Monoamine Release in the Cat Lumbar Spinal Cord during Fictive Locomotion Evoked by the Mesencephalic Locomotor Region

Abstract

Spinal cord neurons active during locomotion are innervated by descending axons that release the monoamines serotonin (5-HT) and norepinephrine (NE) and these neurons express monoaminergic receptor subtypes implicated in the control of locomotion. The timing, level and spinal locations of release of these two substances during centrally-generated locomotor activity should therefore be critical to this control. These variables were measured in real time by fast-cyclic voltammetry in the decerebrate cat’s lumbar spinal cord during fictive locomotion, which was evoked by electrical stimulation of the mesencephalic locomotor region (MLR) and registered as integrated activity in bilateral peripheral nerves to hindlimb muscles. Monoamine release was observed in dorsal horn (DH), intermediate zone/ventral horn (IZ/VH) and adjacent white matter (WM) during evoked locomotion. Extracellular peak levels (all sites) increased above baseline by 138 ± 232.5 nM and 35.6 ± 94.4 nM (mean ± SD) for NE and 5-HT, respectively. For both substances, release usually began prior to the onset of locomotion typically earliest in the IZ/VH and peaks were positively correlated with net activity in peripheral nerves. Monoamine levels gradually returned to baseline levels or below at the end of stimulation in most trials. Monoamine oxidase and uptake inhibitors increased the release magnitude, time-to-peak (TTP) and decline-to-baseline. These results demonstrate that spinal monoamine release is modulated on a timescale of seconds, in tandem with centrally-generated locomotion and indicate that MLR-evoked locomotor activity involves concurrent activation of descending monoaminergic and reticulospinal pathways. These gradual changes in space and time of monoamine concentrations high enough to strongly activate various receptors subtypes on locomotor activated neurons further suggest that during MLR-evoked locomotion, monoamine action is, in part, mediated by extrasynaptic neurotransmission in the spinal cord.

Current Principles of Motor Control, with Special Reference to Vertebrate Locomotion

“…It was later shown that noradrenaline is indeed released by stimulation of MLR (249). These effects are conveyed via the coeruleospinal pathway via ␣ 2 -and ␤ 2 -receptors (360). Although the noradrenergic system thus can contribute, locomotion can still be elicited after it has been inactivated (429).…”

“…The effects of 5-HT precursors have similar, but not identical, effects to that of DOPA, suggesting a 5-HT involvement in the control of locomotor circuits (10,11). In rodents and cats, it has been shown that 5-HT neurons in the raphe magnus nucleus are activated, when locomotor activity is turned on from for instance MLR or spontaneously (80), and that 5-HT is released in the spinal cord (360). These effects are mediated by both 5-HT 1a and 5-HT 7 receptor subtypes.…”

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats

“…These serotoninergic pathways could originate either from brainstem neurons giving rise to the descending tracts (Jordan et al, 2008) or from propriospinal interneurons (Cabaj et al, 2017). Some studies have reported that monoamines are strong modulators and/or activators of the spinal locomotor networks (Noga et al, 2009(Noga et al, , 2017, although they are not necessary to evoke locomotion (Steeves et al, 1980). Sustained monoamine release activates receptors in neurons within the spinal cord, suggesting sustained extrasynaptic transmission (Noga et al, 2017).…”

Biological data questions the support of the self inhibition required for pattern generation in the half center model

“…One possible candidate is synaptic 67 short term depression (STD) to repetitive synaptic activation. For the STD to be able 68 to create alternating oscillatory output, it needs to be at the center of two circuitry 69 components connected by reciprocal inhibition, just like in the classical half center 70 model. This mechanism has been proposed as the self-inhibitory mechanism to explain 71 alternating oscillation in the spinal cord of the lamprey [30].…”

“…The 326 neuromodulator 5-HT promotes persistent inward currents [69], so that even in an in 327 vivo experiment the neurons could be made to behave like in an in vitro setting, where 328 intrinsic conductances become more dominant than the total synaptic input activity to 329 the neuron. In another set of preparations [24,70] the animal was also paralyzed and 330 fictive locomotion was evoked by stimulation of the mesencephalic locomotor region. In 331 this case it cannot be excluded that the oscillatory behavior in the spinal neurons is due 332 to the descending activation from the brainstem.…”