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 foundry-based fabrication that enables mass production at the highest levels of quality and reproducibility. With approximately 20 ?m spacing between recording sites within a proberoughly the size of a single neuronand a large enough number of sites per probe, it will no longer be necessary to fine-tune the positioning of electrodes to isolate the activity of individual neurons. This will be a pivotal advance that opens the door to high-throughput electrophysiology in freely behaving animals and will enable the creation of enormous libraries of spatiotemporal patterns across brain areasan electrophysiological analogue of the genome. Testing the effects of drugs on these patterns will bridge the gap between molecular and behavioral assays with transformative implications for the pharmaceutical and biotechnology industries. Nanoprobe arrays will also have high-impact applications in neurosurgery and brain-machine interfaces, such as the high-resolution localization of epileptic foci and the development of prosthetic devices that can exploit a much richer repertoire of activity patterns than currently possible.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1)
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Freund, Michelle
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California Institute of Technology
Schools of Arts and Sciences
United States
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Hulse, Brad K; Moreaux, Laurent C; Lubenov, Evgueniy V et al. (2016) Membrane Potential Dynamics of CA1 Pyramidal Neurons during Hippocampal Ripples in Awake Mice. Neuron 89:800-13
Rios, Gustavo; Lubenov, Evgueniy V; Chi, Derrick et al. (2016) Nanofabricated Neural Probes for Dense 3-D Recordings of Brain Activity. Nano Lett :
Sauerbrei, Britton A; Lubenov, Evgueniy V; Siapas, Athanassios G (2015) Structured Variability in Purkinje Cell Activity during Locomotion. Neuron 87:840-52