Stimulation of corticospinal neurons by optogenetic cAMP inductions promotes motor recovery after spinal cord injury in female rats via raphespinal tract modulation

Beatriz Martínez-Rojas (), Samuel Martín-Pérez, Esther Giraldo, Eric Lopez-Mocholi, Ana Alastrue, Yuniesky Andrade-Talavera, Jose Prius-Mengual, Guillem Paniagua, Maria Pedraza, Sonia Hingorani, Benjamin R. Rost, Dietmar Schmitz, Marta Llansola, Vicente Felipo, Antonio Rodríguez-Moreno and Victoria Moreno-Manzano ()
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Beatriz Martínez-Rojas: Centro de Investigación Príncipe Felipe
Samuel Martín-Pérez: Centro de Investigación Príncipe Felipe
Esther Giraldo: Centro de Investigación Príncipe Felipe
Eric Lopez-Mocholi: Centro de Investigación Príncipe Felipe
Ana Alastrue: Centro de Investigación Príncipe Felipe
Yuniesky Andrade-Talavera: University Pablo de Olavide
Jose Prius-Mengual: University Pablo de Olavide
Guillem Paniagua: Centro de Investigación Príncipe Felipe
Maria Pedraza: Centro de Investigación Príncipe Felipe
Sonia Hingorani: Centro de Investigación Príncipe Felipe
Benjamin R. Rost: German Center for Neurodegenerative Diseases (DZNE)
Dietmar Schmitz: German Center for Neurodegenerative Diseases (DZNE)
Marta Llansola: Centro de Investigación Príncipe Felipe
Vicente Felipo: Centro de Investigación Príncipe Felipe
Antonio Rodríguez-Moreno: University Pablo de Olavide
Victoria Moreno-Manzano: Centro de Investigación Príncipe Felipe

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61018-3

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