调、药物成瘾、精神分裂症和抑郁症）的奖励、动机和情绪异常。拟议的研究将增强我们对脂肪源性激素脂联素如何调节中脑边缘多巴胺系统的理解，并将对与肥胖和 2 型糖尿病相关的精神疾病产生临床意义。