Holographic activation of ensemble activity during sleep in a mouse model of Alzheimer's disease

Alzheimer’s disease (AD) affects more than 5.8 million elderly adults and is the most fatal dementia in the US. Patients diagnosed with AD present with cognitive decline including a loss in long-term memory. Perceptual memory is encoded on the synchronous firing of cells within a cortical network, and ensemble activity can be recalled with sensory cues, or it can be reactivated spontaneously during sleep. During sleep, the brain is placed in a quiescent state of slow-wave activity, where recently acquired memories are believed to spontaneously reactivate in order to consolidate into long-term storage. Human AD patients show memory deficits along with poor and fragmented sleep. Due to impairments in long term memory and sleep in AD patients and animal models, it is theorized that memory reactivation may also be impaired in AD. At this point memory reactivation has not been studied during sleep in AD. Animal studies where memory reactivation is artificially disrupted show memory deficits, and interestingly, animal research has demonstrated that spurring additional memory reactivation during sleep can improve memory consolidation. Interestingly, even the introduction of auditory stimulation to enhance slow-wave activity during sleep has been shown to aid the retention of new memories. In a recent study, stimulating slow- wave activity during sleep in human patients with mild cognitive impairments led to increases in memory retention. The overall goal of this proposal is to gauge memory reactivation in a mouse model of Alzheimer’s disease and to stimulate memory reactivation during sleep in AD mice to increase memory performance. I will use two-photon microscopy in parallel with recordings of electrophysiology to measure brain activity across wake and sleep. AD model animals will be imaged during sleep following a learning task to test the hypothesis that memory reactivation is impaired in an AD mouse model (Aim 1). In a separate set of experiments, the stimulation of virally delivered opsins will be used to spur additional memory reactivation in sleep following a learning task to test the hypothesis that spurring memory reactivation during sleep will improve memory in a mouse model of AD (Aim 2). The conclusion of this project will determine the specific alterations in memory reactivation during sleep contributing to memory deficits found in an AD mouse model, and identify the potential to modulate network activity during sleep to rescue memory deficits in a mouse model of AD. The completion of this preclinical research may influence early diagnosis of AD and lead to innovations of novel therapeutics for AD. Through the completion of this project, I will be exposed to training in optical techniques, electrophysiology, behavior, and sleep science in preclinical animal models to become an independent research scientist.