Ciliary melanin concentrating hormone receptors and the link to cognitive dysfunction in mice

项目摘要 下丘脑神经肽黑色素浓缩激素(MCH)是一种环状多肽，几乎表达于 仅在下丘脑外侧区(Lh)和未定带(Zi)投射，但投射到整个中枢神经 系统。妇幼保健系统被认为是能量平衡和食物摄入量的调节器，但也 睡眠、压力、情绪、攻击性、奖赏和认知。MCH通过与G相互作用而发挥作用 蛋白偶联受体，MCHR1，在大脑中广泛分布，特别是在额叶 皮质、杏仁核、伏隔核和海马体为MCH在脑内的作用提供了解剖学基础。 调节社会、情感和认知功能。MCHR1是少数几个位于 初级神经元纤毛，小微管骨架，从血浆中突出的毛发状结构 几乎每个细胞的细胞膜，包括神经元。纤毛是细胞的触角，在细胞中起着至关重要的作用 通过检测和转导外界刺激，并调节适当的细胞分化和 迁移。87个纤毛基因的突变与纤毛结构和功能的破坏有关 临床疾病，称为纤毛疾病。在这些基因中，有77个基因与神经系统有关。 缺陷，如认知缺陷和智力残疾。我们最近发现，MCHR1的mRNA水平是 精神分裂症受试者的前额叶皮质(PFC)显著降低。我们还展示了 通过MCHR1胚系缺失或有条件地阻断MCH表达来扰乱MCH系统 神经元导致行为异常，模仿与精神分裂症相关的某些症状：社交和 认知缺陷和感觉运动门控缺陷。这一来自人类和动物研究的证据支持 妇幼保健系统在精神分裂症等神经系统疾病中的作用。鉴于这些初步调查结果， 该项目的目标是了解MCHR1在纤毛膜上的定位是否是 这些受体在纤毛信号中的独特性，通过汇聚不同的感觉信号在 细胞外环境，并将这些信号传输到细胞内。这一点得到了以下事实的支持： MCHR1的激活通过细胞骨架导致体外实验中纤毛长度的缩短 监管。我的研究结果将为理解睫状神经促性腺激素受体在 CRISPR-Cas9的单引导RNA结合Cre-loxP重组酶等方法导致的认知障碍 技术，以及从神经元中删除IFT88，一种负责纤毛功能和结构的纤毛基因 表达MCHR1或MCH的基因。我们还将设计MCH类似物来逆转在我们动物身上看到的效果 模特们。这项研究的结果可能会证明睫状神经MCHR1在认知过程中的作用 精神疾病中出现的功能障碍。

Project Abstract The hypothalamic neuropeptide melanin-concentrating hormone (MCH) is a cyclic peptide expressed almost exclusively in the lateral hypothalamus (LH) and zona incerta (ZI) but projects throughout the central nervous system. The MCH system has been implicated as a regulator of energy homeostasis and food intake but also of sleep, stress, mood, aggression, reward and cognition. MCH exerts its action through interacting with a G protein-coupled receptor, MCHR1, which has a widespread distribution in the brain, particularly in the frontal cortex, amygdala, nucleus accumbens, and hippocampus providing an anatomical basis for an MCH role in the modulation of social, emotional, and cognitive functions. MCHR1 is one of a few GPCRs that are located to the primary neuronal cilia, small microtubule backbones, hair-like structures that protrude from the plasma membrane of almost every cell including neurons. Cilia act as cells' antennas and play crucial roles in cell signaling through detecting and transducing external stimuli, and regulating the proper cell differentiation and migration. Mutations in 87 of cilia genes have been associated with disruptions in ciliary structure and functions clinical disorders, termed ciliopathies. Among these genes, 77 genes have been associated with neurological deficits, such as cognitive deficits and intellectual disability. We recently found that MCHR1 mRNA levels are significantly lower in the prefrontal cortex (PFC) of subjects with schizophrenia. We also showed that the disruption of MCH system by either germline deletion of MCHR1 or conditional ablation of MCH expressing neurons led to behavioral abnormalities mimicking certain symptoms relevant to schizophrenia: social and cognitive deficits, and sensorimotor gating deficits. This evidence from human and animal studies supports a role for the MCH system in neurological disoders such as schizophrenia. Given these preliminary findings the goal of this project is to understand whether the MCHR1 localization on cilia membranes is the basis of the uniqueness of these receptors in the ciliary singling, through converging different sensory signals in the extracellular environment, and transmitting these signals into the cell. This is supported by the fact that the activation of MCHR1 causes shortening of the cilia length in in vitro experiments through cytoskeleton-related regulation. My results will provide new insights into understanding the role that ciliary MCH receptors plays in cognitive deficits via methods such as single guide RNA for CRISPR-Cas9 coupled with Cre-loxP recombinase technology, as well as deleting IFT88, a cilia gene responsible for cilia function and structure, from neurons that express MCHR1 or MCH. We will also design MCH analogues to reverse the effects seen in our animal models. The results of this study will potentially demonstrate the role of ciliary MCHR1 in cognitive dysfunctions seen in psychiatric disorders.