Tools 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.
