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

项目总结/摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其特征在于 有毒蛋白质，异常神经活动，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区域，在AD的早期过程中受到影响。此前，PI和 合作者已经表明，急性暴露于伽马频率（40 Hz）的听觉和光闪烁刺激， 驱动海马体的伽马频率神经活动此外，延长伽马刺激 急性暴露于多天刺激期可挽救小鼠的认知缺陷 AD模型然而，尚不清楚这些行为的改善是如何产生的，以及它们是否是由于 挽救已建立的神经活动缺陷。了解神经回路机制， 长时间操纵海马活动影响认知缺陷， 这项技术可以作为神经退行性疾病的治疗方法。因此，本提案的目标是研究 γ频率感觉刺激对神经连接和神经编码缺陷的功能影响 对于AD小鼠模型海马中的学习和记忆是必需的。目标1将确定如何 延长的γ刺激影响海马中兴奋性锥体细胞的抑制不足。目的2 将研究长期伽马刺激对海马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，将局部场电位和尖峰活动 头部固定的小鼠在虚拟现实（VR）中导航时， 环境这种创新的方法将允许记录清醒的、行为正常的小鼠的神经活动， 疾病的主要动物模型，具有高时间分辨率和研究所需的大量细胞 精确的神经活动拟议的工作有可能导致非侵入性的 一种挽救神经活动缺陷的方法，对阿尔茨海默病具有很有前途的翻译应用， 以及具有改变的振荡神经活动的其他神经疾病。 本申请中提出的培训将在库尔特生物医学工程系进行， 格鲁吉亚理工学院和埃默里大学医学院的联合部门。培训 将由申请人的担保人安娜贝尔·辛格博士和共同担保人加勒特·斯坦利博士监督。的 申请人将接受重要的培训，以发展完成拟议研究所需的新技能。她 我将追求各种专业发展活动，以支持她的长期职业目标，进行基本的 作为一名独立科学家在一家研究机构从事神经退行性疾病的转化研究。

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.