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Reference : UMR8197-NATBOI-080
Workplace : PARIS 05
Date of publication : Monday, July 19, 2021
Scientific Responsible name : Stéphane DIEUDONNE
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 September 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
This project aims to understand how the cerebellum and motor control centers in the brainstem work together to control posture and movement. Postural maintenance and the implementation of harmonious movements both require that the strength of each muscle be continuously adjusted to the motor action during its execution and to the external conditions liable to alter it. However, each muscle is controlled, directly or indirectly, by a stack of independent command centers. The cerebellum, wired as a bypass of the motor and sensory systems, is the only structure in the position to provide global motor coordination. On the one hand, the cerebellum integrates sensorimotor copies from the whole body and, on the other hand, projects back to all hierarchical levels of motor control. Nevertheless, the rules of connectivity between sensory afferents, cerebellum, and descending motor pathways, which allow muscle-to-muscle adjustment, remain to be characterized. This thesis will seek to analyze the functional organization of glutamatergic and glycinergic neurons in the deep nuclei of the cerebellum. Our preliminary data indicate that these neurons project in an orderly manner relative to microzones and lobules of the cerebellar cortex, where they send axon collaterals. We will seek to determine the functional correlates of this organization by privileging the hypothesis, supported by previous results and our current observations, that the cerebellum is functionally organized relative to each muscle, or to each group of muscles providing motor coordination.
The candidate will combine retrograde labelling of deep nucleus neurons from cortical microzones, with viral retrograde labellings (in collaboration) initiated from a specific medullary segment or motor neuron group of muscles involved in postural maintenance. This will reveal how the output nuclei of the cerebellum interface between the process of sensory integration and motor control. We hypothesize that a cerebellar projection neuron controls a single muscle group, but at multiple hierarchical levels. These anatomical investigations will be carried out by a methodology combining tissue clearing, imaging of whole brains, and semi-automated anatomical tracing. This will make it possible to very precisely reconstruct the position of the labelled neurons, to examine a possible somatotopic organization of the pathways revealed, to follow the axonal paths of individual neurons between distant regions, and to detect synaptic contacts between partners at the cellular level.
In parallel, the candidate will analyze the activity of the projection excitatory neurons of the deep nuclei associated with a cortical microzone during motor tasks, by novel in vivo imaging methods at high temporal resolution (see below). He / she will seek to demonstrate the functional correlate of this neuronal activity. Furthermore, the targets of recurrent axons of these neurons in the cerebellar cortex will be identified and the synaptic connections characterized in vitro. The activity and function of these targets during movement will be dissected by calcium or voltage imaging and optogenetic manipulation in vivo.
This project proposes a novel perspective on the functional architecture of motor control, whose different actors, often studied independently, must cooperate for the execution of harmonious movements. These data will ultimately be instrumental in understanding and remedying motor imbalances in pathological conditions affecting the cerebellum or the ascending and descending spinal tracts.
The ENS Institute of Biology (IBENS) teams conduct research aimed at deciphering the fundamental mechanisms at the heart of biological processes. A joint ENS-CNRS-INSERM unit, IBENS welcomes more than 300 staff grouped into 30 independent teams conducting highly collaborative and multidisciplinary research, which combines experimental and theoretical approaches. The research activity covers four main fields: Neurosciences, Developmental biology, Functional genomics, Ecology and evolutionary biology.
Several technological platforms, particularly in imaging, genomics, proteomics and bioinformatics, are available. Research carried out at IBENS benefits from interactions with other disciplines present at ENS (physics, chemistry, cognitive sciences, mathematics). IBENS is actively involved in the training of students and young researchers at all levels.
The "Inhibitory transmission and neural computation" team, led by Séphane Dieudonné, includes 5 statutory researchers, 1 assistant engineer, 2 postdoctoral researchers and 3 doctoral students.
The team's goal is to study the operations performed by the cerebellar microcircuit and understand how they contribute to the genesis of fine-tuned and coordinated motor control. After two decades dedicated to the cellular, molecular and functional dissection of the neuronal types constituting the cerebellar microcircuit, the team's work now mainly focuses on the study of the activity of these neuronal types in awake animals during the performance of motor tasks. To this end, the team developed disruptive optical methods such as two-photon random access microscopy, which made it possible for the first time to record optically the membrane potential of a neuron at depth using genetically encoded voltage indicators (GEVI) developed recently.
The candidate will work in close collaboration with Jonathan Bradley (CR1 INSERM) and Stéphane Dieudonné (DR2 INSERM), particularly for all aspects of the work concerning genetic approaches and the morpho-functional tracing of neuronal connections in the whole brain. He will also interact with Vincent Villette (CR1 CNRS) for aspects concerning behavior and in vivo imaging and with Aurélien Gouhier (PhD student) for aspects concerning quantitative analysis of movement. The thesis project is funded by an ANR in collaboration with Julien Bouvier's team, which will bring its expertise and contribution in terms of the genetic and functional organization of the motor circuits of the brainstem and the spinal cord, as well as for retrograde viral tracing strategies.
Constraints and risks
The candidate should have a solid training in cellular and systems neuroscience and a practice of experimental work in this field. Knowledge of theoretical and computational neuroscience or imaging is a plus. Knowledge and practice of programming languages (Matlab, Python) will be appreciated.
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