SUMMARY1. Vestibular and prepositus hypoglossi (PH) neurones projecting to the abducens (ABD) nucleus were recorded in the alert cat. Their discharge characteristics were analysed to ascertain the origin of the horizontal eye position signal present in ABD neurones.2. Neurones were classified according to: their location with respect to the ABD nucleus; their antidromic activation from the ABD nucleus; the synaptic field potential they induced in the ABD nucleus with the spike-triggered averaging technique; and their activity during spontaneous and vestibularly induced eye movements.3. Vestibular neurones projecting to the ABD nucleus were located in the rostral medial vestibular nucleus. They were excitatory on the contralateral and inhibitory on the ipsilateral ABD neurones. Both types of premotor vestibular neurone showed a firing rate weakly related to eye position, increasing for eye fixations in the contralateral on-direction, and decreasing with ipsilateral fixation. Position sensitivity during eye fixations was (means + S.D.) 1-8 +09 spikes s-' deg-' for excitatory neurones and 2-2 + 1-3 spikes s-I deg-' for inhibitory neurones. Firing rate exhibited a high variability during eye fixations. Their responses during saccades in the off-direction were characterized by a pause that, although less defined, was occasionally present during saccades in the on-direction. Eye velocity sensitivity during spontaneous saccades in the on-direction was 0 17 +0.15 spikes s8-deg-' s-' for excitatory neurones and 0.15 + 0-07 spikes s-' deg-' s-' for inhibitory vestibular neurones. During sinusoidal head stimulation at 0-2 Hz, vestibular neurones showed a type I discharge rate with a phase lead over eye position of 86-0 + 14-1 deg for excitatory and 80-2 + 12-5 deg for inhibitory neurones. Position sensitivity during vestibular stimulation did not differ significantly from values obtained for spontaneous eye movements. However, the velocity sensitivity of premotor vestibular neurones during head rotation was significantly higher (I1 6 + 0-2 spikes s-1 deg-' s-' for excitatory and 1-5 + 0-3 spikes s-I deg-1 s-' for inhibitory neurones) than during spontaneous eye movements.4. PH neurones projecting to the ABD nucleus were located in the rostral one- MS 1118M. ESCUJDERO AND OTHERS third of the nucleus. These neurones were excitatory on the ipsilateral and inhibitory on the contralateral ABD nucleus. Their firing rates were correlated mainly with eye position, increasing for abducting eye positions of the ipsilateral eye and decreasing with adduction movements. Eye position sensitivities were 8 2 + 2-9 and 7-9 + 2-9 spikes s-' deg-' for excitatory and inhibitory neurones, respectively. Variability of the firing rate during eye fixations was lower than that shown by premotor vestibular neurones. During saccades, premotor PH neurones showed low eye velocity sensitivity (0 15 + 021 for the excitatory and 0 32 + 028 spikes s-' deg-' s-' for the inhibitory group) with low coefficients of correlation. During vestibular sinusoidal st...

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.

Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.

ABSTRACT

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