In The Journal of Neuroscience, Vol. 31, Issue 25, pp. 9264-9278, 2011
Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries
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.
Fig. Schematic summary of specific monoaminergic tuning functions and interactions between monoaminergic receptor systems in modulating locomotion of spinal rats. A, Representation of receptor-specific tuning function and their interactions. The size of each circle is proportional to the respective ability of each serotonergic, dopaminergic, and noradrenergic receptor subtype to modulate gait features toward those underlying locomotion of healthy rats (rightmost circle). Since many of the computed kinematic, kinetic, and EMG parameters were associated with similar aspects of locomotion, we regrouped interrelated gait features under a common label or subfunction. We thus distinguished six locomotor subfunctions: reproducibility, extension, flexion, coordination, forces, and stability, as shown for the cluster analysis. The presence and size of the color-coded arrows around each studied receptor, respectively, indicate the modulation of the related subfunction and the amplitude of this tuning. Combinations 1– 4 correspond to the combinatorial monoaminergic interventions (combos 1– 4) . This schematic representation highlights that each of the investigated monoaminergic pathways show the ability to tune unique locomotor subfunctions with distinct modulatory amplitude and that these tuning functions can sum when manipulating multiple pathways simultaneously. B, Theoretical motor functions X–Z are represented within receptors R1 and R2. For each function, the background has been colored if the receptor has the ability to tune this specific function. The intensity of the color represents the amplitude of the modulation. The modulation of functions X–Z with combinatorial interventions of receptors R1 and R2 obey to predictive tuning schemes (preservative, summative, and synergistic) that are shown in the frame R1R2.