RESUMEN
The motor function of the spinal cord requires the computation of the local neuronal circuits within the same segments as well as the long-range coordination of different spinal levels. Implicated players in this process are the propriospinal neurons (PPNs) that project their axons across different levels of the spinal cord. However, their cellular, molecular, and functional properties remain unknown. Here we use a recombinant rabies virus-based method to label a specific type of long-projecting premotor PPNs in the mouse upper spinal cord that are monosynaptically connected to the motor neurons in the lumbar spinal cord. With a whole spinal cord imaging method, we find that these neurons are distributed along the entire length of the upper spinal cord with more in the lower thoracic levels. Among them, a subset of thoracic PPNs receive substantial numbers of sensory inputs, suggesting a function in coordinating the activity of trunk and hindlimb muscles. Although many PPNs in the cervical and thoracic spinal cord receive the synaptic inputs from corticospinal tract or serotonergic axons, limited bouton numbers suggested that these supraspinal inputs might not be major regulators of the PPNs in intact animals. Molecularly, these PPNs appear to be distinct from other known premotor interneurons, but some are derived from Chx10+ lineages. This study provides an anatomical basis for further exploring different functions of PPNs.
Asunto(s)
Neuronas Motoras/citología , Tractos Piramidales/citología , Células Receptoras Sensoriales/citología , Médula Espinal/citología , Animales , Femenino , Masculino , Ratones , Vías Nerviosas/citologíaRESUMEN
Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons. Axonal injury further diminished neuronal mTOR activity in these neurons. Forced upregulation of mTOR activity in corticospinal neurons by conditional deletion of Pten, a negative regulator of mTOR, enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. Furthermore, these regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury. Thus, modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury.
Asunto(s)
Regeneración Nerviosa/fisiología , Neuronas/fisiología , Fosfohidrolasa PTEN/metabolismo , Tractos Piramidales/fisiología , Envejecimiento/fisiología , Animales , Axones/fisiología , Axones/ultraestructura , Vértebras Cervicales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Bulbo Raquídeo/fisiología , Bulbo Raquídeo/fisiopatología , Ratones , Ratones Transgénicos , Neuronas/ultraestructura , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Tractos Piramidales/fisiopatología , Tractos Piramidales/ultraestructura , Corteza Somatosensorial/fisiología , Corteza Somatosensorial/fisiopatología , Médula Espinal/fisiología , Médula Espinal/fisiopatología , Médula Espinal/ultraestructura , Traumatismos de la Médula Espinal/fisiopatología , Sinapsis/fisiología , Sinapsis/ultraestructura , Serina-Treonina Quinasas TOR , Vértebras TorácicasRESUMEN
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.