Interneuron and Network Dysfunction in a Mouse Model of Alzheimer's Disease

阿尔茨海默病小鼠模型中的中间神经元和网络功能障碍

• 批准号: 10326797
• 负责人: Lauren Vetere
• 金额: $ 4.44万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-09 至 2023-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326797
• 关键词: 3xTg-AD mouse; Acute; Address; Affective; Age; Age of Onset; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Animal Diseases; Animal Model; Animals; Antiepileptic Agents; Brain; Brain region; Cells; Chronic; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Communication; Coupling; Dementia; Disease; Disease Progression; Electrophysiology (science); Epilepsy; Frequencies; Functional disorder; Future; Head; Hippocampus (Brain); Human; Impaired cognition; Impairment; Interneuron function; Interneurons; Intervention; Lead; Length; Levetiracetam; Life; Link; Long-Term Potentiation; Measures; Memory; Memory Loss; Memory impairment; Methods; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathology; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Play; Population; Property; Role; Running; Saline; Seizures; Severities; Silicon; Specificity; Symptoms; Technology; Temporal Lobe Epilepsy; Testing; Therapeutic Intervention; Time; Wild Type Mouse; abeta accumulation; awake; behavior test; brain abnormalities; density; dentate gyrus; experimental study; improved; in vivo; mouse model; network dysfunction; prevent; relating to nervous system; spatial memory; support network; tau Proteins; virtual; virtual reality environment; young adult; 3xTg-AD mouse; Acute; Address; Affective; Age; Age of Onset; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Animal Diseases; Animal Model; Animals; Antiepileptic Agents; Brain; Brain region; Cells; Chronic; Clinical Trials; Code; Cognition; Cognitive; Cognitive deficits; Communication; Coupling; Dementia; Disease; Disease Progression; Electrophysiology (science); Epilepsy; Frequencies; Functional disorder; Future; Head; Hippocampus (Brain); Human; Impaired cognition; Impairment; Interneuron function; Interneurons; Intervention; Lead; Length; Levetiracetam; Life; Link; Long-Term Potentiation; Measures; Memory; Memory Loss; Memory impairment; Methods; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathology; Patients; Pattern; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Play; Population; Property; Role; Running; Saline; Seizures; Severities; Silicon; Specificity; Symptoms; Technology; Temporal Lobe Epilepsy; Testing; Therapeutic Intervention; Time; Wild Type Mouse; abeta accumulation; awake; behavior test; brain abnormalities; density; dentate gyrus; experimental study; improved; in vivo; mouse model; network dysfunction; prevent; relating to nervous system; spatial memory; support network; tau Proteins; virtual; virtual reality environment; young adult

Project Summary Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive age- related cognitive decline. Abnormal brain rhythms and interneuron dysfunction have been implicated in AD, but it is unclear how these changes contribute to memory deficits. Studies linking specific network activity patterns in specific circuits to memory decline will be needed in order to leverage new neurostimulation technologies to normalize activity in these circuits and improve memory. Interneurons play a critical role in synchronizing local networks to facilitate memory, but their contribution to impaired hippocampal function in AD is not well understood. My lab has previously shown that proper timing of hippocampal interneuron firing is disrupted in a mouse model of epilepsy, leading to desynchronized communication in the hippocampal circuit. Hyperexcitability, seizures, and interneuron dysfunction have been found in animal models of both epilepsy and AD, suggesting that cognitive dysfunction in these diseases may share common mechanisms. In this proposal, I will test the hypothesis that the timing of hippocampal interneuron firing relative to local oscillations is disrupted in 3xTg-AD mice and that these changes are predictive of future memory impairments. I will use in vivo electrophysiology with silicon probes to record local field potentials and single units throughout CA1, CA3, and dentate gyrus (DG) in head-fixed 3xTg and wild type mice running in a virtual reality environment. Recordings and behavioral tests will be performed in the same animals before and after the emergence of memory impairments. I hypothesize that interneurons in AD mice will lose their temporal specificity relative to the phase of local oscillations, which will desynchronize interneurons across the hippocampus. I further expect that extent of interneuron dysfunction will predict the severity of future memory dysfunction. In order to understand what network activity patterns are associated with improved cognition in AD, I will test the hypothesis that the anti-epileptic drug Levetiracetam (LEV) improves memory by modifying hippocampal network activity and interneuron function. This drug has been shown to normalize hyperexcitability and improve memory in AD, but its precise mechanism is unknown. I will again perform silicon probe recordings in 3xTg and WT mice to measure the acute and chronic impacts of LEV on the hippocampal circuit. I hypothesize that chronic reduction of hyperexcitability by LEV will lead to improved synchrony in the hippocampus, characterized by increased coherence and theta-gamma coupling, as well as increased temporal specificity of interneuron firing. The results of these experiments will highlight specific cell populations and activity patterns associated with memory dysfunction in AD and identify potential targets for early therapeutic interventions.

项目摘要 阿尔茨海默氏病（AD）是一种毁灭性神经退行性疾病，其特征是 相关认知能力下降。 AD中隐含了异常的脑节律和中间功能障碍，但 目前尚不清楚这些变化如何促进内存定义。与特定网络活动模式联系的研究 为了利用新的神经刺激技术，需要在特定的电路中进行记忆下降 将这些电路中的活动归一化并改善记忆力。 中间神经元在同步本地网络以促进记忆方面起着至关重要的作用，但它们对 AD中海马功能受损尚不清楚。我的实验室以前已经表明了适当的时机 海马间神经元的发射在癫痫的小鼠模型中被破坏，导致了异步 海马电路中的通信。过度兴奋，癫痫发作和中间功能障碍已经 在癫痫和AD的动物模型中发现，表明这些疾病中的认知功能障碍可能 共享共同的机制。在此提案中，我将测试海马时间的假设 在3XTG-AD小鼠中，相对于局部振荡的中间神经元发射相对于局部振荡，这些变化是 预测未来记忆障碍。我将使用带有硅问题的体内电生理学记录本地 整个CA1，CA3和齿状回（DG）的现场电位和单个单元中的头部固定3XTG和野生型 在虚拟现实环境中奔跑的小鼠。录音和行为测试将在同一 记忆障碍出现前后的动物。我假设AD小鼠中的中间神经元 相对于局部振荡的阶段，将失去其临时特异性，这将使同步化 横跨海马的神经元。我进一步期望，中间功能障碍的程度将预测 未来记忆功能障碍的严重性。 为了了解哪些网络活动模式与AD中的认知改善有关，我将测试 抗癫痫药物左旋尿素（LEV）通过修饰海马来改善记忆的假设 网络活动和中间神经元功能。该药物已被证明可以使过度兴奋和改善 AD中的记忆，但其精确机制尚不清楚。我将再次在3xtg中执行硅探针录音 WT小鼠测量LEV对海马电路的急性和慢性影响。我假设这一点 LEV长期降低过度兴奋性将导致海马中的同步性改善， 具有提高相干性和theta-gamma耦合的特征，以及提高的临时特异性 Interneuron射击。这些实验的结果将突出特定的细胞种群和活动模式 与AD中的内存功能障碍相关，并确定早期治疗干预措施的潜在靶标。