Integrative Neurobiology of Cholinergic Systems

Leader

Research center

25 rue du Docteur Roux
75015 Paris
Christian Bréchot

Institution

CNRS
ED158
Université Pierre et Marie Curie

Laboratory

Genes, Synapses, Cognition
Phone: 01 45 68 88 05
UMR 3571
LabEx BIO_PYS

Mots clefs

Viral vectors
Available to host a PhD student

publications

MJ Orejarena, A Herrera-Solís, S Pons, U Maskos, R Maldonado & P Robledo (2012) Selective Re-expression of ?2 Nicotinic, Acetylcholine Receptor Subunit in the Ventral Tegmental Area Restores intravenous Nicotine Self-Administration. Neuropharmacology 63, 235-241.

S Tolu, R Eddine, F Marti, V David, M Graupner, S Pons, M Baudonnat, M Husson, M Besson, C Reperant, J Zemdegs, C Pagès, YAH Hay, B Lambolez, J Caboche, B Gutkin, AM Gardier, J-P Changeux, P Faure & U Maskos (2013) Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement. Mol Psychiatry 18, 382-393.

K Maouche, K Medjber, JM Zahm, F Delavoie, C Terryn, C Coraux, S Pons, I Cloëz-Tayarani, JP Changeux, U Maskos, P Birembaut & JM Tournier (2013) ?7 nicotinic receptor regulates CFTR in the airway epithelium and induces CFTR dysfunction under chronic nicotine exposure. Proc Natl Acad Sci U S A 110, 4099-4104.

G Collo, F Bono, L Cavalleri, L Plebani, S Miola, E Merlo Pich, MJ Millan, M Zoli, U Maskos, PF Spano & C Missale (2013) Nicotine-induced structural plasticity in mesencephalic dopaminergic neurons is mediated by functional dopamine D3 receptor and Akt-mTORC1 pathway. Mol Pharmacol 83, 1176-1189.

C Morel*, L Fattore*, S Pons, A Hay, F Marti, B Lambolez, M De Biasi, M Lathrop, W Fratta, U Maskos* & P Faure* (2013) Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol Psychiatry, in press

Fields of research

Neuropharmacology / cell signaling

Research Theme

Our research aims to investigate at multiple levels the molecular mechanisms and neuronal circuits underlying executive function and nicotine reinforcement in a simple animal model. We use mouse models because it lends itself to a large variety of approaches, from genetic manipulations and molecular pharmacology to brain imaging and behaviour.

Our larger goal is to develop a molecular neurobiology of cognitive functions using a novel molecular genetic strategy: stereotaxic injection in defined brain regions of lentiviral vectors to stably express defined genes. The method has already been successfully used to restore executive functions and nicotine reinforcement in the mouse (Maskos et al., Nature, 2005) following re-expression of functional nicotinic acetylcholine receptors (nAChRs) in the VTA of nAChR KO mice. It will be further exploited to differentially express genes in defined categories of neurons, e.g. dopaminergic vs. GABAergic, but also to inactivate genes using the expression of siRNAs. The lentiviral strategy will also be extended to the rat brain and to the construction of genetically modified mice and rats (GMMs and GMRs) by infection of early embryos with lentiviral vectors. Indeed, many advanced behavioural tests cannot be applied to the mouse, but have revealed a wealth of information on rat behaviour. This approach can even be potentially applied to non-human primates.

nAChRs are known to regulate brain functions such as learning and memory, reward processes and addiction, together with anxiety, central processing of pain, selective attention, sleep and wakefulness. Moreover, nAChRs are implicated in a variety of pathologies, like ADHD, Alzheimer’s disease, Tourette’s syndrome, possibly autism, and also ageing. We study the role of defined species of nAChR in the neuronal circuits underlying executive function and nicotine addiction in wild-type and genetically modified organisms.

Our program of research includes the comparative evaluation of the role of the diverse brain areas engaged in executive functions in the mouse, including cortical areas like the prefrontal cortex, primary and secondary sensory areas, the nucleus accumbens, the VTA or the amygdala together with a detailed dissection of the neuromodulatory systems and signal transduction processes under nAChR control. Combined with the latest developments in functional Magnetic Resonance Imaging (fMRI) and novel fiber-optic deep-brain imaging technology, the cellular and anatomical bases of the underlying brain circuits will be further explored.

These data will motivate the development and test of theoretical models (such as the global neuronal workspace) aimed to define the neural processes that underlie generation of cognitive behaviours and their executive control. In particular, a coherent computational network will be built that defines the pathways and processes by which nicotine modifies executive and motivational processes.



Etudiants ENP

Lauriane HARRINGTON

Lab rotation

Role of the nicotinic receptor in Alzheimer’s Disease pathology and treatment

Chercheur responsable: 

MASKOS Uwe

Dates: 

1 September 2016 - 30 June 2017

Date limite de candidature: 

1 September 2016

Lab rotation proposal: 3 months

~ Sep-Dec 2016 ~ Jan-March 2017 ~ Apr-June 2017

Project: 

The nicotinic receptor is a direct target of the Amyloid beta peptide, the causative agent of AD. We have developed novel animal models to study AD and the role of the nicotinic receptor. We are carrying out in vivo two photon imaging of the cortex to analyse the changes occurring in cortical function as a consequence of the direct interaction between A beta and different subunits of the nicotinic receptor. This work can be used to define novel medication for the disease.

Address: Institut Pasteur - 25 rue du Docteur Roux 75015 Paris:

Phone number: + 33 1 45 68 88 06 ; Emailumaskos@pasteur.fr

Website

Superviseur: 

Uwe MASKOS