腹侧下丘脑不同SST阳性神经元对进食动机的调控

Feeding is a complex behavior that includes multiple motivational processes ultimately evoking appetite, food-seeking and eating behaviors. Recently it has been found somatostatin (SST) positive neurons in both the tuberal nucleus (TN) and arcuate nucleus (Arc) of ventral hypothalamus play a crucial role in regulating feeding. However, their roles in motivations of feeding behavior remains unclear. In this project, the activity of SST neurons in TN and Arc will be manipulated separately using genetically engineered mouse lines and optogenetics, and their roles in encoding motivations of feeding will be separately revealed by place preference tests; their rapid dynamics on the time scale of feeding will be checked by fiber photometry; the neural circuit mechanisms of their roles in motivations of feeding will be explored by optogenetics together with neurotropic virus-mediated trans-synaptic neural circuit tracing. This study aims to define the properties of the transmitted valence signals by TN and Arc SST neurons. Furthermore, to separately reveal the downstream brain area and specific cell type in the targeted area through which TN and Arc SST neurons exerts their effects, and also brain-wide inputs of the specific populations of TN and Arc SST neurons that encode motivations of feeding. The results of this project will promise a better understanding of the appetite, and may provide new therapeutic targets for obesity and other metabolic diseases.

进食是一项包含多重动机最终引起食欲、觅食和摄食的复杂行为。腹侧下丘脑结节核Tuberal Nucleus（TN)内的somatostatin（SST）神经元和弓状核arcuate nucleus（Arc）内的SST神经元对进食均有重要的调控作用,但其对进食动机的调控尚不明确。本项目拟利用基因工程小鼠和光遗传学技术分别操控TN和Arc的SST神经元活动，结合位置偏好行为分析，明确其参与进食动机调控情况；运用在体光纤记录明确其对进食过程的动态响应；基于光遗传学和神经环路示踪等技术，探究其编码进食动机的神经环路机制。本项目旨在阐明TN和Arc的SST神经元分别所编码的动机特性;揭示其编码进食动机的下游脑区及受其支配的下游脑区的细胞类型;及编码进食动机的TN SST神经元和Arc SST神经元分别接受的突触输入。此项研究结果将助推对食欲机理的理解，可能为肥胖症及其他代谢性疾病的治疗提供新靶点。

摄食通常由正向（美食带来的愉悦感）或负向（饥饿的不舒适感）动机驱动，并最终引起之后的觅食和食物摄取。我们近期的研究鉴定出了下丘脑中新的食欲性神经元群-SST(somatostatin，SST)阳性神经元,但其对进食动机的调控仍然未知。本项目结合基因工程小鼠、病毒介导的神经环路示踪、光遗传学与化学遗传学、钙信号光纤记录等研究手段，发现下丘脑中结节核（tuberal nucleus, TN)和弓状核（arcuate nucleus，ARC）中SST神经元的激活分别引发了正向及负向的情感效价；利用钙信号光纤记录发现SST神经元在接近奖赏性食物时更加活跃，这点与已知的ARC中AgRP神经元在看到及接近食物时神经活动降低相反；通过光遗传学分别激活腹侧下丘脑SST神经元到其下游脑区MePD及PAG的投射，发现其到MePD投射的激活引发条件性位置厌恶，而到PAG投射的激活引起运动位移的增加，从而暗示下丘脑SST神经元通过投射至不同下游节点协调进食动机；利用RV病毒介导的逆向跨单神经环路示踪技术发现腹侧下丘脑SST神经元接收VTA多巴胺能神经元（TH+）的直接投射；在功能上，VTA多巴胺能神经元到腹侧下丘脑投射的激活可引发位置偏好，从而提示SST神经元介导的正向进食动机与VTA多巴胺能神经元的输入有关。以上结果表明腹侧下丘脑SST神经元可整合奖赏性信息，在摄食动机的调控中具有重要作用。研究结果不仅有助于理解下丘脑不同食欲神经元群的功能差异，也可能为肥胖的治疗和其他代谢性疾病的预防和治疗提供神经环路层面的新视角。