CE37 - Neurosciences intégratives et cognitives

Translational study of the neural circuits underlying the negative emotional biases of depressive disorders and their response to ketamine – EMOKET

Submission summary

Depressive episodes (DE) are among the leading factors in disability worldwide, affecting up to 300 million people annually. Beyond the sad mood, depressed patients exhibit a negative emotional bias (NEB), which involves assigning more negative valences to stimuli salient enough to trigger emotion. The effectiveness of antidepressants in restoring mood requires correction of this bias. While mood cannot be explored in animals, we developed a test to study emotional biases in mice in the presence of innately positive and negative valence odors. We have shown that mice with a depressive phenotype present, as in humans, a bias in the attribution of hedonic valences (pleasant odors are perceived as less pleasant and negative odors as more unpleasant).
Numerous studies have shown structural and functional abnormalities of the central amygdala (AMG) in DEs in humans and recent studies have revealed specific circuits in animals involving the AMG in valence attribution processes.
This translational project aims to study for the first time these mechanisms in a mouse model with a depressive phenotype. We will also study the ability of different families of antidepressants and in particular ketamine in restoring these biases. In parallel, we will evaluate the emotional responses in depressed patients before and after treatment with Ketamine and the changes in the activation of specific regions of the AMG and their connectivities in functional imaging.
Preclinical study. Preliminary research based on an olfactory preference test allowed us to show that a depressive phenotype in mice is associated with a bias in the attribution of the hedonic value of odors. Based on data from the literature, we hypothesize that 1) NEBs are the consequence of altered activity of neuronal subpopulations of the basolateral nucleus of the AMG (BLA), with increased activation of neurons encoding negative stimuli going mainly from the BLA to the central amygdala and ventral hippocampus, and reduced activity of neurons coding for positive stimuli going mainly from the BLA to the nucleus accumbens 2) manipulation of these two populations can mimic and reverse the NEB observed in our model 3) it is possible to reverse the NEB in our model by two types of AD, with different mechanisms of action: a selective serotonin reuptake inhibitor (SSRI) and an N-methyl-D-aspartate receptor antagonist (ketamine), a novel treatment for resistant depression 4) reversal of NEB is associated with response to ADs and restoration of BLA circuit activity.
Clinical study: We will evaluate the existence of concordant data in depressive patients. In humans, it has already been shown that SSRIs restore NEBs early, and that this is a predictive factor for good response to treatment. In order to assess whether there is a final pathway common to all ADs we would like to explore whether 1) ketamine can also reverse NEBs 2) restoration of NEBs is necessary for a good response after 4 weeks of ketamine 3) NEBs are associated with an imbalance in the activity of certain AMG nuclei and their connectivities, the areas of interest of which are determined by preclinical data 4) ketamine induces a normalization of AMG activity reactivity after 4 weeks of treatment.

Project coordination

Chantal Henry (DRCI GHU Paris Psychiatrie et Neurosciences)

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.


IPNP INSTITUT DE PSYCHIATRIE ET NEUROSCIENCES DE PARIS / Institute of Psychiatry and Neurosciences of Paris
IP Institut Pasteur
JOLIOT Institut des sciences du vivant FRÉDÉRIC-JOLIOT
DRCI GHU DRCI GHU Paris Psychiatrie et Neurosciences

Help of the ANR 609,079 euros
Beginning and duration of the scientific project: January 2022 - 48 Months

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