Leptin is a homeostatic regulatory element that signals the presence of adipocyte energy stores, reduces food intake, and increases energy expenditure. Similarly, serotonin (5- HT), a signaling molecule found in both the central and peripheral nervous systems, also controls food intake. Using neuronal tract-tracing, pharmacological and optogenetics approaches, and in vivo microdialysis, combined with behavioral endpoints, we tested the hypothesis that leptin controls food intake not only by activating hypothalamic leptin receptors (LepRs), but also through activation of LepRs expressed by serotonergic raphe neurons that send projections to the arcuate (ARC). We show that microinjection of leptin directly into the dorsal raphe nucleus (DRN) reduces food intake in rats. This effect is mediated by LepR expressing neurons in the DRN as selective optogenetic activation of these neurons at either their DRN cell bodies or their ARC terminals reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing LepRs that send projections to the ARC. Finally, by utilizing in vivo microdialysis, we show that leptin administration to the DRN increases 5-HT efflux into the ARC, and specific antagonism of the 5-HT2C receptors in the ARC diminishes the leptin anorectic effect. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, identifying a new level of interaction between leptin and serotonin to control food intake. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.

中文翻译：

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中缝背侧神经元的瘦素激活抑制摄食行为


瘦素是一种稳态调节元件，可发出脂肪细胞能量储存存在的信号，减少食物摄入并增加能量消耗。同样，血清素 （5-HT） 是一种在中枢和周围神经系统中发现的信号分子，也控制食物摄入量。使用神经元束追踪、药理学和光遗传学方法以及体内微透析，结合行为终点，我们检验了瘦素不仅通过激活下丘脑瘦素受体 （LepR） 来控制食物摄入的假设，而且还通过激活由向弓状 （ARC） 发送投射的血清素能中缝神经元表达的 LepR。我们表明，将瘦素直接显微注射到中缝背核 （DRN） 会减少大鼠的食物摄入量。这种效应是由 DRN 中表达 LepR 的神经元介导的，因为这些神经元在其 DRN 细胞体或 ARC 末端的选择性光遗传学激活减少了食物摄入。在解剖学上，我们确定了一个独特的血清素能中缝神经元群，这些神经元表达 LepR，这些神经元向 ARC 发送投射。最后，通过利用体内微透析，我们表明瘦素对 DRN 的给药增加了 5-HT 流出到 ARC，而 ARC 中 5-HT2C 受体的特异性拮抗作用减弱了瘦素厌食作用。总体而言，本研究确定了通过 DRN-ARC 通路瘦素介导的食物摄入控制的新回路，确定了瘦素和血清素之间控制食物摄入的新水平。这种新途径的表征为了解大脑如何控制饮食行为创造了机会，并为治疗饮食失调开辟了替代途径。