Functional diversity of cholinergic streams modulating cognition

 描述(申请人提供)：胆碱能系统在觉醒、警觉、注意力、感觉门控和记忆过程中起关键作用。此外，胆碱能系统的损害与人类疾病有关，包括阿尔茨海默氏症和帕金森氏病的痴呆症。然而，尽管乙酰胆碱(ACh)对正常认知功能的重要性及其在疾病中的潜在意义，人们对向新皮质提供胆碱能投射的神经元的功能组织以及ACh调节特定皮质功能的电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是必要的，并推进疾病中胆碱能系统功能障碍的机制分析。最近的证据表明，基底前脑中的胆碱能细胞具有不同和特定的皮质神经支配模式。这一建议的工作假设是，不同的胆碱能流在行为过程中具有不同的活动特征，从而建立了一种时空分工来调节认知过程。为了验证这一假说，更广泛地理解胆碱能系统的功能组织，有必要将单个胆碱能神经元在胆碱能依赖的行为任务执行过程中的活动模式与它们的皮质轴突神经联系起来。然而，由于胆碱能细胞在基底前脑中只占少数神经元，因此很难在活体内对胆碱能细胞进行特异性记录，而且胆碱能神经元在任务相关环境中的活动尚未见报道。在这项探索性拨款中，我们将利用一种名为“通道视紫红质辅助修补”的新方法，在执行感觉检测任务期间记录和标记基底前脑中的胆碱能细胞，以调查胆碱能神经元的活动特征之间的相关性。 行为任务中的神经元及其对皮质的神经支配模式，目的是获得支持我们工作假说的证据。这些实验将首次提供具有特定大脑皮层模式的胆碱能神经元活动的信息。 在行为任务中的神经支配，并产生个体的完整的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。

 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.