Jeffrey M. Hubbard, Institut du Cerveau et de la Moelle Épinière, Paris, France

Mechanisms underlying the control of spinal excitability: from fish to mammals

Funded in: 2014, 2015, 2016

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Problem: Secondary damage after SCI results from the inflammatory response, yet little is known about the changes which occur at the level of individual synaptic connections during this neuro-immune interaction.

Target: Cerebro-Spinal Fluid contacting neurons are inhibitory neurons which modulate motor output.

Goal: Determine if CSF-contacting neurons can sense inflammatory chemical cues and transmit this information to wider spinal networks.

Neural circuits in the spinal cord give rise to locomotion through networks which produce rhythmic motor output. These “central pattern generators,” or CPGs, underlie rhythmic activities such as walking, breathing and swallowing. The Interest is focused on a specialized class of spinal neurons which is in direct contact with the cerebrospinal fluid (CSF). These CSF-contacting neurons help to shape motor output by releasing the inhibitory neurotransmitter GABA. Uniquely localized at the interface of the CSF and spinal networks, CSF-contacting neurons may sense chemical cues circulating in the CSF and transfer this information to the neural circuits responsible for generating movement. The chemical composition of the CSF can be altered in certain pathological conditions where the body must initiate an inflammatory response. The project will determine the extent to which CSF-contacting neurons can respond to circulating pro-inflammatory cues in the CSF and what effect these molecules have on CSF-contacting neuron activity.

The approach will
•    combine optogenetic (light mediated) activation of CSF-contacting neurons and electrophysiology to determine which spinal neurons receive monosynaptic innervation from the CSF-contacting neurons.
•    test the neuro-immune interaction for this sensory pathway by initiating an inflammatory response in a simple vertebrate model system, zebrafish larvae.

The findings in this model organism will then be tested in mammals.
The results from these experiments will directly address the effect of pro-inflammatory cytokines on synaptic properties of spinal networks and could help to identify targets for intervention.