The brain is a massively interconnected network of specialized circuits. Three characteristics of these circuits make them particularly challenging: diversity of time scales, diversity of spatial scales, and heterogeneity. Understanding the brain therefore requires spanning these temporal and spatial scales and providing information about cell-types. We need to be able to record the activity of individual neurons across time to understand activity patterns on a millisecond timescale and how those patterns evolve with experience across hours, days, months and even years. We need to be able to record throughout a cortical region, spanning both different parts of the region as well as all layers, to understand both local and distributed information processing. We also need to be able to combine these dense and distributed recordings with imaging to take advantage of the complementary strengths of electrical and optical measurements. This is hindered by multiple challenges: 1) Current approaches lack the spatial extent (spanning multiple structures) required to examine three-dimensional or distributed networks in detail. 2) Current electrophysiological approaches (which do provide the millisecond resolution) typically lack the necessary lifetime to follow long-term dynamics. 3) Current electrophysiological approaches use rigid electrodes that are ill-suited to use with imaging techniques. The overall objective of this project is to optimize a suite of complementary technologies that can address these challenges for the community and make them ready for common use by the neuroscience community. Our central hypothesis is that our recently developed nanoelectronic thread (NET) devices, which have demonstrated biocompatibility, in vivo function longevity, high quality unit recording and compatibility with optical methods, are a potentially ideal candidate for understanding patterns of brain activity. We plan to develop a selection of NET probes and high-density arrays that are suitable for multiple brain regions in different spices. We will engage expert neuroscientists, allowing us to develop and optimize NETs that work across mouse, rat and marmoset, and to expedite the delivery of resulting technologies to the scientific community. We will pursue the following three specific aims: 1) To optimize NET probes for various brain regions and species.; 2) To optimize NET probes for high-density regional and distributed recordings; and 3) To determine the best devices for each species and brain regions. The approach is innovative, because the technology we will develop and put into common use has the potential to drive innovation throughout the field, enabling new, very high density recording studies and allowing investigators to track large ensembles of neurons in unprecedented details and time duration.

The proposed research is relevant to public health because the development of large-scale, high-density, long- term neural recording tools has the potential to help us understand the fundamental mechanisms of neural circuitry and explore treatments of neurological conditions. Thus, the proposed research is relevant to the part of NIH’s mission that pertains to the development of new biomedical techniques and devices that will improve the understanding, treatment, and prevention of disease.