Brain Aging Studies with Single-Neuron Resolution Using Syringe-Injectable Electronics

使用注射器注射电子设备进行单神经元分辨率的脑老化研究

• 批准号: 9789795
• 负责人: Guosong Hong
• 金额: $ 24.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789795
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Award; Axon; Brain; Brain region; Chronic; Cicatrix; Cross-Sectional Studies; Data; Electric Stimulation; Electrodes; Electronics; Electrophysiology (science); Event; Evoked Potentials; Evolution; Feedback; Functional Magnetic Resonance Imaging; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Injectable; Interdisciplinary Study; Knowledge; Learning; Long-Term Depression; Long-Term Potentiation; Longitudinal Studies; Mechanics; Medical; Memory; Memory Loss; Memory impairment; Mentors; Monitor; Motion; Mus; Neurologic; Neuronal Plasticity; Neurons; Pathologic; Patients; Performance; Phase; Population; Primates; Process; Research; Research Project Grants; Resolution; Rodent; Stimulus; Structure; Synapses; Syringes; Techniques; Technology; Therapeutic; Time; Tissues; Training; Transgenic Mice; Wild Type Mouse; age related; aging brain; base; behavior test; brain circuitry; brain tissue; career; classical conditioning; cognitive change; design; experimental study; flexibility; in vivo; interest; mechanical properties; memory retention; middle age; migration; millisecond; morris water maze; nerve stem cell; neural circuit; neuronal cell body; new technology; normal aging; pathological aging; performance tests; physical science; relating to nervous system; skills; spatial memory; spatiotemporal; technology development; tool

PROJECT SUMMARY/ABSTRACT The progress of Alzheimer’s disease involves interactions between multiple brain regions over years yet originates from electrophysiological changes in millisecond-scale firing events from micron-sized individual neurons. The spatiotemporal scales relevant to Alzheimer’s disease span many orders of magnitude and thus make it extremely challenging to study in the brain of live subjects. Our understanding of Alzheimer’s diseasde comes mainly from longitudinal studies with low spatiotemporal resolution (e.g., fMRI on human patients over years), and cross-sectional studies comparing different subject populations due to chronic instability (e.g., single-neuron electrophysiology with invasive brain electrodes). Neither approach can span the spatial-temporal scales necessary to resolve single-neuron activities, unravel long-range functional connections of neurons across multiple brain regions, and track the underlying neural circuit evolution at the single-unit level during the progression of Alzheimer’s disease and its consequential cognitive decline over extended time periods. This project proposes to use syringe-injectable mesh electronics, which has been demonstrated as a powerful tool for stable year-scale chronic tracking of the same individual neurons in rodent brains, for elucidating the single-neuron basis of Alzheimer’s disease. The capability of stable long-term recording, which is not possible with other brain interrogation techniques, is due to the unique tissue-like properties of mesh electronics. These properties include a flexibility comparable to brain tissue, feature sizes on the order of axons/somata, and macroporous structure that allows interpenetration and seamless integration of neural and electronic networks. Tissue-like mesh electronics produce minimal glial scarring that would otherwise insulate neurons from the neural probe and afford studies of the brain in its native state during development of Alzheimer’s disease without perturbing the endogenous distribution of neuronal and glial cells. I propose to carry out in-vivo longitudinal studies of Alzheimer’s disease in mice with single neuron resolution. In the mentored K99 phase of this award, I have accomplished design and fabrication of mesh electronic neural probes with a high multiplexity of 128 independent recording channels. I have optimized the in-vivo recording interface with high yield and small footprint, and the topology and spatial distribution of neural recording electrodes to afford more sensitive detection of single-unit action potentials from neurons in key brain regions underlying spatial memory. In addition, I have performed surgeries to implant the optimized mesh probes into hippocampus and other memory-related mouse brain regions via a minimally invasive injection process, and achieved chronic brain recordings during behavioral tests of spatial navigation. From chronic neural recording data from the same mouse brains, I have gleaned information on the age-dependent evolution of neural circuit connectivity, providing insight on the single-neuron basis of memory retention deficit and learning impairment during brain aging. In the independent R00 phase of this award, I plan to focus on correlation of chronic in-vivo brain recordings acquired through a wireless interface with memory-related behavioral task performance, from which causal links will be derived between chronically probed neural connectivity/plasticity and the animals’ behavioral performance during the progression of Alzheimer’s disease in a transgenic mouse model. Moreover, I will also focus on further development of this technology through localized electrical and optical stimulation with simultaneous electrophysiological recording of neural activity, to explore potential strategies for ameliorating deleterious changes in brain circuitry associated with memory loss and cognitive decline due to Alzheimer’s. The proposed research projects will demonstrate tissue-like mesh electronics, along with other neurotechnologies to be developed in my independent research lab for minimally-invasive brain interrogation and modulation, as transformative tools for addressing the real-world medical challenges of Alzheimer’s disease and cognitive aging in the brain.

项目总结/摘要 阿尔茨海默病的进展涉及多年来多个大脑区域之间的相互作用，但起源于来自微米大小的个体神经元的毫秒级放电事件的电生理变化。与阿尔茨海默病相关的时空尺度跨越许多数量级，因此在活体受试者的大脑中进行研究极具挑战性。我们对阿尔茨海默病的理解主要来自时空分辨率低的纵向研究（例如，多年来对人类患者的fMRI），以及比较由于慢性不稳定性的不同受试者群体的横断面研究（例如，具有侵入性脑电极的单神经元电生理学）。这两种方法都不能跨越解决单个神经元活动所需的时空尺度，解开跨多个大脑区域的神经元的长距离功能连接，并在阿尔茨海默病的进展过程中在单个单元水平上跟踪潜在的神经回路演变及其在延长的时间段内随之而来的认知下降。 该项目建议使用可注射的网状电子器件，该器件已被证明是一种强大的工具，可用于对啮齿动物大脑中相同的单个神经元进行稳定的年尺度慢性跟踪，以阐明阿尔茨海默病的单神经元基础。稳定的长期记录的能力，这是不可能与其他大脑审讯技术，是由于独特的网状电子组织的性质。这些特性包括与脑组织相当的灵活性，轴突/胞体数量级的特征尺寸，以及允许神经和电子网络相互渗透和无缝集成的大孔结构。组织样网状电子器件产生最小的神经胶质瘢痕，其否则将使神经元与神经探针隔离，并且在阿尔茨海默病的发展期间提供对处于其天然状态的大脑的研究，而不干扰神经元和神经胶质细胞的内源性分布。 我建议进行体内纵向研究阿尔茨海默病的小鼠与单神经元分辨率。在该奖项的指导K99阶段，我完成了网状电子神经探针的设计和制造，具有128个独立记录通道的高复用性。我已经优化了体内记录接口，具有高产量和小足迹，以及神经记录电极的拓扑结构和空间分布，以更灵敏地检测空间记忆相关的关键脑区神经元的单单位动作电位。此外，我还进行了手术，通过微创注射过程将优化的网状探针植入海马和其他与记忆相关的小鼠大脑区域，并在空间导航的行为测试中实现了慢性大脑记录。从来自相同小鼠大脑的慢性神经记录数据中，我收集了关于神经回路连接的年龄依赖性演变的信息，提供了关于大脑老化期间记忆保留缺陷和学习障碍的单神经元基础的见解。在该奖项的独立R00阶段，我计划专注于通过无线接口获得的慢性体内大脑记录与记忆相关行为任务表现的相关性，从长期探测的神经连接/可塑性和动物之间的因果关系中得出在转基因小鼠模型中阿尔茨海默病进展期间的行为表现。此外，我还将专注于进一步发展这项技术，通过局部电刺激和光学刺激，同时电生理记录神经活动，探索改善与阿尔茨海默氏症相关的记忆丧失和认知能力下降的脑回路有害变化的潜在策略。拟议的研究项目将展示类似组织的网状电子器件，沿着其他神经技术，这些技术将在我的独立研究实验室中开发，用于微创大脑询问和调制，作为解决阿尔茨海默病和大脑认知老化的现实医学挑战的变革性工具。