U01NS133971

Enabling submillisecond-timescale two-photon recording of voltage dynamics in three dimensions in vivo - project summary/abstract.

Because neurons integrate and process information via modulation of their membrane potential, the ability to monitor voltage is critical to understanding how single and groups of neurons compute. Genetically encoded voltage indicators (GEVIs) — fluorescent proteins that report voltage dynamics as changes in brightness — are emerging as a preferred recording method because they can track voltage transients with high spatiotemporal resolution and cell type specificity.

Particularly sought after are GEVIs that perform well under two-photon (2P) microscopy, the method of choice for imaging neural activity in highly scattering tissue such as the rodent brain. We have recently demonstrated that a combination of the 2P optical recording method ULOVE and the indicator JEDI-2P enable sustained (> 30 min), fast (> 1 kHz), deep-tissue (< 400 μm) monitoring of voltage dynamics in individual neuronal somas in awake behaving mice.

However, ULOVE is fundamentally unable to record from cells and structures located in different focal planes. This is a critical limitation as neuronal computations typically involve cells or neurites located at different depths. The goal of this proposal is to address this technology gap and enable three-dimensional optical voltage recordings in awake-behaving mice.

We propose to optimize 3D-CASH, a new method that enables the three-dimensional recording of calcium dynamics but whose lower signal-to-noise ratio prevents reliable voltage recordings. We propose several complementary but independent approaches to improving the signal-to-noise ratio of voltage recordings, including hardware-based strategies for efficiently exciting cells/structures while minimizing motion artifacts and neuropil background fluorescence (Aim 1).

We also propose a new generation of GEVIs that improve the detectability of subthreshold and spikes (Aim 2) and optimized methods for subcellular localization of GEVIs to increase the signal from specific structures of interest such as dendrites or somas while reducing background contamination (Aim 3).

We anticipate that this project will produce improved GEVIs of general utility for neuroscience applications and a new optical approach that enables three-dimensional voltage recordings in vivo. These new technologies will allow the neuroscience community to ask questions that are currently technically infeasible, paving the way for a more detailed understanding of dendritic integration and neural network computations in living animals.

Baylor College Of Medicine

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.372 - 21st Century Cures Act - Brain Research through Advancing Innovative Neurotechnologies

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Houston, Texas 770303411 United States

Single Zip Code

BRAIN Initiative: Optimization of Transformative Technologies for Recording and Modulation in the Nervous System (U01 Clinical Trials Not Allowed) (RFA-NS-21-027)

Amendment Since initial award the total obligations have increased 1924% from $152,944 to $3,094,840.