Reference : UMR8246-THOBES-002
Workplace : PARIS 05
Date of publication : Wednesday, September 14, 2022
Scientific Responsible name : Thomas Bessaih
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 6 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
In the mammalian brain, the cerebral cortex is the seat of integration in time and space of information from the outside world, but the proper execution of these integrations relies on a specific subcortical area: the thalamus. The thalamus is both a gateway - almost obligatory - for information flowing from the periphery to the cortex, and orchestrates the interactions between different cortical areas. The thalamus can be divided into first-order and higher-order nuclei. First-order thalamic nuclei are considered relays of sensory information flowing from the external world to the cerebral cortex, they receive only cortical modulatory inputs from layer 6 cortical neurons, while higher-order thalamic nuclei receive powerful excitatory inputs from layer 5 cortex in addition to subcortical inputs (Halassa and Sherman, 2019). The higher order thalamic nuclei occupy a large portion of the thalamus. They include the posterior part of the lateral thalamus (including the pulvinar, primarily activated by striate cortex and essential for vision), and the mediodorsal complex (primarily activated by prefrontal cortices) essential for learning and decision making (Halassa and Kastner, 2017).
It is commonly accepted that within the first-order thalamic nuclei, filtering processes of sensory information take place; in contrast, the integration processes that take place in the higher-order nuclei are poorly understood. From a functional point of view, it has been proposed that higher-order thalamic nuclei are involved in sensory processing by integrating top-down control, and thus participate in the expression of memory or in the updating of generative models of the environment based on sensory activity.
Higher-order thalamic nuclei typically receive convergent inputs from a variety of cortical and subcortical sources and are thus complex integrative centers. How these inputs are distributed at the single cell level, how they interact with each other, and how they are coordinated during brain operations are key questions that need to be addressed in order to understand the function of these thalamic nuclei.
The project aims to clarify the integration that takes place in a higher order sensory nucleus related to the somatosensory system, the posterior medial thalamus (Pom). Specifically, we will take advantage of the anatomically well-defined mouse somatosensory system that processes information from the whiskers (Petersen, 2019). The Pom receives excitatory sensory-motor afferents from the brainstem (spinal interpolar nucleus of the trigeminal complex (SpVi)), somatosensory cortex, cerebellum, and superior colliculus. But the integration of this information in the higher-order thalamus is counterbalanced by extra-thalamic inhibitory control provided by the zona incerta (ZI) and the pretectal area (APT) (Halassa and Acsády, 2016). These structures complement the inhibition provided by the reticular thalamus on most thalamic nuclei. Extra-thalamic inhibition has been proposed to be a focal, time-resolved inhibition adjusted to behavioral demand.
In particular, the ZI receives inputs from motor cortex, and it has been proposed that this structure conditions the integration of information from vibrissae into goal-directed motor behaviors (Urbain and Deschênes, 2007).
In contrast, there is very little data on the possible role of the APT. It is known that this structure is the target of different afferents, notably from layer V of the somatotosensory cortex, the cerebellum, the SpV and the ZI. Furthermore, this structure is known to be heterogeneous in terms of neuron populations (Bokor et al., 2005). In preliminary experiments in mice, our team characterized in vitro the properties of APT neurons expressing parvalbumin (PV+) and projecting to the Pom. By coupling electrophysiological recordings and single-cell RT-PCR, the team showed that these neurons are predominantly GABAergic. Moreover, by using extracellular recordings in vivo, the team also obtained preliminary data indicating that some of these neurons present responses evoked by whisker stimulations. Finally, in preliminary in vitro experiments the team have shown that optogenetic activation of these neurons evokes inhibitory postsynaptic potentials in some Pom neurons.
In this context, the objective of the project is threefold: 1) to define the anatomy of the projections of the PV+ neurons of the APT at the level of the Pom, 2) to characterize the biophysical properties of the synapse between these neurons and the neurons of the Pom, and 3) finally, to study the impact of these neurons on the responses evoked at the level of the Pom evoked by whisker stimulations.
The project will be co-supervised by Thomas Bessaih (Senior Lecturer SU), Régis Lambert (Professor SU) and Nathalie Leresche (Research Director CNRS). The PhD will also benefit from a technical support (Engineer of study SU, which will be recruited in January 2023). The project is supported by an ANR funding (ANR-21-CE16-0017-02 of the Pom-Pom project).
Constraints and risks
The project involves experiments on rodents, in vitro and in vivo electrophysiological recordings, and stereotactic virus injections. Training in animal experimentation (designer level) as well as training in surgery will be required for the project.
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