Circadian changes in network excitability and Alzheimer disease pathogenesis

项目摘要 在AD中，以癫痫活动形式出现的网络过度兴奋具有明显的昼夜模式，且更为常见 在晚上和睡觉的时候。我们的工作集中在分子生物钟作为AD相关来源的研究上 过度兴奋性，因为它是负责调节细胞中神经生理学和兴奋性的机制 特定于类型的方式。分子时钟通过时钟基因的振荡表达来调节兴奋性 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，如小白蛋白 海马区和大脑皮层的中间神经元在AD相关的过度兴奋性中起关键作用。 细胞在海马体和皮质中最为丰富。 我们的工作模型假设，PV中间神经元的昼夜节律失调是造成昼夜突起的原因 非活动/静息期AD相关的超兴奋性。这里概述的实验将检验这一假说 AD相关的PV中间神经元细胞自主分子时钟的破坏会扰乱日常变化 钟控基因在阿尔茨海默病小鼠模型中的表达。在目标1中，我们将测量时钟基因的变化 以及PV海马区和大脑皮层中间神经元中钟控基因的表达。在目标2中，我们将测量 利用机器学习在阿尔茨海默病小鼠模型中的自然主义行为。

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.