R01NS123681

The Power of Positivity: A Novel Class of Voltage Indicators for High-Fidelity Brain Activity Imaging - Abstract

To understand how the brain functions in health, and how sensory, motor, and cognitive functions are affected in disease, it is crucial to be able to record the activities of large numbers of individual neurons in real time.

In the past two decades, calcium imaging in neuronal cell bodies has provided a conveniently qualitative view of neuronal activity, allowing action potential firing in specific neuron types or in various brain regions to be correlated with sensory input, decision-making, or internal representations of emotional or physiological parameters. However, somatic calcium is generally insensitive to subthreshold activity, i.e. to synaptic inputs that depolarize the membrane potential without eliciting action potentials, and lacks the temporal precision to determine the timing relationship between action potentials within a circuit.

Our understanding of the brain would benefit greatly from understanding how neuronal circuits use transmembrane voltage to represent and process information. Outstanding questions include how neuronal types differ in their summation of inputs to initiate an action potential output, how neuronal circuits extract salient features or make a decision based on complex patterns of input activity, and how experience or neuromodulation or disease affects these processes.

We propose to address this problem by creating a class of high-performance genetically encoded voltage indicators (GEVIs) to record both subthreshold and spiking activity in large numbers of neurons in living animals. In particular, we find that positively tuned GEVIs have the potential for detecting spikes with many times greater signal-to-noise ratio than GECIs while achieving useful discriminability of subthreshold potentials.

We propose an intense effort to develop such positively tuned GEVIs toward ideal performance specifications identified by quantitative modeling. Aims include:

1. Comprehensive screening of residues in a prototype positively tuned GEVI to identify positions modulating voltage tuning and fluorescence responsiveness, followed by deep combinatorial mutagenesis of identified sites.
2. Validation of indicators in vivo in 1-photon and 2-photon imaging in flies and mice.
3. Development of an ultra-high-throughput single-cell screening system to further accelerate GEVI improvement.

The Leland Stanford Junior University

(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.

93.865 - Child Health and Human Development Extramural Research

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

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

BRAIN Initiative: New Technologies and Novel Approaches for Large-Scale Recording and Modulation in the Nervous System (R01 Clinical Trials Not Allowed) (RFA-NS-18-020)

Amendment Since initial award the total obligations have increased 8% from $3,300,000 to $3,578,964.