PhD project: Cortico-pallidal circuits and motor functions: optogenetic, fiber photometry and behavioral studies in normal and Parkinsonian mice

The basal ganglia (BG) are a set of interconnected subcortical nuclei involved in voluntary motor control and are target of many neurodegenerative disorders, including Parkinson’s disease (PD). The external segment of the globus pallidus (GPe) has long been regarded as a simple relay within the BG, connecting the striatum and the subthalamic nucleus in the indirect pathway. In the past years, a diversity of GABAergic cell type and anatomical connectivity of GPe were uncovered suggesting that it may rather act as an integrative hub for shaping motor and non-motor aspects of behavior. More recently, direct projections from the neocortex to GPe were uncovered indicating that these nuclei provides an entry for cortical information to the BG. Despite surge of interest over the past years, our understanding of the functional significance of the cellular diversity and anatomical connectivity of GPe remains largely incomplete.  

The aim of this project is to specify the nature of the functional relationship between the cortex and GPe in normal conditions and pathological states associated with PD. Using optogenetic approach, we recently showed that reduced neuronal activity of the GPe is a key mechanism contributing to motor deficits of PD (Di Bisceglie Caballero et al., 2023, Int. J. Mol. Sci. 24, 7935). In the present flow up project, we will use our mouse models of PD and multidisciplinary approach combining original optogenetic tools with calcium imaging and behavioral techniques to selectively manipulate cortico-pallidal projections and GPe neurons and clarify their contribution to motor deficits. Transgenic mice (FoxP2-cre and Parvalbumin (PV)-cre) will be used to specifically target FoxP2-expressing and PV-expressing neurons, which represent two distinct populations of GPe projection neurons. Dual-color optogenetic studies with blue and red lights will be used to manipulate conjointly the activity of cortical projections and GPe output neurons and determine when and how cortical control of GPe takes place. Photometric calcium recordings will be conducted in parallel to monitor changes of postsynaptic cortico-pallidal transmission. As well as enhancing our understanding of the pathophysiological mechanisms of PD, this project will also provide new grounds that may guide development of more effective and well-tailored DBS treatments.  

This project will be conducted in the team “Cognition and Pathophysiology of Basal Ganglia” headed by Drs. AM. Ouagazzal & P. Gubellini. The research team has broad-based expertise that spans neuropharmacology, biochemistry, optogenetic, behavioral genetics and patch-clamp electrophysiology. During his (her) PhD work, the student will acquire strong expertise in behavioral analysis (battery of test for cognitive, emotional and motor functions) optogenetic and fiber photometry. He/she will also acquire immunofluorescence techniques to map protein expression and brain circuitry. The student will benefit from a rich scientific and technical environment, in the CRPN, that will let him develop his/her researcher potential and communication skills. 

Skills: knowledge in optogenetic or fiber photometry, immunochemistry, Matlab or python programming.