Effects of non-invasive gamma stimulation on hippocampal neural codes in a mouse model of Alzheimerâs disease

项目摘要/摘要 阿尔茨海默病(AD)是一种以积聚为特征的破坏性神经退行性疾病 有毒蛋白质，异常神经活动，以及空间学习和记忆缺陷。海马体，一个区域 大脑中对空间学习和记忆至关重要的部分在阿尔茨海默病早期就会受到影响。在此之前，PI和 合作者已经证明，急性暴露在伽马频率(40赫兹)的听觉和光闪烁刺激下 推动海马体中伽马频率的神经活动。此外，延长伽马刺激 急性症状暴露于多天刺激期可挽救小鼠的认知缺陷 AD的模型。然而，尚不清楚这些行为的改善是如何产生的，以及它们是否归因于 挽救已有的神经活动缺陷。了解神经回路机制，通过它 长时间操控海马区活动以影响认知缺陷对脑缺血的发生至关重要。 这种技术是治疗神经退行性疾病的一种方法。因此，这项建议的目标是研究 伽马频率感觉刺激对神经连接和神经编码缺陷的功能影响 对阿尔茨海默病小鼠模型的学习和记忆至关重要。目标1将确定如何 长时间的伽马刺激影响对海马区兴奋性锥体细胞的缺乏抑制。目标2 将研究长期伽马刺激对海马区活动模式缺陷的影响 对学习和记忆很重要。为了实现这些目标，当地的场势和尖峰活动将 从头部固定的小鼠在虚拟现实(VR)中导航时的许多单个神经元记录下来的 环境。这种创新的方法将允许从清醒的、表现良好的小鼠、 疾病的主要动物模型，具有高时间分辨率和大量需要研究的细胞 海马体中精确的神经活动。拟议的工作有可能导致非侵入性的 修复神经活动缺陷的方法，具有治疗阿尔茨海默病的有前景的翻译应用，如 以及其他神经活动振荡改变的神经系统疾病。 本申请中建议的培训将在库尔特生物医学工程系进行， 佐治亚理工学院和埃默里大学医学院的联合系。培训 将由申请者的赞助人安娜贝尔·辛格博士和共同赞助人加勒特·斯坦利博士监督。这个 申请者将接受大量培训，以发展完成拟议研究所需的新技能。她 会从事各种职业发展活动，支持她长期的职业目标，进行基本 作为一家研究机构的独立科学家，从事神经退行性疾病的翻译研究。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is characterized by the accumulation of toxic proteins, aberrant neural activity, and deficits in spatial learning and memory. The hippocampus, an area of the brain crucial for spatial learning and memory, is affected early in the course of AD. Previously, the PI and collaborators have shown that acute exposure to gamma frequency (40 Hz) auditory and light flicker stimulation drives gamma frequency neural activity in the hippocampus. Furthermore, extending gamma stimulation exposure from acute presentations to multiple days of stimulation periods rescues cognitive deficits in a mouse model of AD. However, it is unknown how these improvements in behavior arise, and if they are due to the rescue of established neural activity deficits. Understanding the neural circuit mechanism through which the prolonged manipulation of hippocampal activity acts to affect cognitive deficits is crucial for the development of this technique as a therapeutic for neurodegenerative disease. Thus, the goal of this proposal is to study the functional effects of gamma frequency sensory stimulation on deficits in neural connections and neural codes essential for learning and memory in the hippocampus of a mouse model of AD. Aim 1 will establish how prolonged gamma stimulation affects deficient inhibition of excitatory pyramidal cells in the hippocampus. Aim 2 will examine the effects of prolonged gamma stimulation on deficits in patterns of hippocampal activity that are important for learning and memory. To achieve these aims, local field potentials and spiking activity will be recorded from many single neurons in head-fixed mice as they navigate through a virtual reality (VR) environment. This innovative approach will allow neural activity to be recorded from awake, behaving mice, the primary animal model of disease, with the high temporal resolution and large number of cells needed to study precise neural activity in the hippocampus. The proposed work has the potential to result in a non-invasive method to rescue neural activity deficits, carrying promising translational applications to Alzheimer’s disease, as well as other neurological diseases with altered oscillatory neural activity. The training proposed in this application will take place in the Coulter Department of Biomedical Engineering, a joint department between Georgia Institute of Technology and Emory University School of Medicine. Training will be overseen by the applicant’s sponsor, Dr. Annabelle Singer, and co-sponsor, Dr. Garrett Stanley. The applicant will receive significant training to develop new skills necessary to complete the proposed research. She will pursue a variety of professional development activities to support her long-term career goal to conduct basic and translational research in neurodegenerative disease as an independent scientist at a research institution.