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.
Some example projects include:
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.
The organization of reticulospinal neurons controlling movements and posture. Among descending motor tracts, those originating in the brainstem reticular formation and termed reticulospinal neurons are the most relevant for a rapid gating of motor actions. The interruption of their connectivity is the major source of loss of motor autonomy following spinal cord injury. Yet, information about functional diversity and specialization of reticulospinal neurons is very sparse, hindering meaningful incorporation of relevant cell-types and circuits into rehabilitative contexts. We are currently pursuing investigations aiming at deciphering the diversity and specialization of reticulospinal neurons, with a particular focus on locomotion, orienting manoeuvers, and postural control.
Functional and anatomical plasticity of reticulospinal tracts following spinal cord injury. Establishing means of providing locomotor-relevant descending inputs below the lesion is thus an absolute requirement. We are thus addressing how various types of reticulospinal neurons show substantial plasticity following an experimental lesion model and contribute functionally to the improvements of locomotor function.
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 and motion capture 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