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

睫状黑色素浓缩激素受体及其与小鼠认知功能障碍的联系

• 批准号: 10488061
• 负责人: Wedad S Alhassen
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488061
• 关键词: Ablation; Affect; Aggressive behavior; Amino Acids; Amygdaloid structure; Anatomy; Animal Model; Animals; Behavioral; Binding; Brain; CRISPR/Cas technology; Cell Differentiation process; Cell membrane; Cells; Cilia; Clinical; Cognition; Cognition Disorders; Cognitive deficits; Complex; Coupled; Cre lox recombination system; Cre-LoxP; Cyclic Peptides; Cytoskeleton; Delusions; Disease; Eating; Emotions; Environment; Environmental Risk Factor; Excision; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genes; Goals; Guide RNA; Hair; Hallucinations; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Impaired cognition; Impairment; In Vitro; Injections; Intellectual functioning disability; Kinesin; Knock-out; Lateral; Left; Length; Link; MCHR1 gene; Membrane; Mental disorders; Messenger RNA; Methods; Microtubules; Moods; Mus; Mutation; Neuraxis; Neurologic; Neurologic Deficit; Neurons; Neuropeptides; Nucleus Accumbens; Patients; Perception; Phenotype; Play; Population; Prefrontal Cortex; Proteins; Regulation; Research; Rewards; Role; Schizophrenia; Sensory; Signal Transduction; Sleep; Social Functioning; Stimulus; Stress; Structure; Symptoms; System; Tamoxifen; Technology; Thinking; Vertebral column; Withdrawal; Work; anterograde transport; base; behavioral response; cell motility; ciliopathy; cognitive function; design; emotional functioning; experimental study; extracellular; frontal lobe; genetic manipulation; hormonal signals; hormone analog; hormone regulation; improved; insight; male; melanin-concentrating hormone; melanin-concentrating hormone receptor; nanoparticle; negative affect; neuropsychiatric disorder; novel therapeutic intervention; receptor; repetitive behavior; selective expression; side effect; social; social deficits; transcriptome; zona incerta

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.

项目摘要 下丘脑神经肽黑色素浓集激素（MCH）是一种环肽， 仅在外侧下丘脑（LH）和齿状回（ZI）中，但投射到整个中枢神经系统 系统MCH系统被认为是能量稳态和食物摄入的调节器， 睡眠、压力、情绪、攻击性、奖励和认知。MCH通过与G 蛋白偶联受体，MCHR 1，它广泛分布在大脑中，特别是在额叶 皮质、杏仁核、杏仁核和海马，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。MCHR 1是少数几个位于 初级神经元纤毛，小微管骨架，从血浆中突出的毛状结构 几乎所有细胞的膜，包括神经元。纤毛作为细胞的天线，在细胞内起着至关重要的作用， 通过检测和转导外部刺激信号，并调节适当的细胞分化， 迁移87个纤毛基因的突变与纤毛结构和功能的破坏有关 临床病症，称为纤毛病。在这些基因中，有77个基因与神经系统相关， 缺陷，如认知缺陷和智力残疾。我们最近发现，MCHR 1 mRNA水平是 在精神分裂症患者的前额叶皮层（PFC）中显著降低。我们还表明， 通过MCHR 1种系缺失或MCH表达的条件性消除来破坏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。来自人类和动物研究的证据支持 MCH系统在精神分裂症等神经系统疾病中的作用。根据这些初步调查结果， 该项目的目标是了解MCHR 1在纤毛膜上的定位是否是 这些受体的独特性，在纤毛单一，通过汇聚不同的感觉信号， 细胞外环境，并将这些信号传递到细胞内。这一点得到以下事实的支持： 在体外实验中，MCHR 1的激活通过与细胞因子相关的细胞因子引起纤毛长度的缩短。 调控我的研究结果将提供新的见解，了解睫状体MCH受体的作用， 通过诸如用于CRISPR-Cas9的单向导RNA与Cre-loxP重组酶偶联的方法的认知缺陷 技术，以及从神经元中删除负责纤毛功能和结构的纤毛基因IFFT 88， 表达MCHR 1或MCH。我们还将设计MCH类似物来逆转在我们的动物中观察到的效果 模型这项研究的结果将潜在地证明睫状体MCHR 1在认知功能中的作用。 精神疾病中的功能障碍。