Parkinson's disease, which is caused by the degeneration of dopamine neurons in the substantia nigra pars compacta affects more than 4 million people worldwide and is characterized by bradykinesia, rigidity and resting tremor. The Basal Ganglia (BG) are a group of subcortical nuclei involved in motor control and movement related disorders. Within the BG, the GABAergic globus pallidus (GP) occupies a critical position through its widespread projections to the entire network. Furthermore, emergence of abnormal synchronised rhythmic bursting in the GP is associated with akinesia and resting tremor in Parkinson's disease (PD). Therefore, understanding the origin of the synchronization and rhythmic oscillations in this nucleus is of particular interest. The GP can be subdivided in two main populations of GABAergic neurons which express either enkephalin (GP-ENK) or parvalbumin (GP-PV). GP neurons control each other's activity via axon collaterals, but the nature of the interactions between these two populations remains elusive. In addition, GABAergic GP neurons are reciprocally connected with glutamatergic subthalamic nucleus (STN) neurons and this excitatory-inhibitory circuit is considered as the central pattern generator of the BG. As GP neurons excitability is under the control of their axon collaterals, alteration of lateral inhibition in the GP has been proposed to be a key factor in the emergence of correlated bursting activity in the GP-STN network. The main hypothesis that will be tested in this project is that the loss of dopamine in PD leads to abnormal lateral inhibition in the GP, which contribute in part to the emergence of pathological firing pattern. Therefore, the main objective is to study lateral inhibition in the GP and its regulation by dopamine by using electrophysiological recordings of GP neurons in rat brain slices combined to molecular biology and immunohistochemistry. The influence of dopamine will be assessed by comparing neuronal excitability and GABAergic synaptic transmission in absence and presence of dopamine receptor agonists and in normal and dopamine-depleted animals. There are 3 specific aims (SA) of this project: SA1:. We will characterize the impact of dopamine on neuronal excitability, the nature of the dopamine receptor(s) involved in this modulation and determine which ionic channels are the effectors of this modulation in these two population of neurons. SA2: We will study pallidal lateral inhibition by defining the properties of pallido-pallidal synapses, by determining their synaptic plasticity and the influence of dopamine on the release of GABA in the GP. We will also determine how GABAergic inhibition is integrated by GP neurons and how it affects their excitability. SA3: Finally, the alteration of lateral inhibition in dopamine-depleted animals will be studied. We will use the gold-standard model of PD, the unilateral 6-hydroxydopamine lesioned rats and we will look for changes of lateral inhibition and GABAA receptor subunit expression between intact and dopamine-depleted animals. With the present project, we expect to elucidate the GABAergic microcircuit in the GP, and its role in normal and pathological neuronal activity. This project will generate a comprehensive analysis of GABAergic regulation of this nucleus.

The present conception of social justice is progressively concentrating on fighting discriminations. One questions less the inequalities between social positions than the access of a number of individuals and groups to all kinds of social positions. In this picture, the inequalities considered most scandalous are those resulting from discriminations against foreigners, migrants, disabled persons or women, as they cannot equally compete for access to certain goods, particularly education, employment, housing, media, politics…, being more or less brutally and explicitly discriminated. A great number of measures, laws, charts of good conduct and institutions, including the HALDE, aim at fighting these discriminations. Support to this model of justice and to the representations of social life it mobilizes is so strong that, very often, we just limit ourselves to measuring discriminations and denouncing them. Our research project does not aim at measuring discriminations or at analysing the effects of political actions intending to reduce them. Our goal is first of all to analyse the social experience of discriminated persons in order to find out how they cope and explain the discriminations suffered, how they perceive them as injustices, why they rebel, give up or adapt. In this way, we want to seize discriminations as social experiences and as implementations of a “spontaneous” practical political philosophy defining situations and conducts as being more or less just. In order to understand experiences discriminated persons go through, we have to also study the experiences of actors who more or less voluntarily inflict these discriminations. Ultimately, we will try to define the normative syntax of actors of discriminations on both sides. The duration of this research project is 30 months. It will concern women and “visible minorities” in four areas: education, work, media and politics. In each field, in Paris and the provinces, we intend to make about thirty personal interviews and to organize a sociological intervention, i.e. several sessions of debate between discriminated and discriminating persons. In the end, this research will be based on observations, approximately 120 personal interviews and 4 sociological interventions during which persons in charge and militants of the fields will be heard. We thus wish to understand the experiences, reasons and arguments of actors directly concerned with discriminations. We make the hypothesis that there may be a certain distance between the philosophies and politics leading the denunciation and fight against discriminations, and the practical experiences and political philosophies of actors directly concerned by them. This research will be conducted within the CADIS in Bordeaux (UMR EHESS/Bordeaux 2). The team of researchers is composed of François Dubet (Pr.), project manager, Olivier Cousin (Pr.), Eric Macé (Pr.) and Sandrine Rui (Mcf), all of them teaching staff of the University of Bordeaux 2. These researchers have already conducted and published results of researches on feelings of injustice, education, work, media and politics. The results of this project will be published as a book and several articles and conference papers in France and abroad. This project is based on no particular institutional construction. It aims at allowing researchers to work in areas they know well, at developing and renewing already old interrogations on inequalities, recognition of singularities and social justice, in fields and situations in which they are experts.

This project will evaluate the effect of chronic exposure to house dust mite (HDM) on the bronchial smooth muscle (BSM) remodelling observed in asthma and particularly the number of mitochondria. Indeed, the increased number of mitochondria is a key factor of BSM remodelling. The increased mass of BSM in asthma is still insensitive to current therapeutics, and has been associated with a poor prognosis including decrease in lung function and high morbidity. In addition, chronic exposure to HDM is an important determinant of asthma control but preventing human exposure to HDM allergens is difficult to implement. Thus, a better understanding of the effect of chronic exposure to BSM remodelling and reversing BSM remodelling must be the main objectives for the future treatment of asthma. The general aim of this project is to determine the effect of HDM on BSM mitochondria. The specific aims are (i) to determine the effects of chronic exposure to HDM on BSM mitochondria in vivo, (ii) to explore the effects of chronic exposure to HDM on BSM mitochondria in an in vitro model of BE/BSM interaction, (iii) to identify the role of mitochondria in allergic asthmatic BSM cell apoptosis in vitro, and (iv) to develop pro-apoptotic strategies of allergic asthmatic BSM cells targeted on mitochondria. This is a translational project which associates in vivo approach using a murine model of asthma, and in vitro approaches using BSM cells obtained from allergic asthmatic patients. For this purpose, we will use samples from recent clinical trials such as “Remodel’Asthme” study supported by both PHRC and INSERM-DHOS grants.