Serotonin Signaling in Zona Incerta and Paraventricular Thalamus Regulate Feeding Behavior

项目摘要 越来越多的证据表明，室旁丘脑（PVT）和室旁神经节（ZI）都起着重要的作用。 在饮食调节中的作用。我们以前的研究报告，激活ZI GABA神经元及其 对PVT的预测会迅速引起暴饮暴食。食物剥夺激活ZI GABA神经元， ZIGABA神经元的消融抑制小鼠的每日食物摄入和体重增加，支持 ZI GABA神经元在生理摄食控制中的重要性。然而，在很大程度上仍然不知道如何 ZI-PVT通路受神经支配并由其他脑区控制，用于摄食调节。在这 应用，我们建议研究如何中央5-羟色胺（5-HT）信号靶向ZI和PVT的， 饲养控制尽管中枢5-HT信号在饱腹感调节中的重要性已为人们所熟知， 中缝核5-HT投射调控摄食动机的机制尚不清楚。我们的试验数据显示， 中缝背核和中缝内侧核均有密集的5-HT投射。食物匮乏 抑制中缝背核投射到ZI和PVT的神经元的活动，5-HT还兴奋PVT 神经元，但抑制ZI神经元以及ZI-PVT GABA传递。基于ZI的重要作用- PVT神经通路在摄食控制中的作用，我们推测：1）中缝核神经元通过5-HT信号调节 ZI和PVT神经元，并抑制ZI-PVT GABA传递。2)中缝5-HT向ZI和PVT的投射 调节进食动机和食物摄入量。3)慢性高脂高糖（HFHS）饮食改变5-HT抑制 对PVT投射的ZI神经元和ZI-PVT GABA传递的影响。该提案的目标1侧重于研究 关于中缝核向ZI和PVT的功能性5-HT神经投射，以及5-HT的调节作用， ZI和PVT神经元上的HT信号传导。利用切片电生理学结合光遗传学进行靶向 脑切片中的特定神经元，我们将证实5-HT信号对ZI和PVT的差异调节 神经元以及ZI-PVT GABA传递。在目标2中，我们将研究中缝核5-HT投射到 ZI和PVT调节摄食动机和食物摄入。在行为研究的拟议实验中， 我们将使用光遗传学工具来操纵中缝5-HT神经元及其向ZI和PVT的投射。 并利用脑片电生理和c-fos免疫反应研究了ZI和PVT投射5-HT神经元 反应的代谢状态，揭示了中缝5-HT投射到ZI和PVT的生理作用， 摄食调节在目标3中，我们将研究慢性HFHS饮食如何改变5-HT对PVT投射ZI的抑制 神经元和ZI-PVT GABA传递。总之，本申请中的建议将阐明一种新颖的作用， 通过靶向ZI和PVT调节食物摄入量的5-HT信号传导。此外， 该项目将有助于进一步了解功能失调的大脑5-HT信号是如何参与暴饮暴食和肥胖的。

PROJECT SUMMARY Increasing evidence indicates that both zona incerta (ZI) and paraventricular thalamus (PVT) play important roles in the regulation of feeding. Our previous study reported that activation of ZI GABA neurons and their projections to PVT rapidly evokes binge-like eating. Food deprivation activates ZI GABA neurons and selective ablation of ZI GABA neurons suppresses daily food intake and body weight gain in mice, supporting the importance of ZI GABA neurons in the physiological feeding control. However, it remains largely unknown how the ZI-PVT pathway is innervated and controlled by other brain areas for the feeding regulation. In this application, we propose to study how central serotonin (5-HT) signaling targeting both ZI and PVT for the feeding control. Although the importance of central 5-HT signaling in the satiety regulation is well-known, little is known what raphe 5-HT projections regulate feeding motivation. Our pilot data show that both ZI and PVT receive dense 5-HT projections from raphe nuclei, including both dorsal and medial raphe. Food deprivation depressed the activity of dorsal raphe neurons that project to ZI and PVT. In addition, 5-HT excited PVT neurons but inhibited ZI neurons as well as ZI-PVT GABA transmission. Based on the significant role of the ZI- PVT neural pathway in feeding control, we hypothesize that: 1) raphe neurons send 5-HT signaling to modulate both ZI and PVT neurons, and inhibit ZI-PVT GABA transmission. 2) raphe 5-HT projections to ZI and PVT regulate feeding motivation and food intake. 3) chronic high-fat high-sugar (HFHS) diet alters 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Aim 1 of the proposal is focused on the study about the functional 5-HT neural projections from raphe to both ZI and PVT, and the modulatory effects of 5- HT signaling on ZI and PVT neurons. Using slice electrophysiology in combination with optogenetics to target specific neurons in brain slices, we will corroborate the differential modulation of 5-HT signaling on ZI and PVT neurons as well as ZI-PVT GABA transmission. In Aim 2, we will examine how raphe 5-HT projections to both ZI and PVT regulate feeding motivation and food intake. In the proposed experiments for the behavioral study, we will use optogenetic tools to manipulate raphe 5-HT neurons and their projections to ZI and PVT. We will also use slice electrophysiology and c-fos immunoreactivity to study how ZI- and PVT-projecting 5-HT neurons respond to the metabolic states, revealing the role of raphe 5-HT projections to ZI and PVT in the physiological feeding regulation. In Aim 3, we will study how chronic HFHS diets alter 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Together, the proposal in this application will elucidate a novel role of 5-HT signaling in the regulation of food intake by targeting both ZI and PVT. Also, the findings from this project will help further understand how dysfunctional brain 5-HT signaling is involved in overeating and obesity.