Holographic reprogramming of memories during sleep in a mouse model of Alzheimers disease

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Cortical activity underlying perceptual memory is believed to occur in the organized firing of neuronal ensembles. Memory formation can be decomposed into acquisition and consolidation processes, wherein information is gained and stored respectively. Memory consolidation is thought to occur while we sleep, when the brain is in a quiescent state to allow previously formed neuronal ensembles to reactivate. While memory reactivation and its consequent role in consolidation has been largely documented, stimulating the replay of individual ensembles during sleep to enhance memory outcomes has been only indirectly explored. Indeed, impairments to memory reactivation alter memory consolidation and this may contribute to the cognitive deficits in neurodegenerative diseases such as Alzheimer’s disease (AD). AD is the leading cause of dementia in the United States, and yet the network mechanisms contributing to cognitive decline are unclear. The disease progression is associated with depositions of senile plaques of beta amyloid (Aβ) aggregates as well as neurodegeneration. Beta amyloid pathology has been shown to disrupt cortical homeostasis and desynchronize neuronal networks, however disturbances caused by Aβ pathology on sleep-mediated memory reactivation remain unknown. The overall goal of this proposal is to determine the role of memory reactivation on memory consolidation during sleep, as well as characterize beta amyloid induced impairments in reactivation in a mouse model of amyloidosis. To assess memory reactivation during sleep, I will monitor neuronal calcium activity from thousands of neurons using 3D holographic two-photon microscopy simultaneously with local field potential recordings of neuronal network activity in vivo. In order to stimulate specific ensemble activity, I will excite individual cells in previously observed ensembles using holographic targeted optogenetics. While monitoring and stimulating the visual cortex during sleep following a Go/No-Go set learning task, I will test the hypothesis that stimulating memory reactivation during sleep will enhance memory consolidation, and memory reactivation is altered in a mouse model of AD. I will begin by comparing neuronal ensemble stability following optogenetic stimulation across wake – sleep states (Aim 1a). I will then monitor behavioral performance following targeted optogenetic stimulation across wake and sleep to identify improvements in behavioral outcome (Aim 1b). Due to its overexpression of beta amyloid, I will use the 5XFAD mouse model of AD to evaluate the impact of Aβ plaques on ensemble reactivation during sleep (Aim 2a). Finally, I will monitor neuronal network activity and behavior in the 5XFAD mouse model to assess cellular and behavioral enhancements following optogenetic targeted replay during sleep (Aim 2b). This project will aid in the elucidation of sleep memory processing stages that may be disrupted by beta amyloid pathology, and provide potential therapeutic targets for the treatment of AD neurocognitive symptoms. Neuronal ensemble activity and its relation to behavior will be examined. I will be trained on a multitude of cutting-edge research techniques that I will be able to use and build upon throughout my career as an independent research scientist.