DESCRIPTION Abstract: Although great strides have been made in characterizing the properties of single neurons, enormous challenges remain before we understand how billions of neurons work in concert to produce complex phenomena such as perception, learning, and memory. Far and away, the biggest obstacle towards progress in systems neuroscience has been the difficulty of observing the activity of large populations of neurons in freely behaving animals. The flow of electricity in the form of action potentials and synaptic currents is the currency of the brain, and neural activity and synaptic changes are sensitive to millisecond timescales. Hence electrophysiology has been the gold standard for monitoring the brain since it directly measures electrical activity with sub-millisecond resolution. However, state of the art multi-electrode arrays have about 100 recording sites and can thus sample neuronal activity only very sparsely. This constraint makes it difficult to infer anything about global brain patterns and their evolution in time. To overcome these limitations, we propose to develop nanoprobe arrays which preserve the exceptional temporal resolution of electrophysiology while drastically increasing its spatial resolution and scale. The proposed arrays will have tens of thousands of recording sites-two orders of magnitude higher than current devices-and will enable mapping brain activity across entire volumes of brain tissue with unprecedented spatiotemporal resolution, exposing fundamental regularities far beyond the reach of current technologies. This development will fuel innovations at many levels: the design and nanofabrication of probes, integration with active electronics, development of high-speed acquisition systems, implantable interfaces for extensive testing in behaving animals, and development of computational and analysis infrastructure. Our goal is to go beyond proof of concept prototypes towards widely available transformative research tools by employing foundr

Public Health Relevancy Statement The nanoprobe arrays that we propose to develop will enable the efficient creation and standardization of large public libraries of activity patterns across multiple brain areas in freely behaving animals. These libraries will help the research community identify irregular brain activity in animal models of diseases, such as Alzheimer¿s disease and schizophrenia, and greatly accelerate testing the effects of drugs on brain activity, providing a much needed bridge between the molecular and behavioral tests that currently dominate the pharmaceutical and biotechnology industries. Finally, nanoprobe arrays will have immediate high-impact applications in neurosurgery, such as the high-resolution localization of epileptic foci, and would lead to development of brain prosthetic devices that can exploit a much richer repertoire of activity patterns than currently possible.