R01NS121014

Multiplexed Neurochemical Methods to Understand Adenosine Neuromodulation - Project Summary

What is the role of adenosine as a rapid modulator of neurotransmission and how can we harness its power for potential therapeutic use? To answer questions such as these, we need analytical tools that can measure multiple neurochemicals simultaneously with high temporal and spatial resolution.

Our lab pioneered fast-scan cyclic voltammetry (FSCV) for adenosine and discovered spontaneous, transient adenosine signaling that lasts only a few seconds. However, the range and effects of rapid adenosine neuromodulation are not well understood.

Genetically-encoded sensors have recently been developed for neurotransmitter and calcium detection that offer high sensitivity, selectivity, and spatial resolution. While they can monitor a wide variety of neurochemicals, and not just electroactive molecules, there are still limited colors to detect different analytes.

FSCV combined with genetically-encoded sensors would be advantageous to detect the neuromodulator adenosine and measure its downstream effects on dopamine and glutamate neurotransmission, as well as neuronal activity.

The long-term goal of my lab is to develop new tools for monitoring real-time neuromodulation in the brain. The goal of this project is to develop multiplexed tools to understand neurochemical interactions and apply these tools to understand adenosine modulation of glutamate, dopamine, and calcium.

The central hypothesis is that rapid adenosine release provides transient, but spatially localized, modulation of neurotransmitters in the brain.

In the first aim, we will develop multichannel FSCV, with an array of four electrodes, to determine how far adenosine diffuses in brain slices and the range of its neuromodulatory effects on dopamine release.

In the second aim, we will combine FSCV with genetically-encoded fluorescent sensors to probe the spatial and temporal profile of adenosine (measured with FSCV) modulation of dopamine (measured with GRABDA) or glutamate (measured with IGLUSNFR).

In the third aim, we will combine multichannel FSCV and in vivo fiber photometry measurements of genetically-encoded sensors. We will demonstrate in vivo detection of adenosine, dopamine, and calcium changes to probe adenosine neuromodulation of neurotransmission and neuronal activity simultaneously.

This research is significant because it develops tools that are broadly applicable for multiplexing neurotransmitter and neuromodulator measurements, harnessing the combined strengths of FSCV and genetically-encoded sensors. It is also significant because multiplexed tools will provide an unprecedented picture of the temporal and spatial dynamics of adenosine neuromodulation.

The biological impact is understanding the rapid and local nature of adenosine neuromodulation, which is important for designing adenosine-based therapeutics for diseases such as Parkinson's, ischemia, or traumatic brain injury where adenosine could be neuroprotective.

The multiplexed tools could be applied to monitoring many other neurochemical interactions, in brain slices or in vivo, and will advance the field of neurochemical monitoring beyond one neurochemical at a time sensing.

Rector & Visitors Of The University Of Virginia

(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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

Charlottesville, Virginia 229041002 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 380% from $629,449 to $3,018,333.