Stimulation of corticospinal neurons by optogenetic cAMP inductions promotes motor recovery after spinal cord injury in female rats via raphespinal tract modulation.
Por:
Martínez-Rojas B, Martín-Pérez S, Giraldo E, Lopez-Mocholi E, Alastrue A, Andrade-Talavera Y, Prius-Mengual J, Paniagua G, Pedraza M, Hingorani S, Rost BR, Schmitz D, Llansola M, Felipo V, Rodríguez-Moreno A and Moreno-Manzano V
Publicada:
1 jul 2025
Resumen:
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.
Filiaciones:
Martínez-Rojas B:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Martín-Pérez S:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain
UPV-CIPF Joint Research Unit Disease Mechanisms and Nanomedicine, Centro de Investigación Príncipe Felipe, Valencia, Spain
Lopez-Mocholi E:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Alastrue A:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Andrade-Talavera Y:
Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain
Prius-Mengual J:
Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain
Paniagua G:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Pedraza M:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Sharestist, Valencia, Spain
Hingorani S:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
Rost BR:
German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
Schmitz D:
German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
Institute of Cell Biology and Neurobiology & Neuroscience Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany
:
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
:
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain
Rodríguez-Moreno A:
Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain
:
Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain.
Green Submitted, gold
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