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

项目总结/摘要 大脑的衰老涉及多个大脑区域之间多年的相互作用， 这是来自微米大小的个体神经元的毫秒级放电事件的电生理学变化。的 与衰老有关的时空尺度跨越了许多数量级，因此使其极其重要。 研究活体受试者大脑的衰老具有挑战性。我们对大脑衰老的理解主要来自于 具有低时空分辨率的纵向研究（例如，多年来对人类患者和灵长类动物的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，表示“单”之义 具有侵入性脑电极的神经元电生理学）。这两种方法都不能跨越时空 解决单个神经元活动所需的尺度，解开神经元的长距离功能连接 在多个大脑区域，并跟踪神经活动的演变与衰老相关的认知衰退 在很长一段时间内。最近，我们的团队展示了可注射的网状电子器件， 一个强大的工具，用于稳定长期慢性跟踪啮齿动物和灵长类动物大脑中相同的单个神经元 ≥8个月。这些能力，这是不可能与其他大脑审讯技术，是由于 网状电子器件的独特机械和结构设计。这种设计包含了灵活性 与脑组织相当，轴突/胞体数量级的特征尺寸，以及允许 神经元通过电子设备的相互渗透产生最小的胶质瘢痕， 在慢性实验期间，探针可以从探针中分离神经元，并消除探针相对于神经元的运动。我 建议在具有稳定的单细胞衰老的小鼠中进行自然和病理衰老的体内纵向研究， 神经元级分辨率。在这个奖项的指导阶段，我将专注于开发和使用注射器- 具有高复用性和适当分布的记录电极的可注射网状电子器件， 长期跟踪单个神经元和相应神经回路的电生理学演变 同时从多个关键的大脑区域，重点是神经连接和可塑性的改变 与记忆力减退和学习障碍有关。在这个奖项的独立阶段，我将 通过结合同步电刺激， 并记录神经活动，以探索改善脑内有害变化的潜在策略 与记忆和学习有关的电路。研究项目将展示 网状电子作为一种变革性工具，用于应对现实世界中的老龄化医疗挑战， 使我能够获得所需的知识和技能，超越我在物理科学方面的培训， 成功过渡到独立和高度多学科的研究生涯。

PROJECT SUMMARY/ABSTRACT Aging in the brain 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 aging span many orders of magnitude and thus make it extremely challenging to study aging in the brain of live subjects. Our understanding of brain aging comes mainly from longitudinal studies with low spatiotemporal resolution (e.g., fMRI on human patients and primates 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 evolution of neural activity during aging-related cognitive decline over extended time periods. Recently our group has demonstrated syringe-injectable mesh-like electronics as a powerful tool for stable long-term chronic tracking of the same single neurons in rodent and primate brains for ≥8 months. These capabilities, which are not possible with other brain interrogation techniques, are due to the unique mechanical and structural design of the mesh-like electronics. This design encompasses a flexibility comparable to brain tissue, feature sizes on the order of axons/somata, and macroporous structure that allows interpenetration of neurons through the electronics produce minimal glial scarring that would otherwise insulate neurons from the probe and eliminate motion of probe relative to neurons during chronic experiments. I propose to carry out in-vivo longitudinal studies of natural and pathological aging in mice with stable single- neuron-level resolution. In the mentored phase of this award, I will focus on developing and using syringe- injectable mesh electronics with high multiplexity and appropriate distribution of recording electrodes to chronically track the electrophysiological evolution of individual neurons and corresponding neural circuitry from multiple key brain regions simultaneously, with a focus on alterations in neural connectivity and plasticity associated with memory retention deficit and learning impairment. In the independent phase of this award, I will focus on further development of this technology through incorporation of simultaneous electrical stimulation and recording of neural activity, to explore potential strategies for ameliorating deleterious changes in brain circuitry associated with memory and learning due to aging. The proposed research projects will demonstrate mesh electronics as a transformative tool for addressing the real-world medical challenges of aging, and enable me to acquire the needed knowledge and skills beyond my training in the physical sciences for successful transition to an independent and highly multidisciplinary research career.