Neuronal primary cilia and cognitive disorders

神经元初级纤毛和认知障碍

• 批准号: 10202982
• 负责人: Xuanmao Chen
• 金额: $ 45.15万
• 依托单位: UNIVERSITY OF NEW HAMPSHIRE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202982
• 关键词: Ablation; Acute; Adenylate Cyclase; Affect; Antidepressive Agents; Appearance; Award; Brain; Cilia; Cilium Microtubule; Cognition; Cognition Disorders; Coupled; Cyclic AMP; Defect; Diffusion; Disease; Environment; Enzymes; Esthesia; Exhibits; Exposure to; Functional disorder; G-Protein-Coupled Receptors; Goals; Hippocampus (Brain); Hormones; Human; Impaired cognition; Impairment; Intellectual functioning disability; Intervention; Investigation; Lead; Learning; Length; Lipids; Location; LoxP-flanked allele; Mammalian Cell; Mediating; Membrane Potentials; Memory; Molecular; Mus; Nerve Degeneration; Nervous system structure; Neurons; Neurotransmitters; New Hampshire; Obesity; Organelles; Pathologic; Physiological; Post-Traumatic Stress Disorders; Proteins; Research; Research Training; Retrieval; Role; Seizures; Sensory; Sertraline; Signal Pathway; Signal Transduction; Slice; Structure; Synapses; System; Testing; Transgenic Mice; Universities; Work; autism spectrum disorder; base; combat; conditioned fear; energy balance; experimental study; extracellular; fear memory; hippocampal pyramidal neuron; imaging study; improved; in vivo calcium imaging; in vivo imaging; laboratory experience; nervous system disorder; neuron loss; neuronal cell body; neuronal excitability; novel; novel therapeutics; olfactory sensory neurons; recruit; tool; undergraduate student

Project Summary Primary cilia are microtubule-based sensory organelles expressed in most mammalian cells including neurons. They regulate numerous physiological functions including sensation, cognition, and energy balance. Malfunctions of neuronal primary cilia cause many neurological disorders such as cognitive impairment, intellectual disability, neurodegeneration, and obesity. The type 3 adenylyl cyclase (AC3) is a key enzyme that mediates the cyclic adenosine monophosphate (cAMP) signaling pathway in neuronal cilia throughout the nervous system. Mechanistically, it remains to be elucidated how neuronal primary cilia and ciliary cAMP modulate neuronal function and contribute to learning and memory formation. Our long-term goals are to determine the role of neuronal primary cilia and ciliary cAMP signaling in regulating neuronal activity and modulating hippocampus-dependent memory formation, understand how defects in neuronal primary cilia cause cognition dysfunction-related disorders, and develop novel intervention strategies to treat cognitive disorders by modulating ciliary signaling. Recently, based on in vivo calcium imaging coupled with trace fear conditioning experiments, we discovered that the overall activity levels of hippocampal principal neurons exhibit a right- skewed lognormal distribution, with a small portion of highly active “primed” hippocampal neurons actively engaged with trace memory formation and retrieval. Intriguingly, the appearance of burst synchronization among primed hippocampal neurons coincides with trace memory formation and retrieval. These findings suggest that both the priming of hippocampal neurons and burst synchronization among the primed neurons are important for forming trace fear memory. Here, we will test the hypothesis that neuronal primary cilia and AC3 regulate the priming of hippocampal neurons by elevating their basal neuronal excitability, affecting the induction of burst synchronization among hippocampal neurons and memory formation. To this end, we will first determine if ablation of neuronal primary cilia or AC3 affects the priming of hippocampal neurons and trace memory formation. Second, we will determine the roles of elongated neuronal primary cilia in regulating basal neuronal activity and memory formation. This work will advance our understanding of the contribution of neuronal primary cilia to modulating memory formation. In addition, this AREA award will enrich the research environment at the University of New Hampshire (UNH) and provide laboratory experience to at least four undergraduate students, who otherwise would not have the opportunity to be exposed to such research training.

项目摘要 初级纤毛是在大多数哺乳动物细胞包括神经元中表达的基于微管的感觉细胞器。 它们调节许多生理功能，包括感觉，认知和能量平衡。 神经元初级纤毛的功能障碍导致许多神经系统疾病，如认知障碍， 智力残疾、神经退化和肥胖。3型腺苷酸环化酶（AC 3）是一种关键酶， 介导的环磷酸腺苷（cAMP）信号通路在神经元纤毛整个 神经系统机制上，神经元初级纤毛和纤毛cAMP 调节神经元功能并有助于学习和记忆的形成。我们的长期目标是 确定神经元初级纤毛和纤毛cAMP信号传导在调节神经元活性中的作用， 调节海马体依赖的记忆形成，了解神经元初级纤毛缺陷如何导致 认知功能障碍相关疾病，并开发新的干预策略来治疗认知障碍， 调节纤毛信号传导。最近，基于体内钙成像加上微量恐惧条件反射， 实验中，我们发现海马主要神经元的整体活动水平表现出右- 偏对数正态分布，一小部分高度活跃的“启动”海马神经元活跃 参与痕迹记忆的形成和提取。有趣的是，突发同步的出现， 启动海马神经元与痕迹记忆的形成和提取相一致。这些发现表明 海马神经元的启动和启动神经元之间的爆发同步都是重要的 来形成恐惧记忆在这里，我们将测试神经元初级纤毛和AC 3调节细胞增殖的假设。 通过提高海马神经元的基础神经元兴奋性来引发海马神经元，影响爆发的诱导 海马神经元之间的同步和记忆形成。为此，我们将首先确定， 神经元初级纤毛或AC 3的消融影响海马神经元的启动和痕迹记忆 阵第二，我们将确定伸长的神经元初级纤毛在调节基底神经元纤毛中的作用。 活动和记忆的形成。这项工作将促进我们对神经元原发性 纤毛来调节记忆的形成。此外，该地区奖将丰富研究环境， 新罕布什尔州（UNH）的大学，并提供实验室经验，以至少四名本科生， 否则他们将没有机会接受这种研究培训。