Optogenetic Targeting of Astrocytes Restores Sleep-Dependent Brain Rhythm Function and Slows Alzheimer's Disease

Abstract

Patients with Alzheimer’s disease (AD) exhibit sleep disturbances, specifically deficits in deep non-rapid eye movement (NREM) sleep. Disruption of NREM slow waves occurs early in the disease progression and is recapitulated in transgenic mouse models of beta-amyloidosis. However, the mechanisms underlying slow-wave disruptions remain unknown. Also, it is not clear if these sleep disturbances are a cause or effect of AD. Because astrocytes contribute to slow-wave activity, we used multiphoton microscopy and optogenetics to investigate whether they contribute to slow-wave disruptions in APP mice. The power but not the frequency of astrocytic calcium transients was reduced. Optogenetic activation of astrocytes at the endogenous frequency of slow waves restored slow-wave power, reduced amyloid deposition, prevented neuronal calcium elevations, and improved memory performance. Our findings revealed malfunction of the astrocytic network driving slow-wave disruptions. Thus, targeting astrocytes to restore circuit activity underlying sleep and memory disruptions in AD could ameliorate disease progression.

Keywords: optogenetics, astrocytes, sleep, slow oscillations, Alzheimer's Disease, Multiphoton imaging, neuroinflammation, memory consolidation, calcium