BRAIN-WIDE, STATE-DEPENDENT GABAERGIC NEURAL POPULATION DYNAMICS IN AN ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases, accounting for 60-70% of dementia cases. Amyloid beta accumulation is a pathological hallmark of AD, presumably arising from an imbalance between its production and clearance. The abnormal accumulation triggers synaptic and circuit impairments, leading to various cognitive deficits. While the development of novel immunotherapy is on the horizon, the efficacy remains suboptimal. Sleep disruption has long been implicated as both an early indicator and an active contributor to the progression of AD. However, it remains unclear how amyloid pathology affects sleep-regulating circuits. Although GABAergic neurons are widely distributed and play a critical role in inhibiting wake-promoting circuits, we know little about how amyloid pathology disrupts GABAergic neural activity across the brain and sleep-wake cycles. Here we address this issue in an AD mouse model. We express jGCaMP8s in GABAergic (GAD2+ or parvalbumin+) neurons across the brain of 5xFAD mice by creating triple transgenic mice. We use a novel multi-fiber photometry approach to monitor GABAergic neural signals across multiple regions. In conjunction with electrophysiology and pupillometry, we characterize the state-dependence of GABAergic neural population activity. In the session, we will also discuss how the disruption of brain-wide, state-dependent GABAergic neural activity impairs sleep-wake regulation in AD.