Martínez-Rojas Beatriz, Martín-Pérez Samuel, Giraldo Esther, Lopez-Mocholi Eric, Alastrue Ana, Andrade-Talavera Yuniesky, Prius-Mengual Jose, Paniagua Guillem, Pedraza Maria, Hingorani Sonia, Rost Benjamin R, Schmitz Dietmar, Llansola Marta, Felipo Vicente, Rodríguez-Moreno Antonio, Moreno-Manzano Victoria
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain.
Nat Commun. 2025 Jul 1;16(1):5885. doi: 10.1038/s41467-025-61018-3.
After spinal cord injury (SCI), cyclic adenosine monophosphate (cAMP) levels drop in the spinal cord, cortex and brainstem, unlike in regenerating peripheral neurons. To address SCI recovery, we expressed photoactivatable adenylate cyclase (bPAC) in corticospinal neurons of female rats with dorsal hemisection for on-demand cAMP inductions. bPAC stimulation restored passive and firing properties of corticospinal neurons, promoted early and sustained locomotor recovery and increased corticospinal tract plasticity. Additionally, bPAC enhanced sparing of lumbar-projecting brainstem neurons after SCI, accompanied by activation of cAMP signaling in the raphe-reticular formation and increased excitatory/inhibitory neurotransmitter balance. Accordingly, augmented density of serotonergic tracts was found caudal to the injury in bPAC rats, correlating with enhanced functional performance. Serotonergic implication in motor recovery was further evidenced by selective depletion, resulting in the abrogation of bPAC-mediated recovery. Overall, our findings underscore that cAMP induction in corticospinal neurons enhances locomotion after SCI, through a cortical rerouting pathway via the serotonergic descending tract.
脊髓损伤（SCI）后，脊髓、皮质和脑干中的环磷酸腺苷（cAMP）水平会下降，这与再生的外周神经元不同。为了解决脊髓损伤后的恢复问题，我们在雌性大鼠的皮质脊髓神经元中表达了光激活腺苷酸环化酶（bPAC），这些大鼠进行了背侧半切术，以按需诱导cAMP。bPAC刺激恢复了皮质脊髓神经元的被动和放电特性，促进了早期和持续的运动恢复，并增加了皮质脊髓束的可塑性。此外，bPAC增强了脊髓损伤后腰投射脑干神经元的保留，同时伴有中缝-网状结构中cAMP信号的激活以及兴奋性/抑制性神经递质平衡的增加。因此，在bPAC大鼠损伤部位尾侧发现5-羟色胺能纤维束密度增加，这与功能表现的增强相关。5-羟色胺能在运动恢复中的作用通过选择性耗竭进一步得到证实，导致bPAC介导的恢复被消除。总体而言，我们的研究结果强调，皮质脊髓神经元中的cAMP诱导通过5-羟色胺能下行束的皮质重新布线途径增强脊髓损伤后的运动。
