Functional diversity of cholinergic streams modulating cognition

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 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.