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

基本信息

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
项目类别：
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

项目摘要

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）是一种环肽，几乎在仅存在于下丘脑外侧 (LH) 和未定带 (ZI)，但投射到整个中枢神经系统。 MCH 系统被认为是能量稳态和食物摄入的调节器，但也睡眠、压力、情绪、攻击性、奖励和认知。 MCH通过与G相互作用发挥作用蛋白质偶联受体 MCHR1，在大脑中广泛分布，特别是在额叶皮层、杏仁核、伏隔核和海马体为 MCH 在社交、情感和认知功能的调节。 MCHR1 是少数几个位于初级神经元纤毛、小微管骨干、从血浆中突出的毛发状结构几乎每个细胞的膜，包括神经元。纤毛作为细胞的天线，在细胞中发挥着至关重要的作用通过检测和转导外部刺激来发出信号，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，称为纤毛病。在这些基因中，77个基因与神经系统相关缺陷，例如认知缺陷和智力障碍。我们最近发现 MCHR1 mRNA 水平精神分裂症患者的前额皮质（PFC）显着降低。我们还表明通过种系删除 MCHR1 或条件性消除 MCH 表达来破坏 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。鉴于这些初步发现该项目的目标是了解纤毛膜上的 MCHR1 定位是否是这些受体在纤毛单调中的独特性，通过汇聚不同的感觉信号细胞外环境，并将这些信号传输到细胞内。这得到了以下事实的支持：体外实验中MCHR1的激活通过细胞骨架相关导致纤毛长度缩短规定。我的研究结果将为理解睫状 MCH 受体在通过 CRISPR-Cas9 的单引导 RNA 与 Cre-loxP 重组酶结合等方法来治疗认知缺陷技术，以及从神经元中删除负责纤毛功能和结构的纤毛基因 IFT88 表达 MCHR1 或 MCH。我们还将设计 MCH 类似物来逆转在我们的动物身上看到的影响模型。这项研究的结果将有可能证明睫状体 MCHR1 在认知中的作用精神障碍中常见的功能障碍。