Determining How Circadian Rhythm Regulates Sleep Fragmentations in Tauopathy

The goal of this project is to elucidate how sodium channel dynamical states modulate tau pathology in circadian neurons to alter circadian rhythms and sleep.

In Aim 1, we will evaluate how inactivation states of voltage-gated sodium channels alter tau proteostasis, core clock system regulation, and circadian activity. In Aim 2, we will investigate the effect of pharmacological manipulations of inactivation states of voltage-gated sodium channels on clock neuron electrophysiology, sleep behavior, cognition, and lifespan in the adult Drosophila brain. In Aim 3, we will demonstrate that the inactivation states of voltage-gated sodium channels are altered in the iPS cells derived from human patients.

By using Drosophila, the research proposal can precisely but rapidly capture behaviorally important molecular phenotypes of Alzheimer’s disease, and we can validate the conservation of these phenotypes in human iPS cell-derived neurons, by using our state-of-the-art data acquisition methodology of simultaneous electrophysiology and arousal/sleep measurements with sophisticated machine learning platforms to construct mathematical models to extract the features of the temporal structure of neural activity patterns. We believe that this approach is novel, and will attract worldwide attention.

Completion of our study will help us address the gap in our knowledge of how alterations in voltage-gated channel states contribute to Alzheimer’s disease and related tauopathies, in the context of circadian regulation of sleep. Further, it will help pave the way towards the development of new therapeutic strategies for Alzheimer’s disease.