Optogenetic Entrainment of Slow Brain Rhythms in Alzheimers Mice

Alzheimers disease (AD) is a major neurogenerative disorder without a cure. Slow brain rhythms, including slow oscillations, are important for consolidation of memory during sleep, and AD patients experience memory disturbances. Thus, we sought to examine slow wave activity using the voltage-sensitive dye RH1691 in an animal model of AD (APP mice). The power of slow oscillations at 0.6Hz was decreased starting at 3 months of age. Soluble amyloid-beta was sufficient to disrupt the slow waves. Next we sought to manipulate slow waves in APP mice with optogenetics. Driving slow oscillations at normal frequency with light activation of channelrhodopsin-2 (ChR2) restored slow wave power by synchronizing neuronal activity. Using multiphoton microscopy, we performed longitudinal imaging of senile plaques and monitored intracellular calcium. Cytosolic calcium is a surrogate marker of neuronal activity and is normally tightly regulated. We had previously demonstrated that resting calcium levels measured with the genetically encoded calcium sensor YC3.6 were elevated in a subset of neurons in APP transgenics, and hypothesized that an effective treatment would restore calcium to control levels. Driving slow oscillation activity with optogenetics halted amyloid plaque deposition and prevented calcium overload associated with this pathology. On the other hand, driving slow oscillation activity at twice the normal frequency (1.2Hz) resulted in increased amyloid production, increased amyloid plaque deposition, disruptions in neuronal calcium homeostasis, and loss of synaptic spines. Therefore, use of optogenetics allowed to determine that while restoration of physiological circuit dynamics was sufficient to abrogate the progression of Alzheimer's disease pathology and should be considered an avenue for clinical treatment of patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.