Circadian clock gene Rev-erb in memory dysfunction in Alzheimer's disease

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ABSTRACT/SUMMARY Abnormal circadian rhythms of locomotor activities, body temperature, and hormonal levels not only are strongly associated many neurodegenerative disorders including Alzheimer’s disease (AD) in both human patients and animal models, but also precede cognitive deficits. However, it is unclear whether and how circadian disruption per se causes cognitive deficits. It is also unclear whether and how the central circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus contributes to cognitive functions. Here we found that an AD mouse model (APP NL-G-F) displays disrupted SCN molecular clock, including nuclear receptors Rev-erbα and Rev-erbβ, and these molecular deficits proceed detectable cognitive dysfunctions. Circadian disruptions, either by constant light exposure or by genetic deletion of Rev-erb in the SCN GABAergic neurons, cause cognitive dysfunctions resembling those in APP NL-G-F mice. We hypothesize that disrupted circadian clock in the SCN and alterations in SCN-originated neural circuitry contributes to cognitive dysfunctions in AD. We will determine whether restoration of Rev-erb in the SCN rescues cognitive deficits in APP NL-G-F mice; determine whether rhythmic SCN GABA neuron firing pattern is required to maintain normal cognitive functions; and determine whether the GABA-SCN>PVT circuit regulates cognitive functions. Modern human society is featured with nighttime light, nighttime feeding, social jetlag, and shift work. These circadian disruptions are highly associated with memory deficits and neurodegenerative diseases, especially in aged populations. The proposed study combines unique genetic animal models, light schedule manipulation, precise neuromodulation tools, and cutting-edge molecular methods to address mechanisms of how circadian disruptions cause cognitive deficits. Accomplishing these aims will provide novel insights into the pathophysiology of AD-related dementia, and lay groundwork for chronotherapeutic interventions.