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Circadian dysfunction and neurodegenerative disease

昼夜节律功能障碍和神经退行性疾病

基本信息

批准号：
10373948
负责人：
Karen L Gamble
金额：
$ 53.54万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373948
关键词：
ARNTL gene Address Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Animal Model Behavioral Assay Binding Proteins Brain region Cells Chronotherapy Circadian Dysregulation Clock protein Cognition Coupled Data Early Intervention Electrophysiology (science)Equilibrium Evaluation Exhibits Feedback Gene Expression Gene Expression Profile Gene Expression Profiling Gene Expression Regulation Genes Genetic Transcription Goals Hippocampus (Brain)Hour Hyperactivity Image Immunohistochemistry Impaired cognition Impairment Individual Interneurons Investigation Ion Channel Knockout Mice Ligands Long-Term Potentiation Luciferases Membrane Membrane Potentials Memory Memory Loss Memory impairment Mus Mutation Myoepithelial cell Neurodegenerative Disorders Neurons Parvalbumins Pathogenesis Pathologic Periodicity Phase Phosphotransferases Physiological Population Property Pyramidal Cells Regulation Reporting Rest Role Sampling Slice Source Synaptic plasticity Testing Time Transgenic Mice Transgenic Organisms bioluminescence imaging cell type circadian circadian pacemaker circadian regulation cognitive function designer receptors exclusively activated by designer drugs excitatory neuron experimental study familial Alzheimer disease gamma-Aminobutyric Acid hippocampal pyramidal neuron inhibitory neuron insight molecular clock mouse model neuronal excitability neuroregulation novel prevent receptor restoration suprachiasmatic nucleus

项目摘要

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.

认知功能在白天和晚上变化很大，这是由于一个内在的分子钟定位海马细胞在我们的上一个项目期间，我们证明了神经元的昼夜差异，兴奋性、长时程增强和记忆受生物钟控制机制的调节例如激酶激活和离子通道调节，以及中枢时钟神经元兴奋性阿尔茨海默病小鼠模型中视交叉上核失调然而，关于海马体中分子钟对神经元兴奋性的潜在调节，生理和病理状态。被动和主动的昼夜节律调节的进一步研究兴奋性锥体细胞以及抑制性、表达小清蛋白的中间神经元的膜特性，需要发现新的慢性策略，以早期干预过度兴奋，认知功能障碍和阿尔茨海默病的发病机制。在此竞争性续订请求中，我们将测试新的假设，细胞自主的分子钟驱动昼夜差异的主动和被动锥体神经元和PV+中间神经元在一天中相反时间的膜特性。我们预测这些反相关系促进兴奋-抑制平衡、突触可塑性和记忆，以及海马膜特性的昼夜节律调节的破坏，有助于网络的过度兴奋性，并加速认知障碍和发病机制。使用条件转基因小鼠，切片电生理学，生物发光成像，化学遗传学，和行为实验中，我们将测试是否有节奏的转录和兴奋性的CA 1锥体神经元（目的1），表达小清蛋白的中间神经元（Aim 2）由分子钟驱动，是昼夜节律所必需的。记忆力和可塑性的差异。目的3将使用化学遗传学来确定是否恢复白天- CA 1锥体神经元的去极化状态和内在兴奋性的夜间差异是保护性的对抗阿尔茨海默病病理学和记忆障碍。总之，这些实验具有有可能揭示海马时钟调节昼夜的全新机制在可塑性和认知方面的差异，并可能对阿尔茨海默病的过度兴奋性提供重要的见解，记忆障碍和发病机制。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolism as an integral cog in the mammalian circadian clockwork.

DOI：
10.3109/10409238.2013.786672
发表时间：
2013-07
期刊：
Critical reviews in biochemistry and molecular biology
影响因子：
6.5
作者：
Gamble KL;Young ME
通讯作者：
Young ME

Circadian clock control of endocrine factors.

DOI：
10.1038/nrendo.2014.78
发表时间：
2014-08
期刊：
Nature reviews. Endocrinology
影响因子：
0
作者：
通讯作者：

Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability.

DOI：
10.1038/ncomms13470
发表时间：
2016-11-14
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Paul, Jodi R.;DeWoskin, Daniel;McMeekin, Laura J.;Cowell, Rita M.;Forger, Daniel B.;Gamble, Karen L.
通讯作者：
Gamble, Karen L.

The Molecular Circadian Clock and Alcohol-Induced Liver Injury.