All-optical electrophysiology: probing real-time dynamics of neural circuits

全光学电生理学：探测神经回路的实时动态

• 批准号: BB/W010623/1
• 负责人: Jacques Carolan
• 金额: $ 51.8万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW010623%2F1
• 关键词: optical; electrophysiology; probing; real; time

Understanding how patterns of electrical signals within the brain give rise to complex behaviour --- the 'neural code' --- is critical for not only discovering the neural basis of fundamental processes such as learning, decision making and cognition; but also for treating neuropsychiatric pathologies and motor impairments. The challenge is that unlike a computer, the neurons in the brain are highly recurrent, nonlinear and have long range interactions that vary across very short (millisecond) and very long (years) times-scales. The overall aim of this fellowship is to develop a tool that can dynamically interact with the brain at sufficient scale and resolution to reverse-engineer the neural circuitry. Much like how self driving cars build a model of the world (e.g. other cars, road geometry, road surface) by dynamically interacting with it (accelerating, braking, imaging); the systems proposed here will dynamically interrogate populations of neurons --- at cellular-level resolution and with temporal dynamics comparable to individual action potentials --- to generate models of key neural processes and 'reverse engineer' the neural circuitry. Such a system would not only have radical implications for our understanding of basic processes such neural representation; but also could be used to 'drive' neuronal circuits, which would enable new frontiers in brain machine interfaces for neuropsychiatric prosthetics and clinical applications such as seizure prevention.The gold-standard for interrogating electrical signals from individual neurons are electrophysiology techniques. However these require bulky electrical probes to be inserted into the brain, making it impossible to access large populations of neurons. Instead, I will address neuronal circuits using an entirely different modality: light. Nature has provided us with light sensitive proteins that can either optically report electrical changes with variations in fluorescence or generate an electrical signal under optical excitation. By engineering these proteins into neurons, it is possible to optically readout and control electrical activity in the brain. This fellowship will perfect a new type of reporter called a 'voltage indicator' that directly reports action potentials rather than proxies for voltage change, such as calcium variations. Calcium changes happen two orders of magnitude slower than a typical action potential, meaning that critical timing information is lost. In contrast, voltage indicators observe action potentials in real-time, which is critical for dynamically interacting with the brain --- a self-driving car with a camera delay would quickly crash! To keep pace with these rapid dynamics, I will develop ultra-fast optical hardware to readout and control electrical signals all within the time it takes an action potential to propagate, and at sufficient scale to access neuronal circuits. Moreover, by closing the loop between readout and control, it will be possible to trigger a neuron to spike, then 'track' the neurons that respond, thus determining the wiring diagram. This 'all-optical' approach enables high-throughput cellular resolution connectomics (i.e. functional connection mapping of circuits) in vivo, and would be transformative to our understanding of the structure of the nervous system, e.g. for identifying circuit defects in neuropsychiatric disorders.This fellowship, hosted at the Wolfson Institute for Biomedical Research at UCL, builds tools to ask entirely new questions about the function and structure of the brain, which are not possible using existing technology. It would have wide ranging applications in neuroscience and beyond (including cardiac, renal, and hepatic physiology). The proposed fellowship is therefore very well aligned with the BBSRC priority area 'biosciences for health' under the 'technology development for the biosciences' responsive mode priority.

了解大脑内的电信号模式如何产生复杂的行为——“神经代码”——不仅对于发现学习、决策和认知等基本过程的神经基础至关重要，而且对于发现学习、决策和认知等基本过程的神经基础也至关重要。还用于治疗神经精神病理和运动障碍。挑战在于，与计算机不同，大脑中的神经元具有高度重复性、非线性，并且具有长程相互作用，这些相互作用在很短（毫秒）和很长（年）的时间尺度上变化。该奖学金的总体目标是开发一种工具，能够以足够的规模和分辨率与大脑动态交互，以对神经回路进行逆向工程。就像自动驾驶汽车如何通过动态交互（加速、制动、成像）来构建世界模型（例如其他汽车、道路几何形状、路面）；这里提出的系统将动态地询问神经元群体——以细胞水平的分辨率和与个体动作电位相当的时间动态——生成关键神经过程的模型并对神经电路进行“逆向工程”。这样的系统不仅会对我们理解神经表征等基本过程产生根本性的影响；而且还可以用于“驱动”神经元回路，这将为神经精神假肢和癫痫预防等临床应用的脑机接口开辟新领域。询问单个神经元电信号的黄金标准是电生理学技术。然而，这些需要将笨重的电探针插入大脑，从而无法访问大量神经元。相反，我将使用一种完全不同的方式来处理神经元回路：光。大自然为我们提供了光敏蛋白质，它们可以通过光学方式报告荧光变化的电变化，也可以在光激发下产生电信号。通过将这些蛋白质工程化到神经元中，可以光学读出并控制大脑中的电活动。该奖学金将完善一种称为“电压指示器”的新型报告器，它直接报告动作电位，而不是电压变化的代理，例如钙变化。钙变化的发生速度比典型动作电位慢两个数量级，这意味着关键的计时信息丢失。相比之下，电压指示器实时观察动作电位，这对于与大脑动态交互至关重要——带有摄像头延迟的自动驾驶汽车很快就会崩溃！为了跟上这些快速动态的步伐，我将开发超快光学硬件，以在动作电位传播的时间内读出和控制电信号，并以足够的规模访问神经元电路。此外，通过闭合读出和控制之间的循环，将有可能触发神经元尖峰，然后“跟踪”做出响应的神经元，从而确定接线图。这种“全光学”方法可以实现体内高通量细胞分辨率连接组学（即电路的功能连接映射），并将彻底改变我们对神经系统结构的理解，例如神经系统。用于识别神经精神疾病中的回路缺陷。该奖学金由伦敦大学学院沃尔夫森生物医学研究所主办，旨在构建工具来提出有关大脑功能和结构的全新问题，这是使用现有技术无法实现的。它将在神经科学及其他领域（包括心脏、肾脏和肝脏生理学）具有广泛的应用。因此，拟议的研究金与 BBSRC 在“生物科学技术开发”响应模式优先事项下的优先领域“生物科学促进健康”非常一致。