BACKGROUND Evidence from anatomical, pharmacological, and genetic studies supports a role for the neuropeptide melanin concentrating hormone system in modulating emotional and cognitive functions. Genome-wide association studies revealed a potential association between the melanin concentrating hormone receptor (MCHR1) gene locus and schizophrenia, and the largest genome-wide association study conducted to date shows a credible genome-wide association. METHODS We analyzed MCHR1 and pro-melanin concentrating hormone RNA-Seq expression in the prefrontal cortex in schizophrenia patients and healthy controls. Disruptions in the melanin concentrating hormone system were modeled in the mouse brain by germline deletion of MCHR1 and by conditional ablation of melanin concentrating hormone expressing neurons using a Cre-inducible diphtheria toxin system. RESULTS MCHR1 expression is decreased in the prefrontal cortex of schizophrenia samples (false discovery rate (FDR) P < .05, CommonMind and PsychEncode combined datasets, n = 901) while pro-melanin concentrating hormone is below the detection threshold. MCHR1 expression decreased with aging (P = 6.6E-57) in human dorsolateral prefrontal cortex. The deletion of MCHR1 was found to lead to behavioral abnormalities mimicking schizophrenia-like phenotypes: hyperactivity, increased stereotypic and repetitive behavior, social impairment, impaired sensorimotor gating, and disrupted cognitive functions. Conditional ablation of pro-melanin concentrating hormone neurons increased repetitive behavior and produced a deficit in sensorimotor gating. CONCLUSIONS Our study indicates that early disruption of the melanin concentrating hormone system interferes with neurodevelopmental processes, which may contribute to the pathogenesis of schizophrenia. Further neurobiological research on the developmental timing and circuits that are affected by melanin concentrating hormone may lead to a therapeutic target for early prevention of schizophrenia.

中文翻译：

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精神分裂症中黑色素浓缩激素信号不足：与记忆力和社交障碍以及异常感觉运动门控相关。

背景技术来自解剖学，药理学和遗传学研究的证据支持神经肽黑色素浓缩激素系统在​​调节情绪和认知功能中的作用。全基因组关联研究表明，黑色素浓缩激素受体（MCHR1）基因位点与精神分裂症之间存在潜在的关联，而迄今为止进行的最大的全基因组关联研究显示，可信的全基因组关联。方法我们分析了精神分裂症患者和健康对照者前额叶皮层中MCHR1和黑色素浓缩激素RNA-Seq的表达。通过MCHR1的种系缺失和使用Cre可诱导的白喉毒素系统有条件地消融表达黑色素的荷尔蒙表达神经元来模拟小鼠大脑中黑色素的荷尔蒙系统的破坏。结果精神分裂症样本的前额叶皮层MCHR1表达降低（假发现率（FDR）P <.05，CommonMind和PsychEncode组合数据集，n = 901），而黑色素原浓缩激素低于检测阈值。在人背外侧前额叶皮层中，MCHR1表达随着年龄的增长而降低（P = 6.6E-57）。发现MCHR1的缺失会导致模仿精神分裂症样表型的行为异常：活动过度，刻板印象和重复行为增加，社交障碍，感觉运动门控受损和认知功能受损。有条件地消融前黑色素浓缩激素神经元会增加重复行为，并在感觉运动门控方面产生缺陷。结论我们的研究表明，黑色素浓缩激素系统的早期破坏会干扰神经发育过程，这可能有助于精神分裂症的发病。受黑色素浓缩激素影响的发育时机和回路的进一步神经生物学研究可能会导致早期预防精神分裂症的治疗目标。