Matthieu Pierre Gautier | EPFL Graph Search

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Longitudinal interrogation of sympathetic neural circuits and hemodynamics in preclinical models

Suje Amir, Quentin Barraud, Grégoire Courtine, Matthieu Pierre Gautier, Rémi Bernard René Hudelle, Loïs Thomas Romain Mahe, Victor Perez Puchalt, Jan Elaine Cuevas Soriano, Jordan Squair

Neurological disorders, including spinal cord injury, result in hemodynamic instability due to the disruption of supraspinal projections to the sympathetic circuits located in the spinal cord. We recently developed a preclinical model that allows the identification of the topology and dynamics through which sympathetic circuits modulate hemodynamics, supporting the development of a neuroprosthetic baroreflex that precisely controls blood pressure in rats, monkeys and humans with spinal cord injuries. Here, we describe the continuous monitoring of arterial blood pressure and sympathetic nerve activity over several months in preclinical models of chronic neurological disorders using commercially available telemetry technologies, as well as optogenetic and neuronal tract-tracing procedures specifically adapted to the sympathetic circuitry. Using a blueprint to construct a negative-pressure chamber, the approach enables the reproduction, in rats, of well-controlled and reproducible episodes of hypotension-mimicking orthostatic challenges already used in humans. Blood pressure variations can thus be directly induced and linked to the molecular, functional and anatomical properties of specific neurons in the brainstem, spinal cord and ganglia. Each procedure can be completed in under 2 h, while the construction of the negative-pressure chamber requires up to 1 week. With training, individuals with a basic understanding of cardiovascular physiology, engineering or neuroscience can collect longitudinal recordings of hemodynamics and sympathetic nerve activity over several months. An approach to reproducing episodes of hypotension-mimicking orthostatic challenges while monitoring arterial blood pressure and sympathetic nerve activity over several months in preclinical models of chronic neurological disorders, using a combination of available telemetry technologies, optogenetics and neuronal tract tracing.

NATURE PORTFOLIO2022

Natural and targeted circuit reorganization after spinal cord injury

Mark Andrew Anderson, Quentin Barraud, Jocelyne Bloch, Grégoire Courtine, Matthieu Pierre Gautier, Thomas Haynes Hutson, Claudia Kathe, Jordan Squair

The authors summarize changes in circuits after spinal cord injury and current strategies to target these circuits in order to improve recovery, but also advocate for new concepts of reorganizing circuits informed by multi-omic single-cell atlases. A spinal cord injury disrupts communication between the brain and the circuits in the spinal cord that regulate neurological functions. The consequences are permanent paralysis, loss of sensation and debilitating dysautonomia. However, the majority of circuits located above and below the injury remain anatomically intact, and these circuits can reorganize naturally to improve function. In addition, various neuromodulation therapies have tapped into these processes to further augment recovery. Emerging research is illuminating the requirements to reconstitute damaged circuits. Here, we summarize these natural and targeted reorganizations of circuits after a spinal cord injury. We also advocate for new concepts of reorganizing circuits informed by multi-omic single-cell atlases of recovery from injury. These atlases will uncover the molecular logic that governs the selection of 'recovery-organizing' neuronal subpopulations, and are poised to herald a new era in spinal cord medicine.

NATURE PORTFOLIO2022

Confronting false discoveries in single-cell differential expression

Mark Andrew Anderson, Quentin Barraud, Grégoire Courtine, Matthieu Pierre Gautier, Rémi Bernard René Hudelle, Thomas Haynes Hutson, Nicholas David James, Claudia Kathe, Gioele La Manno, Michael Alexander Skinnider, Jordan Squair

Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries. Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.

NATURE PORTFOLIO2021