Neuronal primary cilia and cognitive disorders

神经元初级纤毛和认知障碍

基本信息

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
项目类别：
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

项目摘要

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.

项目概要原发纤毛是基于微管的感觉细胞器，在包括神经元在内的大多数哺乳动物细胞中表达。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会导致许多神经系统疾病，例如认知障碍、 3 型腺苷酸环化酶 (AC3) 是导致智力障碍、神经变性和肥胖的关键酶。介导神经元纤毛中的环磷酸腺苷 (cAMP) 信号通路从机制上讲，神经初级纤毛和纤毛 cAMP 的作用机制仍有待阐明。调节神经功能并有助于学习和记忆形成。确定神经元初级纤毛和纤毛 cAMP 信号在调节神经元活动中的作用调节海马依赖性记忆形成，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，并制定新的干预策略来治疗认知障碍最近，基于体内钙成像与微量恐惧调节相结合。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”海马神经元活跃有趣的是，它们之间出现了突发同步。启动的海马神经元与痕迹记忆的形成和检索同时发生。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很重要在这里，我们将检验神经初级纤毛和 AC3 调节恐惧记忆的假设。通过提高海马神经元的基底神经元兴奋性来启动海马神经元，影响爆发的诱导为此，我们首先要确定海马神经元之间的同步性和记忆形成。神经元初级纤毛或 AC3 的消融影响海马神经元的启动和痕迹记忆其次，我们将确定延长的神经元初级纤毛在调节基底神经元中的作用。这项工作将增进我们对神经初级贡献的理解。此外，该 AREA 奖项将丰富该研究环境。新罕布什尔大学 (UNH) 并为至少四名本科生提供实验室经验，否则他们将没有机会接受此类研究培训。