A fully biological platform for monitoring mesoscale neural activity One of the barriers to understanding the human brain is due to its geometry. Accessing brain tissue at single cell resolution has classically involved implanting electrodes (metallic or optical) directly into the brain. For deep subcortical structures, these approaches result in tissue destruction across the shallow brain areas that must be traversed to access deeper targets. Thus, classic approaches are fundamentally unable to allow concurrent sampling of activity from healthy fully intact tissue at all sites of the brain. While many novel technologies that exploit miniaturized nanoscale recording electrodes will increase number of single cells that can be recorded concurrently in the same brain, these approaches do not address the challenge raised by the geometry of the brain. We intend to develop a new technology to ‘functionally’ change the geometry of the brain by biologically projecting neural activity onto a flat surface outside of the brain. This ‘biological electrode’ will allow for the concurrent acquisition of single cell activity from all depths of fully intact brain tissue in awake-behaving animals. Furthermore, this technology will offer several advantages over currently available approaches: 1) Unlike metallic recording electrodes which induce fibrosis at the metal-brain interface and ultimately diminish signal quality, the fully biological electrode will allow investigators to stably monitor brain activity throughout the entire lifespan of model organisms; 2) The biological patch will utilize engineered proteins to form physical connections with target cell types. Thus, this technology will rival gold-standard in vivo intracellular recording approaches such as glass-pipette patching; 3) Since the engineered proteins that form the physical connections between the biological electrode and target cells can be targeted to individual cellular compartments, the biological patch will allow neural activity to be directly acquired from the soma, dendritic spines, and/or axons of single cells in a cell type specific manner; 4) Finally, the biological patch will be readily scalable to allow for recordings from 100,000s of single cells simultaneously. Thus, successful completion of this high-risk project will revolutionize neural recordings across model species and humans.

One of the barriers to understanding the human brain is due to its geometry. We intend to develop a new technology to ‘functionally’ change the geometry of the brain from 3D dimensions by biologically projecting it onto a 2D surface that can be imaged in real time. This approach will be readily scalable to allow for recordings from millions of single cells simultaneously throughout the entire depth of the brain, revolutionizing neural recordings across model species and humans.