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Principal Investigator: Akira Nagamori
Organization: SALK INSTITUTE FOR BIOLOGICAL STUDIES
Fiscal Year: 2024
Award: $32,662
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
The ability to perform rapid, goal-directed movements accurately and efficiently is critical for interacting with the
environment. These movements have provided a key behavioral paradigm for experimental and clinical study,
helping to establish theories of sensorimotor control and to characterize motor impairments in many neurological
disorders. The accurate execution of rapid, goal-directed movements is enabled by the characteristic, reciprocal
activation of opposing muscles that accelerate and decelerate the limb in a temporally precise manner. Many
sensorimotor disorders across the nervous system (e.g. sensory deafferentation and cerebellar disease) disrupt
this characteristic muscle activation, leading to impaired motor performance. Therefore, the emergence and
disruption of this stereotyped pattern of muscle recruitment offer theoretical and clinical insights into how
sensorimotor circuits enable speed and accuracy. Yet the neural mechanisms that establish and control this
reciprocal muscle recruitment remain elusive, in large part because the relative contribution of proprioceptive
feedback from the muscles has not been clearly established. Although behavioral observations and
computational models have implicated proprioceptive feedback in coordinating limb movements, the direct
causal role of these sensory pathways in driving temporally precise muscle activation in intact, behaving animals
has been difficult to investigate. The challenge is due, in part, to the inability of traditional experimental methods
to perturb specific neural circuits in a temporally precise and reversible manner. To address these issues, this
proposal will combine a computational model of the spinal sensorimotor system with temporally precise, circuit
specific manipulation of the following: a) selective proprioceptive afferent pathways and b) a set of inhibitory
spinal interneurons that modulate the strength of proprioceptive feedback in behaving mice. Specifically, two
Aims will address key outstanding questions: 1) What are the specific proprioceptive feedback pathways that
contribute to stereotyped muscle activation patterns during the acceleration and deceleration phases of limb
movement, and during which phases of movement is proprioceptive feedback required (Aim 1)? 2) How does
temporally precise modulation of feedback strength (gain) by spinal interneurons ensure appropriate muscle
activation patterns (Aim 2)? The overarching hypothesis of this proposal is that the amplitude and timing of
agonist and antagonist muscle activity depend critically on temporally precise tuning of selective proprioceptive
feedback pathways, and disruption of such feedback causes aberrant and inaccurate movements. Answering
these questions will help to uncover the computational logic implemented by sensorimotor pathways for the
accurate and efficient execution of rapid movements and reveal how disruption of these pathways produces
motor deficits. In addition, by defining spinal circuit mechanisms that control limb movement, this work will lay
the groundwork for future studies investigating how descending motor systems recruit spinal circuits to ensure
appropriate muscle activation patterns.
Terms: <Acceleration><Address><Affect><Afferent Pathways><Agonist><Animals><Apoplexy><Automobile Driving><Behavior><Behavioral Paradigm><Biophysics><Brain Vascular Accident><Cell Communication and Signaling><Cell Signaling><Cerebellar Diseases><Cerebellar Disorders><Cerebellar Dysfunction><Cerebellar Syndromes><Cerebellum Diseases><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Characteristics><Clinical><Clinical Research><Clinical Study><Computer Models><Computerized Models><Connector Neuron><Data><Deafferentation><Deafferentation procedure><Deceleration><Diagnosis><Disease><Disorder><Dyskinesia Syndromes><Elbow><Ensure><Environment><Extensor><Extremities><Feedback><Flexor><Forelimb><Foundations><Future><Genetic><Goals><Impairment><Injury><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Joystick><Knowledge><Lead><Limb structure><Limbs><Logic><Mediating><Methods><Mice><Mice Mammals><Modeling><Molecular Genetics><Motor><Movement><Movement Disorder Syndromes><Movement Disorders><Murine><Mus><Muscle><Muscle Tissue><Nerve Cells><Nerve Unit><Nervous System><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Body System><Neurologic Disorders><Neurologic Organ System><Neurological Disorders><Neurons><Non-Trunk><Pathway interactions><Pattern><Pb element><Performance><Phase><Proprioception><QOL><Quality of life><Role><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Speed><Spinal><Stereotyping><Stroke><Structure><System><Testing><Viral><Work><antagonism><antagonist><behavior observation><behavioral observation><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><body movement><brain attack><cerebral vascular accident><cerebrovascular accident><computational modeling><computational models><computer based models><computerized modeling><defined contribution><driving><experiment><experimental research><experimental study><experiments><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><heavy metal Pb><heavy metal lead><improved><injuries><insight><kinematic model><kinematics><limb movement><motor deficit><motor impairment><mouse model><movement impairment><movement limitation><murine model><muscular><neural circuit><neural circuitry><neural mechanism><neurocircuitry><neurological disease><neuromechanism><neuronal><optogenetics><pathway><presynaptic><recruit><sensorimotor system><sensory motor system><social role><stroked><strokes><synapse inhibition><synaptic circuit><synaptic circuitry><synaptic inhibition><theories><tool>