CAREER: A Neurophotonic Platform for Causal Brain Analysis

1053233 Boyden能够以时间精确的方式扰动特定细胞过程的工具在神经科学领域中对于确定这些过程何时以及如何对神经计算、行为和病理做出贡献至关重要。如果没有这样的工具，对神经元和神经网络功能的机械理解有时是试探性的，不仅限制了基础科学，也限制了临床进展，因为有助于正常功能和疾病状态的核心机制，以及可能实现潜在治疗的核心机制，可能仍然是模糊的。为了打开测试定义的神经元在紧急大脑功能中的因果作用的能力，PI最近开创了一套分子工具，当在大脑内的特定神经元类别中遗传表达时，使这些神经元能够响应特定颜色的光而被电激活和沉默。这些分子是视蛋白，来自自然界的光驱动膜蛋白，当被照射时，将电荷从细胞膜的一侧转移到另一侧。由于神经元是可电兴奋的细胞，因此这些基因在神经元中的表达和所得转基因神经元的光照可以影响它们的电激活或沉默。在过去的几年里，麻省理工学院的这个实验室已经将这些“光遗传学”试剂分发给世界各地的300个研究实验室，使这些研究小组能够研究特定细胞类型在大脑功能中的因果作用。尽管这些工具具有广泛的影响力，但它们主要用于分析神经回路，以了解特定细胞如何因果地影响行为和神经动力学;它们不能详细分析神经元内的计算过程（由特定离子通道和受体介导）对神经网络操作的贡献。因此，PI建议设计新一代分子试剂和硬件，以研究受体和离子通道在神经计算和行为中的因果作用。

1053233BoydenTools that enable the perturbation of specific cellular processes in a temporally-precise manner are critical in the field of neuroscience for determining when and how such processes contribute to neural computations, behaviors, and pathologies. Without such tools, mechanistic understandings of how neurons and neural networks function are sometimes tentative, limiting not only basic science but also clinical progress, as the core mechanisms that contribute to normal function and disease states, and that might enable potential therapies, can remain obscure. To open up the ability to test the causal role of defined neurons in emergent brain functions, the PI has recently pioneered a set of molecular tools that, when genetically expressed in specific neuron classes within the brain, enable those neurons to be electrically activated and silenced in response to specific colors of light. These molecules are opsins, light-driven membrane proteins from nature that, when illuminated, transport charge from one side of the cellular membrane to the other. Since neurons are electrically excitable cells, expression of these genes in neurons and illumination of the resultant transgenic neurons can effect their electrical activation or silencing. Over the last few years, this lab at MIT has distributed these "optogenetic" reagents to ~300 research labs around the world, enabling these groups to study the causal role of specific cell types in brain functions. Despite their broad impact, these tools are chiefly useful for analyzing neural circuits at the level of seeing how specific cells causally affect behavior and neural dynamics; they do not enable detailed analysis of the contribution of computational processes within neurons, mediated by specific ion channels and receptors, to neural network operation. Accordingly, the PI proposes to engineer a new generation of molecular reagents and hardware to enable the study of the causal roles of receptors and ion channels in neural computations and behaviors.