CNS Pathways Regulating Ghrelin Effects on Body Weight

描述（由申请人提供）：下丘脑弓状核中的两种不同的肽能（POMC和NPY/AgRP）神经元群对代谢信号（如瘦素）作出反应。另一种重要的代谢激素，生长激素释放肽，已被确定为调节食物摄入量和体重。有证据表明，中枢神经系统神经元群是ghrelin的靶点。这包括弓状核中的NPY/AgRP神经元。该项目将采用最先进的功能神经解剖学技术，包括束跟踪，生长激素释放肽诱导的基因表达，使用原位杂交组织化学，和神经元表型的化学鉴定（单独和组合），以确定生长激素释放肽反应神经元的解剖投影。我们将确定表达NPY/AGRP和POMC/CART的弓状神经元和视交叉后神经元中的ghrelin反应神经元群体投射到包括脊髓、迷走神经背侧运动核、下丘脑外侧区和室旁核在内的部位的程度，这些部位可能在激活ghrelin激活的传出通路中发挥独特的作用。我们将直接测试的假设，生长激素释放肽受体表达仅在弓状核，下丘脑腹内侧核，迷走神经背侧复合体的神经元是足以介导的生长激素释放肽的影响，以增加食物摄入量和减少能量消耗。为了实现这一点，我们将使用一种新的小鼠模型，是空的生长激素释放肽受体表达。制备小鼠，使得Crerecombinase的作用将重新激活生长素释放肽受体表达。我们将我们的小鼠与AgRP-Cre和SF-1-Cre小鼠杂交，这将导致仅在弓状核和腹内侧核中表达ghrelin受体的小鼠。我们还将用腺相关病毒载体注射背侧迷走神经复合体，以将Cre重组酶递送至背侧迷走神经复合体。在所有小鼠中，我们将评估野生型、无效和再活化小鼠对急性胃饥饿素施用的反应和对饮食诱导的肥胖的敏感性。这些研究将大大扩展我们对ghrelin参与的神经回路的了解。

DESCRIPTION (provided by applicant): Two distinct populations of peptidergic (POMC and NPY/AgRP) neurons in the arcuate nucleus of the hypothalamus respond to metabolic cues such as leptin. Another critical metabolic hormone, ghrelin, has been identified to regulate food intake and body weight. Evidence suggests that CNS neuronal groups are targets of ghrelin. This includes NPY/AgRP neurons in the arcuate nucleus. This project will employ state of the art functional neuroanatomical techniques including tract tracing, ghrelin induced gene expression using in situ hybridization histochemistry, and chemical identification of neuronal phenotypes (alone and in combination) to identify the anatomical projections of ghrelin-responsive neurons. We will determine to what degree populations of ghrelin responsive neurons in the arcuate and retrochiasmatic neurons expressing NPY/AGRP and POMC/CART project to sites including spinal cord, dorsal motor nucleus of the vagus, the lateral hypothalamic area and the paraventricular nucleus, which are likely to play a distinct role in activating the efferent pathways activated by ghrelin. We will directly test the hypothesis that ghrelin receptor expression only in neurons in the arcuate nucleus, ventromedial hypothalamic nucleus, and the dorsal vagal complex is sufficient to mediate the effects of ghrelin to increase food intake and decrease energy expenditure. To accomplish this we will use a novel mouse model that is null for ghrelin receptor expression. The mouse is made such that the action of Crerecombinase will reactivate ghrelin receptor expression. We will cross our mice to AgRP-Cre and SF-1-Cre mice, which will result in mice with ghrelin receptor expression only in the arcuate and ventromedial nuclei. We will also inject the dorsal vagal complex with adeno-associated viral vectors to deliver Cre-recombinase to the dorsal vagal complex. In all mice, we will assess the responses to acute ghrelin administration and sensitivity to diet induced obesity in wild type, null, and reactivated mice. These studies will substantially expand our knowledge of the neural circuits engaged by ghrelin.