Circadian changes in network excitability and Alzheimer disease pathogenesis

项目总结

Project Summary In AD, network hyperexcitability in the form of epileptic activity has a clear diurnal pattern and is more common at night and during sleep. Our work focuses on the molecular circadian clock as a source of AD-related hyperexcitability, as it is the mechanism responsible for regulating neurophysiology and excitability in a cell type-specific manner. The molecular clock regulates excitability through oscillating expression of clock genes and clock-controlled genes in the neocortex and hippocampus. Inhibitory interneurons, such as parvalbumin (PV+) interneurons in the hippocampus and cortex, play a critical role in AD-related hyperexcitability, with PV+ cells being the most abundant in the hippocampus and cortex. Our working model posits that circadian dysfunction in PV+ interneurons contributes to the diurnal prominence of AD-related hyperexcitability in the inactive/rest phase. The experiments outlined here will test the hypothesis that AD-related disruption of the cell-autonomous molecular clock in PV+ interneurons disrupt daily changes in clock-controlled gene expression in a mouse model of AD. In Aim 1 we will measure changes in clock gene and clock-controlled gene expression in PV+ hippocampal and cortical interneurons. In Aim 2 we will measure naturalistic behaviors in mouse models of Alzheimer’s using machine learning.