Abstract
Spinal motor networks are formed by diverse populations of interneurons that set the strength and rhythmicity of behaviors such as locomotion. A small cluster of cholinergic interneurons, expressing the transcription factor Pitx2, modulates the intensity of muscle activation via 'C-bouton' inputs to motoneurons. However, the synaptic mechanisms underlying this neuromodulation remain unclear. Here, we confirm in mice that Pitx2+ interneurons are active during fictive locomotion and that their chemogenetic inhibition reduces the amplitude of motor output. Furthermore, after genetic ablation of cholinergic Pitx2+ interneurons, M2 receptor-dependent regulation of the intensity of locomotor output is lost. Conversely, chemogenetic stimulation of Pitx2+ interneurons leads to activation of M2 receptors on motoneurons, regulation of Kv2.1 channels and greater motoneuron output due to an increase in the inter-spike afterhyperpolarization and a reduction in spike half-width. Our findings elucidate synaptic mechanisms by which cholinergic spinal interneurons modulate the final common pathway for motor output.
Highlights
Locomotion is controlled by neuronal networks of the spinal cord, referred to as central pattern generators (CPGs), which can generate and sustain rhythmic patterns of muscle activity[1,2,3]
These data clearly demonstrate that groups of Pitx2+ interneurons are rhythmically active during fictive locomotion and that, as indicated by previous single cell recordings[8], their activity patterns are tightly locked to the locomotor cycle. 125 Chemogenetic inhibition of Pitx2+ INs decreases the amplitude of locomotor output We sought to directly demonstrate the role that Pitx2+ interneurons play in controlling motoneuron output during locomotor network activity
We first investigated whether Pitx2+ interneurons could be effectively inhibited using designer receptors exclusively activated by designer drugs (DREADDs) expression
Summary
Locomotion is controlled by neuronal networks of the spinal cord, referred to as central pattern generators (CPGs), which can generate and sustain rhythmic patterns of muscle activity[1,2,3]. The CPG for locomotion is located within the spinal cord and is formed by genetically distinct classes of interneurons that drive motoneuron activity in coordinated sequences that cause precise muscle activation necessary for behaviors such as walking or swimming. These spinal neurons are functionally diverse, as evidenced by the variety of different inhibitory, excitatory and modulatory transmitters they release to shape the pattern and frequency of motoneuron firing. Our findings provide the first direct evidence of the synaptic and cellular mechanisms involved in
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