MODULATIONSPINALCORD

Modulating motor output in the mammalian spinal cord

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Control of motor behaviour is a crucial factor in activities like learning to tie shoe laces or kicking a ball. EU research is investigating how the control circuitry of the nervous system manages to be so flexible.

Descrizione progetto (Article)

Variability in motor control is largely provided by systems that modulate the output of motor circuits by adjusting the properties of their neurons. One neuromodulatory system which controls movement is the C bouton system.

Using acetylcholine to send its messages, termed cholinergic, C boutons are derived from a small cluster of spinal interneurons known as ventral horn interneuron (V0C). This subset of interneurons fine-tune motor neuron firing and muscle activation according to the task being undertaken.

If acetylcholine output is reduced for genetic reasons, for example, then the ability to increase muscle activation is lost, but only partially. As this suggests some compensatory mechanism, the 'Modulating motor output in the mammalian spinal cord' (MODULATIONSPINALCORD) project set up a virus-based system to manipulate the V0C activity using light. The researchers then examined the impact on movement following inactivation or forced activation.

Recent research has indicated that the cocaine amphetamine regulated transcript (Cart) neurotransmitter is present in the cell bodies and terminals of V0C neurons. Using confocal microscopy and Volocity software, the project researchers confirmed Cart presence in presynaptic spaces.

The researchers are considering the glutamergic ventral interneurons (V0G) as another potential modulator that works in conjunction with V0C. Work already completed has shown that V0C form synapses (junctions) with V0G cell bodies and vice versa. The team is currently analysing the effects of V0G inactivation on movement.

MODULATIONSPINALCORD results will be used to obtain new insight about the function and operation of these nerve networks. The research can be extended to control of neuronal circuits in other regions of the central nervous system.