Cholinergic signaling in cortical neurons: a unifying hypothesis

皮质神经元中的胆碱能信号传导：一个统一的假设

基本信息

批准号：
8089261
负责人：
Allan T Gulledge
金额：
$ 32.06万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-11 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089261
关键词：
Acetylcholine Action Potentials Address Affinity Aging Alzheimer&apos s Disease Amiloride Biological Brain Cadmium Calcium Calcium Signaling Cations Cell physiology Cerebral cortex Chemicals Cholinergic Receptors Cognition Cognitive deficits Complement Conflict (Psychology)Data Dementia Disease Drug Delivery Systems Drug Design Dyes Endoplasmic Reticulum Event Extracellular Space Functional disorder Generations Image Impaired cognition Knockout Mice Knowledge Lewy Body Disease Link Measures Mediating Memory impairment Molecular Mus Muscarinic Acetylcholine Receptor Muscarinic M1 Receptor Muscarinics Neuroglia Neurons Output Parkinson&apos s Dementia Pathway interactions Pharmacology Physiology Play Potassium Preparation Pyramidal Cells Receptor Activation Recovery Regulation Relative (related person)Role Schizophrenia Signal Pathway Signal Transduction Slice System Testing Therapeutic Intervention Time base cell type cholinergic cognitive function hippocampal pyramidal neuron insight neocortical nervous system disorder neuropsychiatry public health relevance receptor research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Acetylcholine (ACh) plays a critical role in cognition, and decreased cholinergic input to the cerebral cortex contributes to the cognitive deficits observed in Alzheimer's disease, dementia with Lewy Bodies, Parkinson's dementia, and other neurological diseases. However, a lack of knowledge regarding the pharmacology of cholinergic effects, or the mechanisms by which ACh influences neuronal activity, have hampered the development of therapies specific to these debilitating diseases. The data that do exist appear conflicting, and have been difficult to reconcile. Indeed, ACh paradoxically generates two opposing responses in the deep-layer pyramidal neurons that provide the majority of cortical output: a fast transient inhibition and a longer-lasting excitation. Although the mechanisms mediating inhibitory cholinergic responses in these neurons (M1-like muscarinic acetylcholine receptor activation, calcium- release from intracellular calcium stores, and subsequent activation of an SK-type calcium-activated potassium conductance) have been well described, the mechanisms mediating cholinergic excitation, and the functional relationship between excitatory and inhibitory cholinergic signaling, remain unknown. This project aims to determine the receptor subtypes, signaling cascades, and ionic mechanisms responsible for cholinergic excitation in cortical layer 5 pyramidal neurons, and to test the overarching hypothesis that excitatory actions of ACh reflect activation of a calcium-permeable non-selective cationic conductance that acts functionally to replenish the intracellular calcium stores that gate inhibitory cholinergic signaling. We propose to use electrophysiological and imaging approaches in a brain slice preparation to address the following three specific aims: 1. To identify the specific muscarinic receptor(s) mediating cholinergic excitation and inhibition in neocortical layer 5 pyramidal neurons. 2. To determine the signaling cascades and ionic mechanism responsible for cholinergic excitation of layer 5 neurons. 3. To test the unifying hypothesis that excitatory cholinergic conductances serve functionally to refill intracellular calcium stores depleted during inhibitory cholinergic signaling. Our results will provide a framework for understanding the biological basis for cholinergic facilitation of cognitive function. This new knowledge will increase our understanding of why dysfunction of cholinergic systems leads to the functional deficits observed in dementia and other disease states, and will provide new targets for therapeutic intervention. The Public Health Relevance: Acetylcholine is a brain chemical necessary for normal cognitive function, and loss of acetylcholine is associated with Alzheimer's disease and other disease states. This project will determine the biological mechanisms by which acetylcholine influences the activity of neurons in the normal cerebral cortex, with the aim of understanding why loss of acetylcholine during aging or disease leads to cognitive dysfunction.

描述（由申请人提供）：乙酰胆碱（ACh）在认知中起着至关重要的作用，大脑皮层的胆碱能输入减少会导致阿尔茨海默病、路易体痴呆、帕金森痴呆和其他神经系统疾病中观察到的认知缺陷。然而，由于缺乏对胆碱能作用的药理学或乙酰胆碱影响神经元活动的机制的了解，阻碍了针对这些衰弱疾病的特异性疗法的开发。确实存在的数据似乎相互矛盾，并且很难协调。事实上，ACh 在提供大部分皮质输出的深层锥体神经元中矛盾地产生两种相反的反应：快速瞬时抑制和更持久的兴奋。尽管介导这些神经元中抑制性胆碱能反应的机制（M1样毒蕈碱乙酰胆碱受体激活、细胞内钙储存的钙释放以及随后的SK型钙激活钾电导的激活）已被充分描述，但介导胆碱能反应的机制兴奋以及兴奋性和抑制性胆碱能信号之间的功能关系仍然未知。该项目旨在确定负责皮质第 5 层锥体神经元胆碱能兴奋的受体亚型、信号级联和离子机制，并测试 ACh 的兴奋作用反映了钙渗透性非选择性阳离子电导的激活这一总体假设。其功能是补充细胞内钙储存，从而控制抑制性胆碱能信号传导。我们建议在脑切片制备中使用电生理学和成像方法来解决以下三个具体目标： 1. 识别新皮质第 5 层锥体神经元中介导胆碱能兴奋和抑制的特定毒蕈碱受体。 2.确定负责第5层神经元胆碱能兴奋的信号级联和离子机制。 3. 测试统一的假设，即兴奋性胆碱能电导在功能上可以补充抑制性胆碱能信号传导过程中耗尽的细胞内钙储备。我们的结果将为理解胆碱能促进认知功能的生物学基础提供一个框架。这一新知识将加深我们对胆碱能系统功能障碍为何导致痴呆和其他疾病状态下观察到的功能缺陷的理解，并将为治疗干预提供新的目标。公共健康相关性：乙酰胆碱是正常认知功能所必需的大脑化学物质，乙酰胆碱的丧失与阿尔茨海默病和其他疾病状态有关。该项目将确定乙酰胆碱影响正常大脑皮层神经元活动的生物学机制，旨在了解为什么衰老或疾病期间乙酰胆碱的丧失会导致认知功能障碍。