Scientific Understanding of Consciousness
Movement Control Smoothed via Presynaptic Inhibition
Nature 509, 43–48 (01 May 2014)
Presynaptic inhibition of spinal sensory feedback ensures smooth movement
Andrew J. P. Fink, Katherine R. Croce, Z. Josh Huang, L. F. Abbott, Thomas M. Jessell & Eiman Azim
Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
Center for Theoretical Neuroscience, Departments of Physiology and Neuroscience, Columbia University, New York, New York 10032, USA
The precision of skilled movement depends on sensory feedback and its refinement by local inhibitory microcircuits. One specialized set of spinal GABAergic interneurons forms axo–axonic contacts with the central terminals of sensory afferents, exerting presynaptic inhibitory control over sensory–motor transmission. The inability to achieve selective access to the GABAergic neurons responsible for this unorthodox inhibitory mechanism has left unresolved the contribution of presynaptic inhibition to motor behaviour. We used Gad2 as a genetic entry point to manipulate the interneurons that contact sensory terminals, and show that activation of these interneurons in mice elicits the defining physiological characteristics of presynaptic inhibition. Selective genetic ablation of Gad2-expressing interneurons severely perturbs goal-directed reaching movements, uncovering a pronounced and stereotypic forelimb motor oscillation, the core features of which are captured by modelling the consequences of sensory feedback at high gain. Our findings define the neural substrate of a genetically hardwired gain control system crucial for the smooth execution of movement.
Animals execute skilled limb movements with seemingly effortless precision, belying an elaborate series of neural transformations that direct each motor act. Spinal motor output relies on local inhibitory interneurons that shape the response of motor neurons to diverse excitatory inputs. Most inhibitory interneurons form direct postsynaptic connections with motor or premotor neurons, but a small subset of GABAergic interneurons instead forms axo–axonic contacts with sensory afferent terminals, regulating sensory–motor drive through a process of presynaptic inhibition. This presynaptic inhibitory system can be recruited by sensory, descending and local neuronal inputs, implying its pivotal role in the control of motor output. However, despite the occurrence of axo–axonic contacts at most sensory terminals, the predominance of postsynaptic inhibition has left unresolved the motor behavioural significance of this presynaptic control system.
Presynaptic inhibition has been characterized most extensively at proprioceptive sensory–motor synapses. Proprioceptors convey the state of muscle contraction to motor neurons, through direct and indirect feedback pathways. Elimination of proprioceptive feedback impairs motor coordination, establishing a basal requirement for sensory transmission in motor control. Conversely, limiting the gain of proprioceptive feedback has been proposed, on theoretical grounds, to be a critical determinant of motor stability. In principle, the divisive nature of presynaptic inhibition provides an effective means of controlling sensory gain but without a way to manipulate the relevant set of inhibitory interneurons it has not been possible to resolve whether, or how, presynaptic inhibition contributes to motor behaviour.
The inhibitory interneurons that form axo–axonic contacts with sensory terminals differ from other spinal GABAergic neurons in that they alone express GAD2 (also known as GAD65), one of two GABA-synthetic enzymes. We have used Gad2 as a genetic entry point for manipulating presynaptic inhibitory interneurons in mice and assessing their role in motor behaviour. Our findings indicate that Gad2-expressing interneurons mediate presynaptic inhibition at sensory–motor synapses, and that selective elimination of these interneurons elicits motor oscillations during goal-directed reaching. The essential features of this motor perturbation can be captured by a simple model in which high-gain proprioceptive feedback induces limb oscillation. This alignment of behaviour and theory argues that presynaptic inhibitory interneurons ensure the smooth operation of goal-directed motor behaviours by modulating the gain of sensory feedback.
Motor circuits throughout the central nervous system are prone to oscillation. Yet the smoothness that normally characterizes limb trajectories implies that oscillations are suppressed before motor neuron activation. Behavioural studies, in conjunction with modelling, suggest that the GABApre gain control system provides one effective means of suppressing forelimb oscillation. We observe that mice at rest lack an overt tremor, consistent with the idea that oscillations are driven by proprioceptive feedback, a central tenet of the gain model.
Our findings also emphasize the modular nature of skilled reach, in that oscillations after GABApre ablation are evident only during the forelimb reach phase, leaving the initiation and later grab phases unscathed. Such modular selectivity implies contextual recruitment of presynaptic inhibition during movement, permitting flexibility in the scaling of sensory gain. The precision of recruitment of GABApre neurons by sensory and descending pathways when coupled with the diversity of sensory neurons influenced by presynaptic inhibition hints at the existence of many GABApre neuronal subtypes, each devoted to gain control across discrete sensory feedback channels.
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