Circadian dysfunction and neurodegenerative disease

由于固有的分子时钟定位，认知功能在白天和晚上都有很大的变化 海马细胞。在我们上一个项目期间，我们展示了神经元的昼夜差异 兴奋性、长时程增强和记忆受昼夜节律钟控机制的调节 如激酶激活和离子通道调节，以及中枢时钟神经元的兴奋性。 在阿尔茨海默病的小鼠模型中，视交叉上核的调节失调。然而，人们对此知之甚少 关于海马区分子钟对神经元兴奋性的潜在调节 生理和病理状态。被动与主动昼夜节律的进一步研究 兴奋性锥体细胞和抑制性小白蛋白表达的中间神经元的膜特性 需要发现新的时间治疗策略来早期干预高兴奋性，认知 阿尔茨海默病的功能障碍和发病机制。在此竞争性续订请求中，我们将测试 细胞自主分子钟驱动主动和被动昼夜差异的新假说 锥体神经元和PV+中间神经元在一天中相反的时间段的膜特性。我们预测 这些反时相关系促进了兴奋-抑制平衡、突触的昼夜差异 可塑性和记忆，以及海马膜特性昼夜节律的破坏可能 有助于网络的过度兴奋，加速认知障碍和发病机制。vbl.使用 条件性转基因小鼠，切片电生理学，生物发光成像，化学遗传学和行为学 我们将测试CA1锥体神经元的节律性转录和兴奋性(目标1)和 表达小白蛋白的中间神经元(Aim 2)由分子时钟驱动，是昼夜所必需的。 记忆和可塑性的差异。目标3将使用化学遗传学来确定是否恢复一天- CA1区锥体神经元去极化状态和内在兴奋性的夜间差异具有保护性 对抗阿尔茨海默氏症的病理和记忆障碍。总而言之，这些实验具有 有可能揭示一种全新的海马钟调节昼夜的机制 可塑性和认知能力的差异，可以为阿尔茨海默病的过度兴奋提供关键的洞察力， 记忆障碍，以及发病机制。

Cognitive function varies greatly throughout the day and night due to an intrinsic molecular clock localized hippocampal cells. In our last project period, we demonstrated that day-night differences in neuronal excitability, long-term potentiation, and memory are regulated by the circadian clock-controlled mechanisms such as kinase activation and ion channel regulation, and that excitability of central clock neurons in the suprachiasmatic nucleus is dysregulated in a mouse model of Alzheimer's disease. However, little is known about the underlying regulation of neuronal excitability by the molecular clock in hippocampus during both physiological and pathological states. Further investigation of the circadian regulation of passive and active membrane properties in excitatory pyramidal cells as well as inhibitory, parvalbumin-expressing interneurons is required to discover novel chronotherapeutic strategies for early intervention of hyper-excitability, cognitive dysfunction, and pathogenesis in Alzheimer's disease. In this competitive renewal request, we will test the novel hypotheses that the cell-autonomous molecular clock drives day-night differences in active and passive membrane properties of pyramidal neurons and PV+ interneurons at opposite times of the day. We predict that these anti-phase relationships promote day-night differences in excitatory-inhibitory balance, synaptic plasticity, and memory, and that disruption of circadian regulation of hippocampal membrane properties could contribute to hyper-excitability of the network and hasten cognitive impairment and pathogenesis. Using conditional transgenic mice, slice electrophysiology, bioluminescence imaging, chemogenetics, and behavioral assays, we will test whether rhythmic transcription and excitability of CA1 pyramidal neurons (Aim 1) and parvalbumin-expressing interneurons (Aim 2) are driven by the molecular clock and necessary for day-night differences in memory and plasticity. Aim 3 will use chemogenetics to determine whether restoration of day- night differences in the depolarization state and intrinsic excitability of CA1 pyramidal neurons is protective against Alzheimer's disease pathology and memory impairment. Altogether, these experiments have the potential to reveal an entirely novel mechanism by which the hippocampal clock regulates day-night differences in plasticity and cognition and could give critical insight into Alzheimer's disease hyperexcitability, memory impairment, and pathogenesis.