METHODS: Using chemogenetic manipulations, we assessed how activation or inhibition of dLSGLP-1R neurons affected food intake in Glp1r-ires-Cre mice. Then, we used channelrhodopsin-assisted circuit mapping, chemogenetics, and electrophysiological recordings to identify and assess the role of the pathway from dLSGLP-1R →LHA projections in regulating food intake.
RESULTS: Chemogenetic inhibition of dLSGLP-1R neurons increases food intake. LHA is a major downstream target of dLSGLP-1R neurons. The dLSGLP-1R→LHA projections are GABAergic, and chemogenetic inhibition of this pathway also promotes food intake. While chemogenetic activation of dLSGLP-1R→LHA projections modestly decreases food intake, optogenetic stimulation of the dLSGLP-1R→LHA projection terminals in the LHA rapidly suppresses feeding behavior. Finally, we demonstrate that the GLP-1R agonist, Exendin 4 enhances dLSGLP-1R →LHA GABA release.
CONCLUSIONS: Together, these results demonstrate that dLS-GLP-1R neurons and the inhibitory pathway to LHA can regulate feeding behavior, which might serve as a potential therapeutic target for the treatment of eating disorders or obesity.
方法:使用化学遗传学操作,我们评估了Glp1r-ires-Cre小鼠中dLSGLP-1R神经元的激活或抑制如何影响食物摄入。然后,我们使用了通道视紫红质辅助电路映射,化学遗传学,和电生理记录,以确定和评估dLSGLP-1R→LHA预测途径在调节食物摄入中的作用。
结果:对dLSGLP-1R神经元的化学遗传抑制增加了食物摄入。LHA是dLSGLP-1R神经元的主要下游靶标。dLSGLP-1R→LHA投影是GABA能的,和该途径的化学遗传抑制也促进食物摄入。虽然dLSGLP-1R→LHA预测的化学遗传激活会适度降低食物摄入量,LHA中dLSGLP-1R→LHA投射末端的光遗传学刺激迅速抑制了摄食行为。最后,我们证明GLP-1R激动剂,Exendin4增强dLSGLP-1R→LHAGABA释放。
结论:一起,这些结果表明,dLS-GLP-1R神经元和对LHA的抑制途径可以调节摄食行为,这可能是治疗饮食失调或肥胖的潜在治疗靶点。