Hypothalamic Control of Forelimb Motor Adaptation.

The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation.SIGNIFICANCE STATEMENT The ability to perform skilled, adaptable movements is a fundamental part of daily life, and is impaired in common neurologic diseases such as stroke. Maintaining motor adaptation is thus of great interest, but the necessary brain components remain incompletely identified. We found that impaired motor adaptation results from disruption of cells not previously implicated in this pathology: hypothalamic orexin/hypocretin neurons (HONs). We show that temporally confined HON signals are associated with skilled movements. Without these newly-identified signals, a resistance to movement that is normally rapidly overcome leads to prolonged movement impairment. These results identify natural brain signals that enable rapid and effective motor adaptation.