The role of presynaptic C1QL3 in a hypothalamic arousal circuit

突触前 C1QL3 在下丘脑唤醒回路中的作用

• 批准号: 10537559
• 负责人: William Patrick Armstrong
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2026-08-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537559
• 关键词: Address; Affect; Anatomy; Arousal; Axon; Behavior; Behavioral; Brain; Brain region; Cataplexy; Disease; Electrophysiology (science); Elements; Epitopes; Excitatory Synapse; Exhibits; Experimental Designs; Fiber; Fluorescent in Situ Hybridization; Gene Expression; Genes; Genetic Markers; Goals; Human; Hypothalamic structure; Immunohistochemistry; In Vitro; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Lateral; Lateral Hypothalamic Area; Light; Mediating; Messenger RNA; Metabolism; Methods; Modernization; Molecular; Molecular Profiling; Mus; Narcolepsy; Nature; Neurons; Neuropeptides; Neurosciences; Obesity; Outcome; Patients; Pattern; Persons; Phenotype; Physiology; Play; Population; Proteins; Research Personnel; Rodent; Role; Science; Scientist; Severities; Signal Transduction; Sleep; Sleep Disorders; Sleep disturbances; Structure; Symptoms; Synapses; Synaptic Transmission; Techniques; Testing; Training; Vertebrates; Viral; Virus; Wakefulness; Work; base; comparative; conditional knockout; density; gene product; hypocretin; insight; interest; locus ceruleus structure; nervous system disorder; noradrenergic; novel; presynaptic; receptor; single molecule; single-cell RNA sequencing; sleep regulation; synaptic function; therapeutic target

PROJECT SUMMARY: Narcolepsy with cataplexy is a debilitating neurological disorder that results in sleep attacks during the day and fragmented sleep at night. This condition is associated with the loss of hypocretin/orexin (HCRT/OX) neurons in the lateral hypothalamic area (LHA), which are important regulators of sleep/wake behavior and arousal states. Despite a broad array of work investigating HCRT/OX neuron function in physiology and behavior, comparatively little is known about the molecular mechanisms underlying their synaptic structure and function. Based on the results of our lab’s recent single cell RNA sequencing (scRNA-seq) analysis of the LHA, we propose that C1ql3, encoding C1QL3, a previously described excitatory synapse organizing protein in other brain regions, may likewise be an important element in excitatory synaptic transmission in HCRT/OX neurons, and help us shed light on the molecular components of these important arousal-regulating synapses. To test this, I will confirm the expression of C1ql3 and its gene product C1QL3 in HCRT/OX neurons, at both the mRNA and protein levels (Aim 1). I will then conditionally knock out the C1ql3 gene in HCRT/OX neurons to determine the consequences of its deletion on HCRT/OX synaptic structure and function (Aim 2), as well as its potential importance for HCRT/OX neuron function in promoting arousal (Aim 3). This work will have several important outcomes, including 1) identifying the role of a novel genetic marker in HCRT/OX neurons, 2) informing us of the importance of C1QL3 in synaptic function and behavior relating to HCRT/OX neurons, and 3) provide me with training in neuroscience techniques ranging from cellular and molecular to behavioral to enable me to become a more well- rounded scientist and scientific communicator, as I pursue my goal of becoming an independent researcher.

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