The impact of aging and amyloidosis on interval timing in corticostriatal circuits and its rescue by controlled cholinergic fiber activation - Project Summary Alzheimer's disease (AD) degrades the ability to learn and make appropriate decisions. As the basal forebrain cholinergic system is highly susceptible to amyloidosis, one neuromodulator that is especially implicated in cognitive decline caused by AD is acetylcholine, which is essential in many forms of learning and memory. While higher-order brain areas associated with decision-making have been intensively investigated as they relate to AD, recently there has been a call for greater focus on the consequences of AD in sensory- and motor-related areas. As we have previously characterized a cholinergic-dependent form of learning and memory in the visual cortex, one sensory- and motor-related system that is particularly attractive in this regard is the visual corticostriatal pathway. A rudimentary, yet fundamental, form of decision-making that epitomizes a sensorimotor transformation carried out by the corticostriatal pathway is when to time reward-seeking actions in response to reward-predicting stimuli. Observation of neural activity from the visual cortex and the dorsal striatum reveal visually-cued timing activity to expected reward, providing a window into the process of transforming visual cues into reward-seeking motor action. By combining a mouse model of AD that develops amyloidosis with a line that affords a means to control and functionally image cholinergic axons, the effects of amyloidosis on cholinergic-dependent interval timing activity can be assessed, neurally and behaviorally, compared to that caused by the normal course of aging, and rescued by augmenting cholinergic signaling of reward using a novel optogenetic intervention. We hypothesize that aging and amyloidosis disrupts the ability of the visual corticostriatal system to learn and produce visually-cued interval timing activity (Aim1-Impairment), which degrades the ability to produce appropriately timed reward-seeking behaviors, and that the proximal cause is a functional impairment of cholinergic signaling of reward (Aim2-Proximal Cause). We further hypothesize that optogenetic augmentation of intact cholinergic fibers' report of reward will rescue visually-cued interval timing activity in the corticostriatal system, thereby re-establishing appropriately timed reward-seeking behavior (Aim3- Intervention). These aims will 1) reveal new neurophysiological and behavioral biomarkers foretelling future onset of the disease (Aim1), 2) lead to a greater understanding of the causative processes underlying cognitive decline (Aim2), and 3) point to new interventions for mitigating dysfunction caused by AD pathology (Aim3).
