Functional diversity of cholinergic streams modulating cognition

 描述（由申请人提供）：胆碱能系统在唤醒、警觉、注意力、感觉门控和记忆过程中起关键作用。此外，胆碱能系统的损伤与人类疾病有关，包括阿尔茨海默氏症和帕金森病的痴呆。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，但提供胆碱能投射到新皮层的神经元的功能组织以及ACh调节特定皮层功能的电路和细胞机制仍知之甚少。这些数据是必要的，以形成在认知过程中的胆碱能系统的功能描述，并推进其在疾病中的功能障碍的机制分析。最近的证据表明，基底前脑的胆碱能细胞有不同的和特定的模式的皮层神经支配。这项建议的工作假设是，不同的胆碱能流有不同的活动过程中的行为，从而建立一个时空分工的调制认知过程。为了检验这一假设，更普遍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执行胆碱能依赖性行为任务期间的活动模式与其皮质轴突神经支配相关联。然而，由于胆碱能细胞代表基底前脑中的少数神经元的事实，在体内特异性地记录胆碱能细胞是非常困难的，并且胆碱能神经元在任务相关背景下的活动还没有报道。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，在执行感觉检测任务时记录和标记基底前脑中的胆碱能细胞，以研究胆碱能细胞活性分布与感觉检测任务之间的相关性。 神经元在行为任务和他们的模式的神经支配的皮层，以获得证据支持我们的工作假设的目标。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。 神经支配的行为任务，并产生一个大的数据库的个人，完整的胆碱能细胞形态的解剖和功能组织的基底前脑胆碱能投射系统的更彻底的描述。

 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.