R35NS132326

How microglia sense and regulate neuronal activity in the adult brain - Project Summary/Abstract

Microglia are innate immune cells of the central nervous system, which interact with neurons in the adult brain. Microglial receptors and pathways have a demonstrated ability to alter complex network function. This process begins with microglia sensing specific neuronal signals. However, the downstream mechanisms used by microglia to enact specific responses/outcomes is not well understood.

The purpose of this research is to understand how microglia sense neuronal activity during hyperactivity (e.g., seizures) and hypoactivity (e.g., anesthesia), which may then trigger unique functional responses to alter neuronal circuits in the adult brain. ATP purine signaling during hyperactivity is a well-documented signal for microglia to interact with neurons in seizure, reducing seizure severity. However, the complexity of microglial intracellular (secondary messenger such as Ca2+ signaling) responses to ATP is only partially understood. Unique intracellular signaling cascades in microglia may differentially influence their functional responses.

These pathways will be interrogated using acute brain slice and in vivo two-photon imaging, along with a suite of new genetic and virus-based tools, to uncover how the calcium pathway of microglia in particular informs seizure responses. During hypoactivity, a loss of norepinephrine signaling allows microglia to better interact with neurons under anesthesia. The purpose of these interactions for network function is unknown but will be dissected using in vivo two-photon imaging of microglia-neuron dynamics in the intact brain, coupled with 3D-electron microscope reconstruction of highly detailed structural interactions.

Previous experience using chemogenetic and conditional knockout approaches to alter microglia function are also utilized to dissect specific pathways regulating hypoactive neural circuit responses. Ultimately, determining how microglia regulate neuronal function, including underlying mechanisms and their impact on circuitry, is essential to fully understand how microglia are integrated into the complex neuronal circuits as they become dysregulated in brain diseases, such as seizures and sleep disorders.

University Of Texas Health Science Center At Houston

(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 THE NEUROSCIENCE WORKFORCE, 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]

Houston, Texas 770303870 United States

Single Zip Code

Research Program Award (R35 Clinical Trial Optional) (RFA-NS-22-038)

Amendment Since initial award the total obligations have increased 453% from $575,685 to $3,182,008.