The International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.

This award will support a twenty-four month research fellowship by Dr. Amanda J. Foust to work with Dr. Valentina Emiliani at Université Paris Descartes, Paris, France.

Voltage imaging has the potential to revolutionize our understanding of how neuronal cells and circuits process and store information through a mixture of analog and digital electrical signaling in the living brain. However, low signal-to-noise ratios and high background have prevented spatial and temporal resolution adequate for tracking electrical activity on cellular and subcellular length scales in-vivo. Light sculpturing techniques such as Gradient Phase Contrast (GPC) and temporal focusing (TF) under development in Dr. Valentina Emiliani's laboratory can improve the spatial resolution of voltage imaging techniques by enabling targeted fluorescence excitation of specified cells and substructures. To this end, we are developing, adapting, and optimizing wavefront shaping technology for imaging the propagation of electrical activity in the axons and dendrites of neurons with voltage-sensitive dyes and fluorescent proteins.

Development of wavefront shaping technology for spatially targeted voltage sensing will provide a powerful tool for investigating the electrical underpinnings of sensation, perception, cognition, and behavior. Moreover, these techniques can be used to determine what fundamental circuit alterations occur with neurological diseases and disorders such as epilepsy and multiple sclerosis, and inform development of more effective therapeutic strategies.

Project Report

Electrical and chemical communication between neurons underlies our every sensation, perception, emotion, thought and action. Tracking the flow of electrical information in brain cells and circuits is essential to understanding healthy brain function, as well as how these mechanisms are compromised by neural damage, diseases, and disorders. Over the past century, investigators have probed neuronal electrical signals with metal and glass microelectrodes, impaling individual cells or "listening" the the collective roar of 100s-1,000,000s of neurons with large electrodes or electroencephalograms (EEG). Both methods generated important discoveries about the electrical nature of neurons. Both, however, fall short of the massively parallel, cellular resolution necessary to decode neuronal circuits. Recent decades have witnessed a renaissance in the ability to optically image neuronal electricity. That is, by adding voltage-sensitive dyes or genetically encodable molecules to neurons, neuroscienctists can image their electrical communication with light. The race to develop ever better voltage-sensitive fluorescence indicators (VSFIs) has engendered parallel evolution of the microscopes used to image voltage fluorescence signals. To date, investigators have exploited VSFIs primarily in "widefield" mode ; that is, by bathing the brain with light and imaging the resulting fluorescence. The drawback of this method is that, due to the scattering properties of brain tissue, images collected from one cell are often polluted by photons scattered from neighboring cells. In order to overcome this limitation, in collaboration with wavefront engineering experts at Univerité Paris Descartes, we adapted and optimized computer-generated holography (CGH) to shape light onto neurons in living brain tissue. Using holography to select which cells and structures to illuminate, we avoided light pollution for neighboring cells and structures. Specifically, by holographically shaping light alternately onto axons and dendrites, we were able to observe differences in the shape of electrical impulses traversing these two unique neuronal structures. In contrast, due to light scattered from neighboring structures, we did not observe the subtle shape differences with widefield illumination. These results demonstrate for the first time how holographically shaping light onto neurons can improve our ability to optically follow their activity. Future investigations can scale this approach up from single-cell interrogation to multi-cell and population levels, bringing neuroscientists one step closer to the goal of understanding electrical communication among neurons in large ensembles. Future insights into neuronal communication enabled by holographic light shaping can inform the development of therapies for neurological diseases and disorders.

National Science Foundation (NSF)
Office of International and Integrative Activities (IIA)
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John Tsapogas
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Foust Amanda J
United States
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