Current Research Axis
To understand brain related diseases we need to understand the operation of the different neuronal networks that generate normal brain functions. This requires deciphering the identities and operating principles of cells executing of the function locally, as well as that of cells standing upstream its purposeful manifestation.
The team addresses this question on the motor behaviors of breathing and walking which are exquisite model systems with privileged experimental accessibility and strong translational outcomes. In these systems, tools from developmental biology are increasingly applied to manipulate – being to trace, record, kill, or modify the connectivity or activity of – subsets of neurons on the basis of their shared history of expression of specific developmental genes. This is progressively unlocking access to homogenous cell types embedded within complex architectures while informing on the intrinsic building logic of neural networks. In combination with functional investigations ex-vivo and behavior in vivo, this led rapid progress in identifying interneuronal subtypes with dedicated functions in the executive circuits for walking or breathing, often referred to as central pattern generators or CPGs. In contrast, the neuronal architecture that stand upstream the CPGs and condition their activity remains elusive. We are exploring this through two parallel projects that both touch upon the cooperative roles of clusters of brainstem and spinal cord neurons in elaborating adaptive respiratory and locomotor behaviors.
Anatomical and functional investigation of the neuronal substrate linking respiration and locomotion. Respiratory increase during exercise is probably the most striking example of respiratory adaptation. While a direct influence of the locomotor neuronal circuit onto the respiratory CPG has been proposed, it has remained largely uncharted. We are currently exploring the neuronal connections that originate in the locomotor circuit, being the CPG in the spinal cord and/or its upstream controllers in the brainstem, and that impinge onto the respiratory CPG and upregulate breathing during locomotor engagement.
Anatomical and functional investigation of reticulospinal neurons controlling locomotion. While the locomotor CPG contains all the elements necessary for producing the normal walking sequence, it is under obligatory control from descending signals conveyed by brainstem reticulospinal neurons. Yet the identities of reticulospinal neurons and that of their post-synaptic partners in the spinal CPG are still little resolved. We are currently addressing this with a particular focus on genetically-identified reticulospinal neurons that control hindlimb movements.
One leitmotiv in these projects is to imprint tools from developmental biology that are increasingly applied to subsets of neurons on the basis of their shared history of expression of specific developmental genes. We therefore use transgenic animals that express various neuronal actuators in genetically-defined cell types in combination with anatomical and functional experiments including:
Ex vivo electrophysiology, optogenetics and calcium-imaging on brainstem-spinal cord preparations;
Anatomical circuit tracing methods using straight and conditional anterograde and retrograde viral tracers;
Standard and advanced histological investigations: immunohistochemistry on tissue sections, and whole-brain clearing followed by volumetric imaging on light-sheet microscopy;
In vivo circuit optogenetics and chemogenetic manipulations;
In vivo calcium imaging of neuronal activity using micro-endoscopy;
In vivo analysis of motor function: treadmill, catwalk, open-field, electromyography, plethysmography, deep learning-based movement tracking.
A fully-equipped BSL2 laboratory is used when handling viral vectors
Confocal microscopy on brain sections is used to capture labelled neuronal circuits
The functional investigation room, equipped with optogenetic and electrophysiology rigs