Circuit reconstruction of functionally-identified neurons in deep brain regions: application to grid cells

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Project Abstract Specialized synaptic wiring motifs have been suspected to be essential building blocks of cognition since the birth of modern neuroscience. However the technology to test these ideas has been historically unavailable. The grid cell system in medial entorhinal cortex (MEC), a deep brain area, is an exemplar of this problem. Grid cells are essential for memory and navigation. They are thought to be key in the development of Alzheimer’s disease. Yet the fundamental mechanisms underlying grid cell activity are not understood, owing to technical barriers in assessing grid cells’ wiring patterns. Here I propose to overcome these barriers, by developing a pipeline for circuit reconstruction of functionally-characterized neurons in deep brain areas. My dissertation work thus far (Aim 1) has involved co-development of such a pipeline for surface brain areas, then adaptation of this procedure for deep brain areas, using a combination of implantable optics, multiphoton calcium imaging during behavior, electron microscopy, and multimodal techniques to register both functional and anatomical data. During the independent phase (F99, Aim 2), I will apply this pipeline to grid cells in MEC, enabling definitive refutation or confirmation of the wiring patterns predicted by current theories of grid cell function. I then provide a postdoctoral plan (K00, Aim 3) for the creation of next-generation multiphoton imaging and rodent behavioral technology. This postdoctoral training at the interface of optical design and engineering methods aims to expand current capabilities for monitoring neural activity, reconstructing neural circuits, and testing theories of brain function. Overall this proposal will enable me to develop skills in circuit reconstruction and methods development for neuroscience, enhancing the probability of a career as an independent investigator in academia. Finally, I anticipate that the proposed studies will advance technical capabilities for neuroscience, and provide fundamental insight into the circuit architectures underlying memory and cognition in a brain circuit highly relevant to pressing health needs.