Understanding the relationship between A? and memory dysfunction in Alzheimer?s disease remains an essential objective. Although animal models of Alzheimer?s that over-express the amyloid precursor protein show perturbed calcium in individual neurons, memory is fundamentally a neural systems property of the intact hippocampus, and how A? impacts the integrity of neural systems calcium activity in the functioning hippocampus is unknown. During exploratory behavior, neurons represent space as place fields, coordinating their action potentials with the hippocampal theta oscillation, a rhythm dependent on acetylcholinergic (ACh) inputs from the medial septum; but during quiet wakefulness and slow wave sleep, ACh levels fall and theta is replaced with a physiological state in which neurons fire instead with sharp- wave ripple events. Given that ACh?s contribution to hippocampal function extends to Alzheimer?s, with ACh esterase inhibitors providing the mainstay of therapy and associated with significant improvements in memory, we hypothesize that the cholinergic system impacts the neurophysiological effects of A? deposition, such that A??s effects on dynamic calcium activity in the functioning hippocampus will depend on hippocampal state and cholinergic tone across the sleep-wake cycle. In addition, since fluctuations in cytoplasmic calcium may derive both from neuronal depolarization and from calcium-induced calcium release, calcium activity may be an imperfect surrogate for electrophysiological activity. To address these issues, we will study (1) the relationship between neuronal calcium activity and hippocampal electrophysiology in freely behaving normal animals, (2) how this relationship is impacted by A??in two Alzheimer?s disease mouse models, and (3) how ACh impacts A?'s effects on calcium activity and action potentials. To investigate these aims, we will combine chronic electrophysiological techniques with newly available miniature microscope imaging technologies (Inscopix head mounted mini-microscope) and robust, genetically encoded calcium fluorophores (GCAMP6f). We will acquire local field potentials together with single unit recordings and calcium imaging of hippocampal neurons as A? over-expressing mice and littermate controls perform a behavioral task and across their sleep-wake cycles. We will attempt to rescue A?-associated abnormalities with a ?-secretase1 inhibitor now in clinical trials, and we will employ pharmacology to evaluate the impact of ACh on A??s effects on hippocampal physiology. Together, these efforts will establish the effects of A??on neuronal action potential activity and calcium activity across the sleep-wake cycle, providing key insights into Alzheimer?s disease and identifying new targets for its treatment.

Public Health Relevance

An outstanding question in Alzheimer?s research is how A? degrades memory: Memory is a neural systems property of the intact brain, dependent on hippocampal state across the sleep- wake cycle and on acetylcholine, but how A? impacts dynamic calcium activity to perturb the function of the intact hippocampus is unknown. To address this knowledge gap, we will assess the effects of A? on hippocampal neuronal calcium activity and action potentials across the sleep-wake cycle of freely behaving animals and will evaluate their modulation by acetylcholine.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Special Emphasis Panel (ZRG1)
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Mackiewicz, Miroslaw
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Massachusetts General Hospital
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