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 de...