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Time-dependent evolution of non-motor symptoms in models of Parkinson's disease: characterization and impact of the tVTA.

Research unit

UPR 3212 - Institut des Neurosciences Cellulaires et Intégratives (INCI)
5, rue Blaise Pascal, 67084 STRASBOURG

Group

Name: Douleur chronique : approche anatomo-fonctionnelle et traitement.

Group leader: BARROT Michel - mbarrot@unistra.fr

Group leader's phone: 0388456633

Website: Visit website

Group organization:
- Chercheurs: 6
- ITA: 3
- Doctorants: 10
- Post-Docs: 0
- Autres: 3

Publications of the team linked to the topic (3 last years):
1) Bourdy R*, Sánchez-Catalán MJ*, Kaufling J, Balcita-Pedicino JJ, Freund-Mercier MJ, Veinante P, Sesack SR, Georges F**, Barrot M** (2014) Control of the nigrostriatal dopamine neuron activity and motor function by the tail of the ventral tegmental area. Neuropsychopharmacology 39:2788-2798.
2) Sánchez-Catalán MJ, Kaufling J, Georges F, Veinante P, Barrot M (2014) The antero-posterior heterogeneity of the ventral tegmental area. Neuroscience 282:198-216.
3) Barrot M (2015) Ineffective VTA disinhibition in protracted opiate withdrawal. Trends Neurosci 38:672-673.

About PhD

PhD Director: BARROT Michel - mbarrot@unistra.fr

Phone: 0388456633

Junior advisor: non

Co-tutely: oui

Co-Director: LAFLEUR Susanne
University of Co-Director: Amsterdam (Pays-Bas)

About PhD topic :

Title: Time-dependent evolution of non-motor symptoms in models of Parkinson's disease: characterization and impact of the tVTA.

Project: Rationale. Parkinson’s disease affects 4-6 million persons worldwide and is the second most frequent neurodegenerative disease, after Alzheimer’s disease. While Parkinson’s disease, characterized by the loss of dopamine neurons, is mostly known for its motor symptoms, it also has deleterious non-motor consequences including weight loss, constipation, pain, anxiodepressive disorders and deficits in executive functions. Most of these non-motor symptoms even appear years before development of the motor ones, which stresses out the need to take this complexity and time-dependent development into consideration in preclinical research. While slowing the neurodegenerative process is a major therapeutic goal, improving yet unmanaged symptoms in already installed disease remains also critical. In this context, newly discovered brain structures can help improving our knowledge of normal brain functions and of brain disorders, and may provide new neuroanatomical targets for treatments. The tail of the ventral tegmental area (tVTA) is a brain structure discovered in the past decade and exerting an inhibitory control on dopamine systems. Recently, we demonstrated that the tVTA controls motor functions, and that its bilateral ablation improves motor performances and motor skill learning. Preliminary data suggest that inhibiting the tVTA may be beneficial on motor symptoms in models of Parkinson’s disease.
Objectives. In this context, the 2 objectives of the present project are: 1) to have a better characterization of the time-dependent development of some non-motor symptoms in 2 models of Parkinson’s disease; 2) to study the impact of a manipulation of the tVTA on these non-motor symptoms.
Content. Within this Strasbourg/Amsterdam collaborative project, we propose to characterize over time non-motor symptoms in 2 rodent models of Parkinson’s disease: the partial 6-OHDA bilateral lesion of substantia nigra pars compacta (SNc) dopamine neurons, and the more recently developed AAV2-9 α-synuclein model of bilateral SNc lesion. Over the 16 weeks following induction of the models, the weekly evolution of body weight, food intake, intestinal motility, metabolism, mechanical and thermal nociceptive sensitivity, reflexes, anxiety-like behaviours and depressive-like behaviours will be characterized, thus providing the first time-chart of non-motor symptom evolution in these models of Parkinson’s disease. Manipulation of the tVTA will then be done through either permanent inactivation by excitotoxic lesion or reversible inhibition through DREADD pharmacogenetic manipulation. The influence of such manipulation will be tested on the above symptoms. Overall, these experiments will provide a first description of non-motor symptom evolution in relevant animal models of Parkinson’s disease, as well as proof-of-concept of whether tVTA may be a relevant neuroanatomical target for these symptoms’ management.
Partnership. Behavioral studies on pain-related and anxiodepressive-related symptoms (12 months) and on tVTA manipulation (12 months) will be performed in Strasbourg under the supervision of Dr. Michel Barrot. Studies on feeding behavior, metabolism and motility (12 months) will be done in Amsterdam under the supervision of Dr. Susanne Lafleur. This partnership will thus provide the student with a large expertise, spanning the fields of Parkinson’s disease, animal models, pain, depression, feeding and metabolism.

Wished skills: Master in a field of life science or in pharmacology.

Expertises which will be acquired during the training: Expertises in neuroscience, Parkinson's disease, animal models, rodent behavior, viral mediated trangenesis, neuroanatomy.