Our team aims at better understanding the mechanisms of cellular interactions, neurodegeneration and neuroplasticity in the context of Parkinson’s disease.

FOR BEGINNERS

Neurodegeneration designs the progressive pathological mechanisms leading to death of nerve cells. Many neurodegenerative disorders, including Parkinson’s disease, occur as a result of neurodegenerative processes whose causes are not fully elucidated. Understanding those mechanisms is essential for the development of preventive or curative treatments.

Adult neurogenesis in the hippocampus: morphology of newborn neuroblasts labeled by DCX (doublecortin) immunocytochemistry.

Neuroplasticity, also known as brain plasticity, refers to the capacity of the nervous system to adapt in response to experience and to internal or external stimulations by modifying the interactions between nerve cells (changes in the connections called “synapses” or in the activity) or by generating new nerve cells. This phenomenon is not limited to embryonic or post-natal development, but occurs all along the life. As an example, the production of new neurons, a process called neurogenesis, is maintained in adulthood, although being restricted to a limited number of brain regions. Neuroplasticity has been notably involved in learning and memory processes. It also occurs under pathological conditions and can either represent compensatory mechanisms counteracting the deficits triggered by neuronal dysfunction or death, or, on the contrary, contribute to or even exacerbate the deficits.

Progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc ; delineated by dotted lines) after dysfunction of excitatory amino acid transporters

Parkinson’s disease is a neurodegenerative disorder with high prevalence (second after Alzheimer’s disease), characterized by severe motor symptoms. These symptoms are resulting from the death of a population of neurons located in a deep brain region called locus niger (or “substantia nigra”) using dopamine as a neurotransmitter. Dopamine deficiency triggers dysfunction in the structures innervated by these neurons, in particular the basal ganglia, a set of structures notably involved in motor learning and movement control. Parkinson’s disease is more common in the elderly, with most cases occurring after the age of 60. The degenerative process is associated with adaptive changes in neuronal networks, including a compensatory overactivity of remaining dopamine neurons and functional or structural remodelling in other neuronal systems. The treatments at long term can also trigger adaptive phenomena underlying the maintenance of their beneficial effects or, on the contrary, the appearance of side effects. Characterizing neuroplasticity in Parkinson’s disease and in response to the current treatments might provide the bases for the development of novel therapeutic strategies.

FOR SPECIALISTS

The team combines multilevel expertise and skills to study cellular interactions and neuroplasticity in the adult brain, in particular in the context of basal ganglia-related pathologies, using rodent models.

Ongoing projects are centered on the pathophysiology and treatment of Parkinson’s disease (PD) and the role of glutamatergic systems, with 4 research axes:

1. The anatomofunctional organization of the basal ganglia network and its remodeling in response to dopamine depletion in PD.

2. The cellular/molecular bases of the beneficial or side-effects of the current treatments for PD, i.e. deep brain stimulation of the subthalamic nucleus and L-DOPA treatment, and their interactions. Particular interest is given to activity-driven plasticity by deep brain stimulation at long-term (we own a patented microstimulator allowing chronic stimulation in behaving rat), in possible relationship with motor and non-motor PD symptoms.

3. The research and preclinical evaluation of new therapeutic strategies (novel anatomical targets for DBS and new pharmacological options targeting glutamate systems, such as metabotropic glutamate receptors).

4. The cell death mechanisms linked to dysfunction of glutamate transporters, with the hypothesis that they might contribute to the progression of PD’s neuropathological processes.

Optogenetic control of the activity of striatal cholinergic neurons : in vivo electrophysiological recording illustrating the inhibition of these interneurons by photostimulation of halorhodopsine.

Our approach combines the use or development of relevant experimental models in rodents (chronic deep brain stimulation, genetic model of cell specific ablation, optogenetic modulation of neuronal activity) with a variety of analytic tools including functional anatomy, electrophysiology (in vitro and in vivo), neurochemistry and molecular/cellular  biology.

INPI n° 2942412 : Microstimulateur cerebral d’accessibilité aisée et méthode d’installation d’un tel microstimulateur (co-inventors: P. Salin, C. Forni, O. Mainard, C. Melon, E. Richard, and D. Goguenheim) CNRS Patent.