Job ID: 118111
PhD project: Cracking the neuronal code that generates the breathing rhythm
Position: Ph.D. Student
Deadline: 14 April 2024
Employment Start Date: 1 October 2024
Contract Length: 3 years
City: Marseille
Country: France
Institution: Aix-Marseille Université
Department: INMED
Description:
The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master’s degree in a non-French university. This project is one of the 13 proposed projects. Not all proposed projects will be funded, check our website for details.
State of the art. Breathing is a vital physiological function, which has to be both robust, to maintain life, and plastic, to fit metabolic and behavioral demands. The command to breath is generated in the brainstem, by a complex network of neurons. At the core of this network lies a small group of neurons, called the preBötzinger Complex (preBötC), which generates the breathing rhythm. Despite the fundamental, vital property of the breathing rhythm, how preBötC neurons generate it remains unknown.
Current theories, based on work in vitro, state that a subgroup of excitatory preBötC neurons generates subthreshold oscillations, which can lead to an excitation build-up among all preBötC neurons. The emergence of actual inspiratory bursts would depend on the level of network excitability and inputs from other brainstem respiratory neurons. However, to test these theories, one must be able to record concomitantly the electrical activity of multiple preBötC neurons, in an integrated preparation that preserves a fully functioning brainstem, while manipulating the level of network excitability or the activity of other respiratory neurons. This is now achievable thanks to recent developments in all-optical recordings and manipulations of neuronal activity.
This project aims at cracking the code of the preBötC, discovering how it generates the breathing rhythm, an unresolved mystery since the discovery of the preBötC 30 years ago.
Objectives.
- SPECIFICITY. We will identify and characterize the subthreshold oscillations in subgroups of preBötC neurons that generate the breathing rhythm.
- ROBUSTNESS. We will test if these subthreshold oscillations persist, as rhythm keepers, in conditions of low network excitability leading to apnea.
- PLASTICITY. We will determine if the subthreshold oscillations are regulated by inputs from other respiratory neurons that modulate the breathing rhythm.
Methods. The activity of preBötC neurons will be measured by 2-photon voltage imaging, on rat Working Heart-Brainstem Preparations that generate a physiological breathing command. Combinations of transgenic rats and viruses will be used to express genetically encoded voltage indicators in subgroups of preBötC neurons. The preBötC network excitability will be modulated pharmacologically, and inputs from other respiratory neurons will be modulated by optogenetics.
Expected results. We expect that a subgroup of glutamatergic preBötC neurons would display subthreshold membrane voltage oscillations at high frequency and in phase with each other via synaptic coupling. These oscillations would persist as the only activity in the preBötC in conditions of low network excitability. External inputs would determine which up-states of these oscillations lead to inspiratory bursts to modulate the breathing rhythm.
Feasibility. This project has received approval from our institutional ethics committee. All equipment and reagents necessary are present and functional in the host laboratory, including the 2-photon voltage imaging set-up (Karthala AODscope). Preliminary proof-of-concept experiments have been performed.
Expected candidate profile. We are looking for a highly motivated candidate, with strong interest in neuronal networks and technological development, and if possible a previous experience in rodent surgery, electrophysiology, and/or signal processing.