Circadian changes in network excitability and Alzheimer disease pathogenesis

项目摘要 在AD中，癫痫活动形式的网络过度兴奋具有明确的昼夜模式，并且更常见 在夜间和睡眠期间。我们的工作重点是分子生物钟作为AD相关的来源。 过度兴奋，因为它是负责调节细胞中神经生理学和兴奋性的机制 特定类型的方式。分子时钟通过时钟基因的振荡表达调节兴奋性 以及大脑皮层和海马体中的时钟控制基因。抑制性中间神经元，如小清蛋白 (PV+）海马和皮质中的中间神经元在AD相关的过度兴奋中起关键作用，PV+ 海马体和皮层中的细胞数量最多。 我们的工作模型假定PV+中间神经元的昼夜节律功能障碍有助于昼夜突出 AD相关的过度兴奋在非活动/休息阶段。这里概述的实验将检验这一假设 AD相关的PV+中间神经元细胞自主分子钟的破坏破坏了PV+中间神经元的日常变化， 在AD小鼠模型中的时钟控制基因表达。在目标1中，我们将测量时钟基因的变化 以及PV+海马和皮质中间神经元中时钟控制的基因表达。在目标2中，我们将测量 使用机器学习的阿尔茨海默氏症小鼠模型的自然行为。

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.