CAREER: Superresolution Neurochemical Probe based on Stochastic Neurotransmitter Localization

了解构成感知、认知和行动基础的大脑功能组件对于开发下一代神经假体和脑机接口至关重要。这依赖于我们从数百万个神经元中重建大脑活动精确图像的能力。然而，传统的电生理技术使用当前“每电极一个神经元”的方法，缺乏可扩展性，无法读取来自数百万神经元的信号。因此，研究与神经元相互作用的新方法至关重要。为了解决这一未满足的需求，这个CAREER项目的目标是发现一种新的神经接口模式，使用脑神经化学物质，可以大规模准确地捕捉大脑的活动。该项目还将通过多维方法，包括新的高中研究项目、本科生研究经验和当地公立学校的讲座活动，在缩小科学和工程领域的知识和兴趣差距方面发挥令人兴奋的作用。该项目的主要思想是利用神经递质扩散的随机性来研究一种超分辨率神经化学成像技术。神经元的兴奋导致动作电位通过神经元体和轴突向突触传播。在突触处，这些动作电位刺激神经递质的分泌。从单个囊泡释放的神经递质分子扩散并随后到达多个相邻的电极进行测量。根据其扩散特性，可以定位神经递质分泌的精确来源。这种定位技术在原理上与三角测量相似，但它考虑了扩散路径，对神经活动进行了精确定位。该方法与三角法相比具有独特的优势，既可以根据扩散特性区分x-y位置，也可以根据扩散特性区分z位置。此外，由于分子的扩散与电压传播相比是一个较慢的过程，因此可以高精度地确定点源。使用这种方法，几个电极就可以产生高空间分辨率的神经化学成像。这种新方法将改变神经接口，使数以百万计的神经元能够同时测量，而不需要同等密度的电极。超分辨率神经化学探针将以高时空分辨率直接绘制大脑神经化学活动，有助于揭示多巴胺空间分布在认知过程中的复杂作用。这个项目不仅会产生迄今为止最先进的神经化学探针，而且还会产生超分辨率算法，可以将空间分辨率提高到纳米级。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding the functional components of the brain that underlie perception, cognition, and action is crucial for developing next-generation neural prostheses and brain-machine interfaces. This relies on our ability to reconstruct accurate images of brain activity from millions of neurons. However, traditional electrophysiological techniques using the current paradigm of the “single-neuron per electrode” approach lack the scalability to read signals from millions of neurons. Therefore, it is critical to investigate new means of interacting with neurons. To address this unmet need, the objective of this CAREER project is to discover a new neural interfacing modality using brain neurochemicals that can accurately capture the brain’s activity at a large scale. The project will also lead an exciting role in closing the knowledge and interest gaps in science and engineering via a multidimensional approach, including a new high-school research program, undergraduate research experience, and teach-in events at local public schools. The main idea of this project is to exploit the stochastic nature of neurotransmitter diffusion to investigate a superresolution neurochemical imaging technique. The excitation of neurons results in action potentials that propagate through the neuronal body and axons toward synapses. At the synapses, these action potentials instigate the secretion of neurotransmitters. Neurotransmitter molecules released from a single vesicle diffuse and subsequently reach multiple adjacent electrodes to be measured. Based on the diffusion characteristics, the precise origin of neurotransmitter secretion can be localized. This localization technique is similar to triangulation in principle, but it considers the diffusion path to make precise localization of neural activities. This method has unique advantages over triangulation by being able to distinguish both x-y location and also z position based on the diffusion characteristic. Also, because the diffusion of molecules is a slower process compared to voltage propagation, the point source can be pinpointed with high accuracy. Using this approach, a few electrodes can produce neurochemical imaging with a high spatial resolution. This new approach will transform neural interfaces by enabling simultaneous measurements from millions of neurons without requiring an equivalent density of electrodes. The superresolution neurochemical probe will help unravel the complex role of dopamine’s spatial distribution in cognitive processes by directly mapping the neurochemical activities in the brain with high spatiotemporal resolution. This project will result in not only the most advanced neurochemical probe available to date but also the superresolution algorithm that can enhance the spatial resolution into nanometers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.