Semple Erin, Hill Jennifer W
Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43606.
Endocrinology. 2018 Jan 1;159(1):439-449. doi: 10.1210/en.2017-00488.
Sexual dysfunction is a poorly understood condition that affects up to one-third of men around the world. Existing treatments that target the periphery do not work for all men. Previous studies have shown that central melanocortins, which are released by pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus, can lead to male erection and increased libido. Several studies specifically implicate the melanocortin 4 receptor (MC4R) in the central control of sexual function, but the specific neural circuitry involved is unknown. We hypothesized that single-minded homolog 1 (Sim1) neurons play an important role in the melanocortin-mediated regulation of male sexual behavior. To test this hypothesis, we examined the sexual behavior of mice expressing MC4R only on Sim1-positive neurons (tbMC4Rsim1 mice) in comparison with tbMC4R null mice and wild-type controls. In tbMC4Rsim1 mice, MC4R reexpression was found in the medial amygdala and paraventricular nucleus of the hypothalamus. These mice were paired with sexually experienced females, and their sexual function and behavior was scored based on mounting, intromission, and ejaculation. tbMC4R null mice showed a longer latency to mount, a reduced intromission efficiency, and an inability to reach ejaculation. Expression of MC4R only on Sim1 neurons reversed the sexual deficits seen in tbMC4R null mice. This study implicates melanocortin signaling via the MC4R on Sim1 neurons in the central control of male sexual behavior.
性功能障碍是一种尚未被充分理解的病症，影响着全球多达三分之一的男性。现有的针对外周的治疗方法并非对所有男性都有效。先前的研究表明，下丘脑弓状核中阿片促黑素原神经元释放的中枢黑皮质素可导致男性勃起和性欲增强。多项研究特别指出黑皮质素4受体（MC4R）在性功能的中枢控制中起作用，但具体涉及的神经回路尚不清楚。我们假设单-minded同源物1（Sim1）神经元在黑皮质素介导的雄性性行为调节中起重要作用。为了验证这一假设，我们将仅在Sim1阳性神经元上表达MC4R的小鼠（tbMC4Rsim1小鼠）与tbMC4R基因敲除小鼠和野生型对照小鼠的性行为进行了比较。在tbMC4Rsim1小鼠中，发现MC4R在下丘脑内侧杏仁核和室旁核中重新表达。将这些小鼠与有性经验的雌性小鼠配对，并根据骑跨、插入和射精情况对它们的性功能和行为进行评分。tbMC4R基因敲除小鼠表现出骑跨潜伏期延长、插入效率降低且无法射精。仅在Sim1神经元上表达MC4R可逆转tbMC4R基因敲除小鼠出现的性功能缺陷。这项研究表明，通过Sim1神经元上的MC4R的黑皮质素信号传导在雄性性行为的中枢控制中起作用。
