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

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

Koukouli F, Rooy M, Tziotis D, Sailor KA, O’Neill HC, Levenga J, Witte M, Nilges M, Changeux J-P, Hoeffer CA, Stitzel JA, Gutkin BS, DiGregorio DA, Maskos U (2017) Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nature Medicine 23, 347-354. 

Koukouli F, Rooy M, Changeux J-P, Maskos U (2016) Nicotinic receptors in mouse prefrontal cortex modulate ultraslow fluctuations related to conscious processing. PNAS 113, 14823-14828. 

Harrington L, Viñals X, Herrera-Solis A, Flores A, Morel C, Tolu S, Faure P, Maldonado R, Maskos U*, Robledo P* (2016) Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice. Neuropsychopharmacology 41, 1790-1802. 

Morel C*, Fattore L*, Pons S, Hay A, Marti F, Lambolez B, De Biasi M, Lathrop M, Fratta W, Maskos U*, Faure P* (2014) Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol Psychiatry 19, 930-936. 

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

Use of two photon imaging to study cortical activity in wake behaving mice

Chercheur responsable: 

MASKOS Uwe

Dates: 

2 January 2018 - 29 June 2018

Date limite de candidature: 

29 June 2018

Period

~ Jan-March 2018

~ April-June 2018

Project

Following up on our study published in Nature Medicine (Koukouli et al, NatMed 23, 347-354), we are pursuing the analysis of human mutations expressed in mouse models of schizophrenia. We will now start imaging deeper cortical layers like lamina 5 and 6.

Contact

Institut Pasteur - 25, rue du Dr Roux 75724 Paris cedex 15 - +33 1 45 68 88 06 - umaskos@pasteur.fr

Superviseur: 

KOUKOULI Fani