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Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries.

ABSTRACT: Descending monoaminergic inputs markedly influence spinal locomotor circuits, but the functional relationships between specific receptors and the control of walking behavior remain poorly understood. To identify these interactions, we manipulated serotonergic, dopaminergic, and noradrenergic neural pathways pharmacologically during locomotion enabled by electrical spinal cord stimulation in adult spinal rats in vivo. Using advanced neurobiomechanical recordings and multidimensional statistical procedures, we reveal that each monoaminergic receptor modulates a broad but distinct spectrum of kinematic, kinetic, and EMG characteristics, which we expressed into receptor-specific functional maps. We then exploited this catalog of monoaminergic tuning functions to devise optimal pharmacological combinations to encourage locomotion in paralyzed rats. We found that, in most cases, receptor-specific modulatory influences summed near algebraically when stimulating multiple pathways concurrently. Capitalizing on these predictive interactions, we elaborated a multidimensional monoaminergic intervention that restored coordinated hindlimb locomotion with normal levels of weight bearing and partial equilibrium maintenance in spinal rats. These findings provide new perspectives on the functions of and interactions between spinal monoaminergic receptor systems in producing stepping, and define a framework to tailor pharmacotherapies for improving neurological functions after CNS disorders.

SUBMITTER: Musienko P

PROVIDER: S-EPMC3422212 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries.

Musienko Pavel P van den Brand Rubia R Märzendorfer Olivia O Roy Roland R RR Gerasimenko Yury Y Edgerton V Reggie VR Courtine Grégoire G

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110601 25

Descending monoaminergic inputs markedly influence spinal locomotor circuits, but the functional relationships between specific receptors and the control of walking behavior remain poorly understood. To identify these interactions, we manipulated serotonergic, dopaminergic, and noradrenergic neural pathways pharmacologically during locomotion enabled by electrical spinal cord stimulation in adult spinal rats in vivo. Using advanced neurobiomechanical recordings and multidimensional statistical p ...[more]

PMID: 21697376

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Project description:Nitric oxide (NO) is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers. To elucidate the mathematical features of NO-mediated heterogeneous responses, the ratios of changes in firing were plotted against their original firing rates. In log-log plots, a linear data distribution demonstrated that NO-mediated heterogeneity in sympathetic firing responses was well described by a power function. Selective antagonists were applied to test if glycinergic, GABAergic, glutamatergic, and cholinergic neurotransmission in the spinal cord are involved in NO-mediated power-law firing modulations (plFM). NO-mediated plFM diminished in the presence of mecamylamine (an open-channel blocker of nicotinic cholinergic receptors), indicating that endogenous nicotinic receptor activities were essential for plFM. Applications of strychnine (a glycine receptor blocker), gabazine (a GABAA receptor blocker), or kynurenate (a broad-spectrum ionotropic glutamate receptor blocker) also caused plFM. However, strychnine- or kynurenate-induced plFM was diminished by L-NAME (an NO synthase inhibitor) pretreatments, indicating that the involvements of glycine or ionotropic glutamate receptor activities in plFM were secondary to NO signaling. To recapitulate the arithmetic natures of the plFM, the plFM were simulated by firing changes in two components: a step increment and a fractional reduction of their basal firing activities. Ionotropic glutamate receptor activities were found to participate in plFM by both components. In contrast, GABAA receptor activities are involved in the component of fractional reduction only. These findings suggest that NO orchestrates a repertoire of excitatory and inhibitory neurotransmissions, incurs a shunting effect on postsynaptic membrane properties, and thus, alters sympathetic firing in a manner of plFM. We propose that the plFM mediated by NO forms a basic scheme of differential controls for heterogeneous sympathetic regulation of visceral functions.

Dataset Information

Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries.

Publications

Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries.

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