SEX- AND DOSE-DEPENDENT MODULATION OF FORELIMB MOTOR OUTPUT BY OREXIN-A IN INTACT AND CERVICAL SPINAL CORD–INJURED MICE

Orexinergic neurons of the lateral hypothalamus regulate arousal, motivation, and motor output, and accumulating evidence implicates orexin-A in the control of effortful, goal-directed movements. Here, we investigate sex- and dose-dependent effects of orexin-A on forelimb motor performance. We further examine how these effects manifest across motor tasks that differ in effort and adaptive demands. Male and female mice were trained in an isometric forelimb pulling task and received acute orexin-A administration at different doses using a within-subject design. During isometric pulling requiring brief force generation, orexin-A produced sex- and dose-dependent effects on motor performance, preferentially improving specific performance metrics in females without altering task engagement, while higher doses impaired performance in males. When task demands were increased by imposing sustained-force requirements, orexin-A effects followed a similar directional pattern. In line with evidence that orexin neurons are preferentially recruited during effortful and adaptive motor behaviors, we next assess orexin-A modulation in a context requiring motor relearning. Ongoing experiments examine orexin-A administration during retraining following unilateral cervical spinal cord injury. This work aims to clarify how neuromodulatory systems influence motor performance under varying effort demands and motor system states, with implications for strategies targeting functional recovery after spinal cord injury.