R01NS123160

Characterization of Spinal Circuits Underlying Motor Synergy Function - Abstract

The CNS performs extremely complex computations with remarkable efficiency. This is exemplified by the ability to seamlessly execute motor behaviors that necessitate the coordination of multiple muscle groups controlling joints with many degrees of freedom. It is thought that one strategy to simplify motor computations is to adopt a circuit organization that links combinations of motor pools into functional units called "synergies" or "primitives". Thus, the circuit elements that underlie motor synergies are thought to represent the basic building blocks for orchestrating the neural control of routine motor behaviors.

Elegant stimulation and recording experiments from labs working with amphibians, rodents, and primates have found evidence for motor synergy circuits within the spinal cord. The major questions addressed in this grant are: (a) what is the underlying cellular and connectivity organization of lumbar spinal motor synergy circuits, (b) what neuronal subtypes comprise these circuits, and (c) what intrinsic and extrinsic factors shape the formation of these circuits?

The laboratory has used trans-synaptic neuronal tracing, optogenetics, and molecular screens to identify a heterogenous (SATB1+, SATB2+, TCFAP2B+, TCF4+) population of interconnected excitatory and inhibitory pre-motor interneurons within lamina V of the lumbar spinal cord. Based on their properties, these lamina V cells are generically referred to as motor synergy encoders (MSE). The hypothesis is that the MSE cell network comprises a major computational node for motor control within the spinal cord. These cells receive inputs from the cortex and sensory neurons such as those that relay proprioceptive information. Thus, MSE neurons are well positioned to mediate coordinated muscle activation patterns arising from command centers for volitional movement as well as reflex pathways activated by sensory feedback locally within the spinal cord.

The aims of this grant are designed to unravel the wiring and cellular constituents within motor synergy circuits and to examine how these circuits form during embryonic development and early postnatal life. Aim 1 will create a cellular atlas and connectivity map of MSE neurons. This will define whether the molecular heterogeneity of MSE neurons corresponds to separate motor pool circuit-modules or physiologically different classes of neurons used for controlling all motor pools. Aim 2 will define the pattern of propriospinal feedback from muscles onto MSE neurons. Here, the goal is to establish whether the MSE circuit is based on simple labeled line pathways or has a more complex input-output relationship. Aim 3 will use transcription factor knockouts to determine whether hardwired intrinsic genetic programs establish the MSE circuitry. Aim 4 will test whether the functional MSE network arises from activity-dependent feedback from proprioceptive sensory neurons.

Taken together, these aims will provide a detailed molecular-cellular understanding of a critical node within the local spinal system for computing and coordinating motor activation patterns. These findings may help target motor circuits using genetics and/or neural activity to facilitate recovery from spinal cord injury.

San Diego, California Salk Institute For Biological Studies

(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]

La Jolla, California 92037 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 399% from $606,776 to $3,029,088.