Deciphering how the brain processes sensory information and makes behavioral decisions ultimately requires methods to record simultaneously from all the neurons in a local circuit. Of techniques used to measure neuronal activity, optical microscopy stands out as one of the few tools with the spatial resolution needed for dense ensemble recordings in thick tissue. Recently, significant progress has been made in developing probes and instrumentation for measuring neuronal activity using fluorescence. For studies of neural circuits, however, this strategy is fundamentally limited by the phototoxicity of the fluorophore: long-term, high-speed imaging needed to study circuits delivers a light dose that damages (and ultimately destroys) fluorescently-labeled cells. To overcome this problem, I propose to develop new approaches to measure spiking activity without fluorescence. The methods we will develop will perform at speeds sufficient to image large three-dimensional volumes of intact tissue thousands of times per second, sensitive enough to record each action potential, and sufficiently non-damaging to record from the same set of neurons for periods of hours. This technical advance will provide an unprecedented look at how neuronal activity generates the central computational functions of the brain. Public Health Relevance This project will develop a new non-invasive method for recording brain activity. One immediate application of the technology will be in neurosurgery, where it could be used for rapid local diagnostics during resections of tumors or epileptogenic tissue. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES. VERTEBRATE ANIMAL (Resume): ACCEPTABLE COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. SCIENTIFIC REVIEW OFFICERS NOTES: Since the NIH Director's Pioneer Award applications are reviewed differentl

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Wehrle, Janna P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Barnes, Terra D; Wozniak, David F; Gutierrez, Joanne et al. (2016) A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations. Curr Biol :
Xu, Pei Sabrina; Lee, Donghoon; Holy, Timothy E (2016) Experience-Dependent Plasticity Drives Individual Differences in Pheromone-Sensing Neurons. Neuron 91:878-892
Barnes, Terra D; Holy, Timothy E (2016) Knockout of Lysosomal Enzyme-Targeting Gene Causes Abnormalities in Mouse Pup Isolation Calls. Front Behav Neurosci 10:237
Miller, Jae-Eun Kang; Granados-Fuentes, Daniel; Wang, Thomas et al. (2014) Vasoactive intestinal polypeptide mediates circadian rhythms in mammalian olfactory bulb and olfaction. J Neurosci 34:6040-6
Turaga, Diwakar; Holy, Timothy E (2012) Organization of vomeronasal sensory coding revealed by fast volumetric calcium imaging. J Neurosci 32:1612-21