Adiponectin regulation of the mesolimbic dopamine system

描述（由申请人提供）：中脑边缘多巴胺系统是奖励、动机和情绪的主要神经基质。这一系统的功能障碍与几种精神疾病有关，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”，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）的多巴胺神经元的激活，脂联素受体1（AdipoR1）在VTA多巴胺神经元中表达，表明脂联素功能与中脑边缘多巴胺系统相互作用。本项目拟研究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腹侧被盖区多巴胺神经元的放电特性和腹侧被盖区多巴胺神经元的主要靶点之一延髓核中多巴胺释放的影响。其次，我们将产生条件性敲除小鼠缺乏特异性的多巴胺神经元AdipoR1，并确定这些突变小鼠的腹侧被盖区多巴胺神经元的放电特性以及多巴胺外排。这些研究将为调节中脑边缘多巴胺通路提供新的信息，并为精神疾病中多巴胺相关过程提供新的见解，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导致异常的奖励，动机和情绪的精神疾病，包括进食障碍，药物添加，精神分裂症和抑郁症。拟议的研究将增强我们对中脑边缘多巴胺系统如何受脂肪源性激素脂联素调节的理解，并将对与肥胖和2型糖尿病相关的精神疾病具有临床意义。

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.