Determining optimal parameters for dynamic cholinergic modulation of associative learning

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Project Summary / Abstract Acetylcholine is an important modulator of brain function and cognition, and cholinergic deficiency is implicated in several neuropsychiatric diseases, including delirium. Cholinergic stimulation would appear to be a promising cognitive therapy, however, cholinesterase inhibitors that broadly augment the action of acetylcholine have had limited clinical success and significant side effects. Therefore, there is a critical need to understand cholinergic circuits better to develop therapies that can precisely maximize their function. To address this need, we must address a knowledge gap regarding whether cholinergic function changes as subjects learn associations between cues, responses, and reinforcers. With a combination of cutting-edge circuit dissection tools, we can now selectively target one of the densest cholinergic projections to a cognitive circuit: the cholinergic projection from the basal forebrain to the basolateral amygdala. Work in this research proposal will identify if the activity and effects of this cholinergic projection are strongest when subjects are uncertain about the associations between cues and reinforcers, as is hypothesized based on preliminary data. The proposed project seeks to determine how the function of basal forebrain cholinergic neurons changes with associative learning, using the framework of a continuous performance task sensitive to cholinergic blockade and analogous to those used in delirium evaluations. A successful outcome of this proposal will be the determination of how spatially and temporally targeted stimulation can significantly benefit cognitive control and associative learning. The additional goals of this Mentored Clinical Scientist Research Career Development Award (K08) for the applicant are to 1. Develop expertise in circuit dissection techniques to investigate how specific circuit functions change with behavioral demands; 2. Develop expertise in targeted neuromodulation in order to maximize circuit function for cognitive benefit; 3. Develop professional skills, including sharing scientific knowledge through papers and presentations, successfully obtaining funding including independent grants, and mentoring and leadership skills to run an interdisciplinary research program. This career development award will extend the applicant's prior training in behavioral electrophysiology and clinical focus on delirium and alterations in mental status in order to connect physiologic and behavioral findings into specific circuits and networks that could be potential therapeutic targets. This award will be a crucial stepping-stone towards the overall goal of developing into an independent clinician-scientist, moving from bedside to bench to research the acute cognitive disorders that are common and yet poorly understood in clinical practice, in particular delirium.