MODULATIONSPINALCORD · Modulating motor output in the mammalian spinal cord

The executive component of movement – the task of determining which muscles to activate, how intensely, and for how long – depends on neural circuits located in the spinal cord. At the core of these circuits are local interneurons (INTs) that regulate the pattern and frequency of motor neuron (MN) firing. Spinal motor activity is shaped by a combination of amino acid mediated excitation and inhibition, but the amplitude of motor bursts depends in large part on modulatory systems. I have identified the source and output of a spinal pre-motor modulatory circuit mediated by muscarinic cholinergic signaling. The transcription factor Pitx2 defines a small set of INTs that further fractionates into V0C cholinergic and V0G glutamatergic subsets. My initial findings have revealed that MNs receive prominent inputs from V0C neurons and that genetic inactivation of the output of V0C neurons impairs a locomotor task-dependent increase in the activation of specific limb muscles. These observations have provided initial information about the function of this intrinsic cholinergic modulatory system, but they leave many unresolved questions about the organization and function of the circuit.-Does V0C innervation pattern respect antagonist relationships in motor pool activity?-What are the inputs that control the function of V0C neurons?-Do V0C neurons also modulate INT output?-Does the limited impairment of motor modulation after disconnecting V0C neurons result from functional adaptation?-Do V0C and V0G neurons cooperate as dual elements in a transcriptionally defined “modulatory operon” for motor control?I will use a combination of mouse genetics, anatomy, physiology and behavior to address these questions. Inactivation or ectopic activation of V0C and V0G neurons during locomotor behaviors will be used in order to obtain new insight about the function of these modulatory networks.