The increase in pain sensitivity that follows injury is regulated by superficially located projection neurons in the dorsal horn of the spinal cord that express the neurokinin-1 (NK1) receptor. After selective ablation of these neurons in rats, we identified changes in receptive field size, mechanical and thermal coding and central sensitization of deeper dorsal horn neurons that are important for both pain sensations and reflexes. We were able to reproduce these changes by pharmacological block of descending serotonergic facilitatory pathways. Using Fos histochemistry, we found changes in the activation of serotonergic neurons in the brainstem as well as evidence for a loss of descending control of spinal excitability. We conclude that NK1-positive spinal projection neurons, activated by primary afferent input, project to higher brain areas that control spinal excitability--and therefore pain sensitivity--primarily through descending pathways from the brainstem.

Retrograde transneuronal tracing with rabies virus from the right orbicularis oculi muscle was used to identify neural networks underlying spontaneous, reflex, and learned blinks. The kinetics of viral transfer was studied at sequential 12 hr intervals between 3 and 5 d after inoculation. Rabies virus immunolabeling was combined with the immunohistochemical detection of choline acetyltransferase expression in brainstem motoneurons or Fluoro-Ruby injections in the rubrospinal tract. Virus uptake involved exclusively orbicularis oculi motoneurons in the dorsolateral division of the facial nucleus. At 3-3.5 d, transneuronal transfer involved premotor interneurons of trigeminal, auditory, and vestibular reflex pathways (in medullary and pontine reticular formation, trigeminal nuclei, periolivary and ventral cochlear nuclei, and medial vestibular nuclei), motor pathways (dorsolateral quadrant of contralateral red nucleus and pararubral area), deep cerebellar nuclei (lateral portion of interpositus nucleus and dorsolateral hump ipsilaterally), limbic relays (parabrachial and Kölliker-Fuse nuclei), and oculomotor structures involved in eye-eyelid coordination (oculomotor nucleus, supraoculomotor area, and interstitial nucleus of Cajal). At 4 d, higher order neurons were revealed in trigeminal, auditory, vestibular, and deep cerebellar nuclei (medial, interpositus, and lateral), oculomotor and visual-related structures (Darkschewitsch, nucleus of the posterior commissure, deep layers of superior colliculus, and pretectal area), lateral hypothalamus, and cerebral cortex (particularly in parietal areas). At 4.5 and 5 d the labeling of higher order neurons occurred in hypothalamus, cerebral cortex, and blink-related areas of cerebellar cortex. These results provide a comprehensive picture of the premotor networks mediating reflex, voluntary, and limbic-related eyelid responses and highlight potential sites of motor learning in eyelid classical conditioning.

Neurotrophins, as target-derived factors, are essential for neuronal survival during development, but during adulthood, their scope of actions widens to become also mediators of synaptic and morphological plasticity. Target disconnection by axotomy produces an initial synaptic stripping ensued by synaptic rearrangement upon target reinnervation. Using abducens motoneurons of the oculomotor system as a model for axotomy, we report that trophic support by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or a mixture of both, delivered to the stump of severed axons, results in either the prevention of synaptic stripping when administered immediately after lesion or in a promotion of reinnervation of afferents to abducens motoneurons once synaptic stripping had occurred, in concert with the recovery of synaptic potentials evoked from the vestibular nerve. Synaptotrophic effects, however, were larger when both neurotrophins were applied together. The axotomy-induced reduction in firing sensitivities related to eye movements were also restored to normal values when BDNF and NT-3 were administered, but discharge characteristics recovered in a complementary manner when only one neurotrophin was used. This is the first report to show selective retrograde trophic dependence of circuit-driven firing properties in vivo indicating that NT-3 restored the phasic firing, whereas BDNF supported the tonic firing of motoneurons during eye movement performance. Therefore, our data report a link between the synaptotrophic actions of neurotrophins, retrogradely delivered, and the alterations of neuronal firing patterns during motor behaviors. These trophic actions could be responsible, in part, for synaptic rearrangements that alter circuit stability and synaptic balance during plastic events of the brain.

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Target-derived neurotrophins exert powerful synaptotrophic actions in the adult brain and are involved in the regulation of different forms of synaptic plasticity. Target disconnection produces a profound synaptic stripping due to the lack of trophic support. Consequently, target reinnervation leads to synaptic remodeling and restoration of cellular functions. Extraocular motoneurons are unique in that they normally express the TrkA neurotrophin receptor in the adult, a feature not seen in other cranial or spinal motoneurons, except after lesions such as axotomy or in neurodegenerative diseases like amyotrophic lateral sclerosis. We investigated the effects of nerve growth factor (NGF) by retrogradely delivering this neurotrophin to abducens motoneurons of adult cats. Axotomy reduced the density of somatic boutons and the overall tonic and phasic firing modulation. Treatment with NGF restored synaptic inputs and firing modulation in axotomized motoneurons. When K252a, a selective inhibitor of tyrosine kinase activity, was applied to specifically test TrkA effects, the NGF-mediated restoration of synapses and firing-related parameters was abolished. Discharge variability and recruitment threshold were, however, increased by NGF compared with control or axotomized motoneurons. Interestingly, these parameters returned to normal following application of REX, an antibody raised against neurotrophin receptor p75 (p75 NTR ). In conclusion, NGF, acting retrogradely through TrkA receptors, supports afferent boutons and regulates the burst and tonic signals correlated with eye movements. On the other hand, p75 NTR activation regulates recruitment threshold, which impacts on firing regularity. To our knowledge, this is the first report showing powerful synaptotrophic effects of NGF on motoneurons in vivo.