Control of voluntary limb movement is predominantly attributed to the contralateral motor cortex. However, increasing evidence suggests the involvement of ipsilateral cortical networks in this process, especially in motor tasks requiring bilateral coordination, such as locomotion. In this study, we combined a unilateral thoracic spinal cord injury (SCI) with a cortical neuroprosthetic approach to investigate the functional role of the ipsilateral motor cortex in rat movement through spared contralesional pathways. Our findings reveal that in all SCI rats, stimulation of the ipsilesional motor cortex promoted a bilateral synergy. This synergy involved the elevation of the contralateral foot along with ipsilateral hindlimb extension. Additionally, in two out of seven animals, stimulation of a sub-region of the hindlimb motor cortex modulated ipsilateral hindlimb flexion. Importantly, ipsilateral cortical stimulation delivered after SCI immediately alleviated multiple locomotor and postural deficits, and this effect persisted after ablation of the homologous motor cortex. These results provide strong evidence of a causal link between cortical activation and precise ipsilateral control of hindlimb movement. This study has significant implications for the development of future neuroprosthetic technology and our understanding of motor control in the context of SCI.

Complexin determines magnitude and kinetics of synchronized secretion, but the underlying molecular mechanisms remained unclear. Here, we show that the hydrophobic face of the amphipathic helix at the C-terminus of Complexin II (CpxII, amino acids 115–134) binds to fusion-promoting SNARE proteins, prevents premature secretion, and allows vesicles to accumulate in a release-ready state in mouse chromaffin cells. Specifically, we demonstrate that an unrelated amphipathic helix functionally substitutes for the C-terminal domain (CTD) of CpxII and that amino acid substitutions on the hydrophobic side compromise the arrest of the pre-fusion intermediate. To facilitate synchronous vesicle fusion, the N-terminal domain (NTD) of CpxII (amino acids 1–27) specifically cooperates with synaptotagmin I (SytI), but not with synaptotagmin VII. Expression of CpxII rescues the slow release kinetics of the Ca²⁺-binding mutant Syt I R233Q, whereas the N-terminally truncated variant of CpxII further delays it. These results indicate that the CpxII NTD regulates mechanisms which are governed by the forward rate of Ca²⁺ binding to Syt I. Overall, our results shed new light on key molecular properties of CpxII that hinder premature exocytosis and accelerate synchronous exocytosis.