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Remodeling of basal ganglia circuitries in Parkinson’s disease

Voluntary movements are orchestrated by a complex network of central nervous system nuclei, the basal ganglia. Among these nuclei, the substantia nigra pars reticulata (SNr) is the output nucleus; receiving, integrating and transferring information to diverse specific output regions. As such the SNr represents a crucial node in the processing of motor control. This ability depends on the SNr anatomical organization, its cellular, morphological, and functional connectivity with both the input basal ganglia nuclei and other diverse output targets, as well as its synaptic plasticity ability, which allows flexibility when integrating motor signals. This implies that such a complex circuit organization relies on specific subcircuits and each of them may be responsible for a precise aspect of motor tasks. 

SNr circuitry
The heterogeneity of GABAergic neurons has been well described in the cortex or in the hippocampus. However the SNr has been neglected so far. Identifying and characterizing each cell population to understand its role in the dynamic of the overall basal ganglia is crucial to assess its impact at the level of motor behavior.

Our strategy relies on the use of cell type-specific transgenic mouse lines combined with viral-mediated gene delivery (optogenetic tools). This allows the identification and manipulation of one SNr neuron subtype at a time. In vitro and in vivo electrophysiology is performed to assess the local SNr functional connectivity as well as the input and output partners. Imaging techniques (confocal and electron microscopy) are valuable tools to further confirm neuronal identity and connectivity. We are developing motor-based behavioral tests that when combined with optogenetic stimulation of SNr neuronal subpopulations provide us with powerful means to assess their specific role in a precise motor task. 

Dopamine neuromodulation
Dopamine is a key modulator of synaptic function in the basal ganglia. It is produced by dopamine neurons of the substantia nigra pars compacta and released in different nuclei of the basal ganglia, including the substantia nigra pars reticulata. Such neuromodulation plays a major role in amplifying or decreasing the activity of specific subcircuits with the famous direct and indirect pathways, leading to coordinated locomotion. Here we aim at refining our knowledge and understanding of these two pathways considering the heterogeneity of the SNr. 

Remodelling of the SNr circuitry in pathological conditions
In Parkinson’s disease, the degeneration of dopamine cells leads to a loss of dopamine neuromodulation modifying neuronal morphology and their connectivity, which impacts synaptic transmission. Such reorganization drives the typical clinical motor symptoms of the disease, specifically a difficulty in initiating movements, resting tremor, stiffness, slowing of movement and postural instability. We are using a chemically induced mouse model of Parkinson’s disease. A complete investigation of the alterations induced after dopamine depletion will provide a ground to develop in vivo optogenetic manipulations in order to reverse or compensate the behavioral motor symptoms.

This study of the SNr circuitry will offer insights into the still poorly understood physiological mechanisms linking cell-type specificity and synaptic function to basal ganglia network activity and behavior. In addition, the study of alterations/remodeling within this system in a model of Parkinson’s disease will provide detailed knowledge of the cellular basis of motor disorders, which may lead to novel therapeutic strategies.

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