Adiponectin regulation of the mesolimbic dopamine system

描述(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底物。这个系统的功能障碍与几种精神疾病有关，包括进食障碍、药物滥用、精神分裂症和抑郁症。最近的研究表明，肥胖状况和脂肪衍生的荷尔蒙，被称为“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VTA多巴胺神经元表达脂联素受体1(AdipoR1)，这表明脂联素与中脑边缘多巴胺系统具有功能相互作用。本项目拟进行的研究是为了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的活性。为了验证这一点，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中多巴胺释放的影响，伏核是VTA多巴胺神经元的主要靶点之一。其次，我们将建立在多巴胺神经元中特异性缺失AdipoR1的条件性基因敲除小鼠，并确定这些突变小鼠的VTA多巴胺神经元的放电特性以及多巴胺的外流。这些研究将为调节中脑边缘多巴胺途径提供新的信息，并对精神疾病，特别是与代谢综合征相关的疾病，如肥胖和糖尿病的多巴胺相关过程提供新的见解。

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.