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: 10390233
• 负责人: Wedad S Alhassen
• 金额: $ 4.19万
• 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/10390233
• 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-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; recombinase-mediated cassette exchange; 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缩激素（MCH）是一种几乎表达的环状肽 仅在下丘脑（LH）和Zona Incerta（Zi）中，但在整个中央紧张 系统。 MCH系统已被牵涉到能量稳态和食物摄入量的调节器，但也是 睡眠，压力，情绪，侵略，奖励和认知。 MCH通过与G互动而发挥作用 蛋白质偶联受体MCHR1，在大脑中具有广泛的分布，尤其是在额叶中 皮质，杏仁核，伏隔核和海马为MCH在该中的作用提供了解剖基础 社会，情感和认知功能的调节。 MCHR1是位于 原代神经元纤毛，小微管骨架，类似头发的结构，从血浆伸出 包括神经元在内的几乎每个细胞的膜。纤毛充当细胞的天线，并在细胞中起关键作用 通过检测和转导外部刺激来传导，并调节适当的细胞分化和 迁移。 87个纤毛基因的突变与睫状结构和功能的破坏有关 临床疾病，称为纤毛病。在这些基因中，有77个基因与神经系统有关 缺陷，例如认知缺陷和智力残疾。我们最近发现MCHR1 mRNA水平是 精神分裂症患者的前额叶皮层（PFC）的明显降低。我们还表明了 通过MCHR1的种系缺失或有条件的MCH表达MCH系统破坏MCH系统 神经元导致了模仿与精神分裂症有关的某些症状的行为异常：社会和 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疾病中的作用。考虑到这些初步发现 该项目的目标是了解MCHR1在纤毛膜上的定位是否是 这些受体在睫状单一的独特性，通过收敛于不同的感觉信号 细胞外环境，并将这些信号传输到细胞中。这是由 MCHR1的激活导致通过细胞骨架相关的体外实验中纤毛长度的缩短 规定。我的结果将为了解睫状MCH受体在中的作用提供新的见解 通过方法（例如CRISPR-CAS9）与CRE-LoxP重物组合酶等方法的认知缺陷 技术以及删除IFT88，是纤毛功能和结构的纤毛基因，来自神经元 表达MCHR1或MCH。我们还将设计MCH类似物以扭转动物中看到的影响 型号。这项研究的结果将有可能证明睫状MCHR1在认知中的作用 在精神疾病中看到的功能障碍。