Neuronal Activity in Sleep & Wake in Alzheimer's Disease Mice

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The deep-brain imaging approach (microendoscopy) is a high throughput method that identifies the temporal and spatial pattern of activity in specific phenotypes of neurons. We have hypothesized that activity in small networks can identify normal versus diseased brains. To test this hypothesis, we will use the two-wavelength miniscope to image activity of a subset of neurons in 5xFAD mice, a validated animal model of Alzheimer’s disease (normal versus the homozygous littermates). We have created promoter- driven calcium sensor that drives the red-shifted calcium indicator, jRGECO, into orexin-arousal neurons. A separate calcium sensor (GCaMP6m) in GABA sleep neurons will be used as comparison. The advantage of imaging neurons with two different wavelengths is that it allows for comparison of arousal versus sleep neurons as the brain transitions between wake and sleep. We will image activity of neurons that contain jRGECO and GCaMP during normal wake-sleep bouts and after 6h sleep loss. We hypothesize that there is an abnormal temporal pattern of fluorescence during the transition from wake to sleep in the brains of 5xFAD mice, and it worsens with progression of disease. This may explain the cause of the disrupted sleep-wake patterns in Alzheimer’s disease. We hypothesize that abnormal activity in deep brain circuits regulating sleep is a harbinger of disease. The overall impact of this small budget project is that it will identify activity of two different juxtapositioned neurons during wake, NREM and REM sleep in wildtype versus a disease model, which will aid in understanding how small clusters of neurons behave as the waking brain falls asleep.