Functional diversity of cholinergic streams modulating cognition

胆碱能流调节认知的功能多样性

基本信息

批准号：
9151636
负责人：
Bernardo Rudy
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2017-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The cholinergic system has critical roles in arousal, alertness, attention, sensory gating and memory processes. Moreover, impairments of the cholinergic system have been associated with human disease, including the dementia of Alzheimer's and Parkinson diseases. However, in spite of the importance of acetylcholine (ACh) for normal cognitive function and its potential significance in disease, the functional organizatio of the neurons providing cholinergic projections to the neocortex, and the circuit and cellular mechanisms by which ACh regulates specific cortical functions are poorly understood. These data are necessary to shape functional descriptions of the cholinergic system in cognitive processes, and advance the mechanistic analysis of its dysfunction in disease. Recent evidence suggests that cholinergic cells in the basal forebrain have diverse and specific patterns of innervation of the cortex. The working hypothesis of this proposal is that distinct cholinergic streams have different activity profiles during behavior thus establishing a spatiotemporal division of labor for the modulation of cognitive processes. In order to test this hypothesis, and more generally to understand the functional organization of the cholinergic system, it is necessary to correlate the activity patterns of individual cholinergic neurons during the performance of a cholinergic-dependent behavioral task with their cortical axonal innervation. However, due to the fact that cholinergic cells represent a minority of the neurons in the basal forebrain, it has been extremely difficult to record specifically from cholinergic cells in vivo, ad the activity of cholinergic neurons in task-related contexts has not been reported. In this exploratory grant we will utilize a novel method known as "channelrhodopsin-assisted patching" to record and label cholinergic cells in the basal forebrain during the execution of a sensory detection task, in order to investigate the correlation between the activity profile of cholinergic neurons during a behavioral task and their pattern of innervation of the cortex, with the goal of obtaining evidence in support of our working hypothesis. The experiments will provide for the first time information about the activity of cholinergic neurons with specific patterns of cortical innervation during a behavioral task, and produce a large database of individual, complete cholinergic cell morphologies for a more thorough description of the anatomical and functional organization of the basal forebrain cholinergic projection system.

描述（由申请人提供）：胆碱能系统在唤醒、警觉性、注意力、感觉门控和记忆过程中发挥着关键作用，此外，胆碱能系统的损伤与人类疾病有关，包括阿尔茨海默病和帕金森病。尽管乙酰胆碱（ACh）对于正常认知功能及其在疾病中的潜在意义非常重要，但神经元的功能组织为神经元提供胆碱能投射人们对新皮质以及乙酰胆碱调节特定皮质功能的回路和细胞机制知之甚少，这些数据对于形成认知过程中胆碱能系统的功能描述以及推进疾病中胆碱能系统功能障碍的机制分析是必要的。基底前脑中的胆碱能细胞具有多样化且特定的皮质神经支配模式，该提议的工作假设是不同的胆碱能流在行为过程中具有不同的活动概况，从而建立了时空分工。为了检验这一假设，并且更广泛地了解胆碱能系统的功能组织，有必要将执行胆碱能依赖性行为任务期间单个胆碱能神经元的活动模式与相关联。然而，由于胆碱能细胞代表了少数神经元，特别是基底前脑，因此在体内记录胆碱能细胞极其困难。胆碱能神经元在任务相关环境中的活动尚未被报道，在这项探索性资助中，我们将利用一种称为“通道视紫红质辅助修补”的新方法来记录和标记执行感觉检测任务期间基底前脑中的胆碱能细胞。，为了研究胆碱能活性谱之间的相关性神经元在行为任务期间及其皮质神经支配模式，目的是获得支持我们的工作假设的证据，这些实验将首次提供有关具有特定皮质模式的胆碱能神经元活动的信息。行为任务期间的神经支配，并产生个体完整胆碱能细胞形态的大型数据库，以便更全面地描述基底前脑胆碱能投射系统的解剖和功能组织。