CE37 - Neurosciences intégratives et cognitives

Noradrenaline and prefrontal neural dynamics for monitoring behavioural flexibility – NORAD

Noradrenaline and prefrontal neural dynamics

our hypothesis is that the locus coeruleus (LC) / norepinephrine (NA) system induces specific neuronal dynamics within the median frontal cortex (mFC) allowing exploratory decisions in a situation of uncertainty.

Main issues raised & general objectives

By combining electrophysiology, pharmacogenetics and optogenetics in a series of experiments in rats and monkeys, we will test:<br />i) Whether the action of NA on the median prefrontal cortex influences behavioral flexibility<br />ii) If the selective and regional disruption of LC / NA afferents induce changes in cortical dynamics and selectively modulate the regulation of exploration<br />iii) Whether precise temporal disturbances of prefrontal LC / NA afferents may interfere with specific aspects of exploration and decision making.

The project is planned on 7 tasks which will make it possible to: establish and fine-tune appropriate behavioral quantifications, assess the effects of global LC / NA stimulation on exploration, test the functional selectivity of LC afferents on mFC, to assess their causal role on frontal cortical dynamics, and to test the temporal specificity of the influence of LC on mFC during exploration.
Pharmacogenetic and optogenetic approaches constituting a revolution in neuroscience because they allow the testing of hypotheses that are impossible to deal with other more traditional approaches. The widespread use and development of these methods in primates benefits scientific research well beyond this project. We also propose an innovative approach to develop viral vectors allowing a non-invasive validation of transfections in animal models but also in humans for applications in gene therapy.

ongoing

NORAD aims at understanding the neural and cognitive principles of adaptive decision making in changing environments. This is relevant for cognitive neuroscience but also behavioural ecology: foraging is a central function, but its mechanisms remain poorly characterized. This project is also relevant for management and education, since identifying the processes underlying exploration, and curiosity, might help develop new teaching methods. It is of course relevant for medicine, since exploration is clearly altered in several psychiatric disorders such as ADHD and depression. For all these reasons, adaptive decision-making is an extremely competitive field and our consortium, devoted to resolving the question of how a major neuromodulatory system impacts on cognition, is unique regarding its complementary expertise. The question has been an enduring challenge for basic and clinical neuroscience since the discovery of antipsychotics. The multi-species and innovative methodological approach of our project will provide unique knowledge with wide scientific implications.

ongoing

Animals improve decision efficiency and reduce uncertainty by being flexible and by exploring and collecting information. Altered control of exploratory decisions can lead to obsessive or disorganized behaviours as in OCD or schizophrenia. One critical issue is to understand how the brain regulates exploration under uncertainty. In NORAD, our hypothesis is that the locus coeruleus (LC)/noradrenaline (NA) system drives specific medial frontal cortical (mFC) dynamics to enable directed exploratory behaviours. Using advanced electrophysiology, chemogenetics and optogenetics in an unprecedented series of experiments in rats and monkeys, we will test whether
NA inputs to the mFC influence behavioural flexibility,
i) selective and regional perturbations of LC/NA cortical inputs enable specific cortical dynamics and impact the regulation of exploration, and
ii) time selective perturbations of LC/NA inputs to prefrontal regions can interferes with precise aspects of exploration and decision making.

The project is planned along 7 tasks that will set and develop appropriate behavioural quantifications, evaluate the impact of global LC/NA stimulation on exploration, test the functional selectivity of LC to mFC inputs, evaluate the causal role of LC/NA inputs on frontal cortical dynamics, and test the temporal specificity of LC influence on mFC during flexible behaviours.

We propose to use advanced chemogenetic approaches to understand the functional relevance of the LC-PFC pathways. Such approaches are a revolution for neuroscience, allowing the testing of hypotheses impossible to address otherwise. The increased use and development of these methods for primates will benefit research well beyond the scope of the present project. We also propose an innovative approach to develop vectors carrying material for non-invasive means of validating transfections in animal models but also potentially in humans for applications with gene therapies. As a result, the multi-species and innovative methodological approaches of our project will provide unprecedented knowledge with wide scientific implications.

Project coordination

Emmanuel Procyk (INSTITUT CELLULE SOUCHE ET CERVEAU (SBRI))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UMR_S 1208 INSTITUT CELLULE SOUCHE ET CERVEAU (SBRI)
INCIA Institut de Neurosciences Cognitives et Intégratives d'Aquitaine
IGMM Institut de Génétique Moléculaire de Montpellier
ICM INSTITUT DU CERVEAU MOELLE EPINIERE

Help of the ANR 814,487 euros
Beginning and duration of the scientific project: December 2019 - 48 Months

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