Consequences of early trauma on Olfaction and underlying Brain alterations in Rodents and Adults patients with depression: toward a Remediation strategy – COBRA

Our approach combines animal and human models, state-of-the-art neuroscience tools, and translational methods to establish a continuum between fundamental and clinical research.

In mice:

Use of the early-life stress model induced by limited bedding and nesting material.

Behavioral assessment of emotional state and hedonic odor perception.

Cellular imaging and optogenetics to analyze the activity of the olfactory bulb (OB) and olfactory tubercle (OT).

Fine morphological analysis of neurons involved in hedonic coding.

Measurement of dopamine release in the reward system using fiber photometry.

Use of TRAP2 mice to compare neuronal activation before and after olfactory training.

Evaluation of the ability of this training, compared with fluoxetine treatment, to restore altered emotional and olfactory behaviors.

In humans:

Inclusion of depressed patients and healthy volunteers with varying levels of early-life stress, assessed using the Childhood Trauma Questionnaire.

Measurement of dopamine release induced by pleasant odors using 11C-Raclopride PET combined with fMRI (hybrid MR-PET system).

Analysis of functional and effective brain connectivity (fMRI, single- and dual-site TMS).

Study of both neural and subjective responses to pleasant and unpleasant odors.

Development of a clinical protocol combining rTMS over the left dorsolateral prefrontal cortex with pleasant olfactory stimulation, compared to rTMS alone in depressed patients.

Integrative approach:
The results obtained in mice will allow us to link morpho-functional alterations of olfactory and dopaminergic circuits to behavioral deficits. These findings will guide the identification of brain biomarkers of early-life stress in humans.

Combining neuroimaging, brain stimulation, and sensory training techniques will allow us to test our central hypothesis: that joint stimulation of olfactory and dopaminergic circuits promotes the restoration of hedonic perception and emotional balance.

This multidisciplinary approach—bridging fundamental neuroscience and clinical research—aims to open the way for a novel therapeutic strategy for depression, directly derived from the mechanistic understanding of the link between stress, olfaction, and pleasure.

The COBRA project has made significant progress in understanding the effects of early life adversity (ELA) on the hedonic perception of odors and associated brain circuits, as well as in developing sensory and brain-based remediation strategies.
Objective 1 – Animal studies
In adult mice, early life stress induces long-lasting emotional alterations and a selective decrease in the perception of pleasant odors. Analyses conducted in the olfactory bulb, the first cortical relay of olfactory information, revealed morphological and functional alterations of newly generated granule cells, disrupting the processing of olfactory input. Restoration of this activity through optogenetic manipulation successfully reinstated both odor hedonic perception and the animal’s emotional state, establishing a causal link between early stress, olfactory processing, and emotional regulation. Moreover, altered activity was observed in the olfactory tubercle, a key region of the brain’s reward circuit, as well as in dopamine release.
In parallel, an olfactory training strategy was implemented in TRAP2 transgenic mice. Preliminary behavioral results show an improvement in both hedonic odor perception and emotional behavior in early-stressed mice following olfactory training.
Objective 2 – Human studies
The human study, which aims to measure dopamine release in response to odors in adults exposed to early life stress, has received ethical approval and is awaiting final authorization from the ANSM. All experimental equipment (olfactometer, odorants, MR-PET) has been validated, and participant inclusion is scheduled to begin in early 2026.
The clinical trial combining repetitive transcranial magnetic stimulation (rTMS) with pleasant olfactory stimulation in treatment-resistant depressed patients is ongoing. To date, 35 patients and 24 matched controls have been included, with an excellent completion rate. fMRI data have been preprocessed, and connectivity analyses are in progress.
Overall, COBRA provides major advances in understanding the interactions between early life stress, olfaction, and the brain’s reward circuitry, establishing a strong translational bridge between fundamental and clinical research.

The results obtained within the COBRA project open several major perspectives, both fundamental and clinical.

At the fundamental level, studies in mice have identified specific neuronal alterations induced by early-life stress in the olfactory bulb and olfactory tubercle, two key regions involved in hedonic coding. These findings represent a significant advance in understanding the links between early experiences, emotions, and sensory processing. The use of transgenic models and in vivo neuroimaging tools will allow a more detailed investigation of the dynamics of these circuits during the perception of pleasant and unpleasant odors.

In parallel, ongoing behavioral and physiological studies in TRAP2 mice will identify the neuronal networks activated by olfactory training and involved in restoring olfactory and emotional pleasure. These data will provide precise biological targets for future therapeutic interventions.

At the translational and clinical level, the continuation of human studies represents a decisive step. The launch of the study in 2026 will, for the first time, directly measure dopamine release in response to pleasant olfactory stimuli in individuals exposed to early-life stress. These results will allow the alterations observed in mice to be linked to measurable brain markers in humans.

The clinical trial combining rTMS and olfactory stimulation opens the way for an innovative therapeutic approach for treatment-resistant depression. Analysis of brain connectivity data and behavioral responses will determine whether simultaneous stimulation of the olfactory and dopaminergic circuits promotes the restoration of motivation and pleasure.

In the medium term, COBRA’s outcomes are expected to contribute to the development of personalized neurostimulation protocols that integrate sensory stimulation as a lever for emotional rehabilitation. These advances could also benefit other psychiatric disorders characterized by anhedonia, such as schizophrenia or severe anxiety disorders.

Athanssi A, François A, Bourinet E, Thevenet M and Mandairon N. Optimized workflow for behavior-coupled fiber photometry experiment: improved data navigation and accessibility. Front. Neurosci. Sec Neuroscience Methods and Techniques. 2025 July doi.org/10.3389/fnins.2025.1601127
Imbert, L., Neige, C., Dumas, M., Bensafi, M., Mandairon, N., & Brunelin, J. (2024). Combining pleasant Olfactory and BRAin stimulations in treatment-resistant depression (COBRA)?: Study protocol for a randomized controlled trial. Frontiers in Psychology, 15. doi.org/10.3389/fpsyg.2024.1451096
Neige, C., Imbert, L., Beynel, L., Fivel, L., Mondino, M., & Brunelin, J. (2024). Dual activation of the reward system using sensory-based intervention and non-invasive brain stimulation in depression?: A way to move forward? Medical Hypotheses, 189, 111403. doi.org/10.1016/j.mehy.2024.111403

Neige, C., Imbert, L., Dumas, M., Athanassi, A., Thévenet, M., Mandairon, N., & Brunelin, J. (2024). Combining a Breath-Synchronized Olfactometer with Brain Simulation to Study the Impact of Odors on Corticospinal Excitability and Effective Connectivity. Journal of Visualized Experiments: JoVE, 203. doi.org/10.3791/65714

Early life adversity (ELA) in the form of poor early life care profoundly alters the development of neural circuits underlying emotion regulation and can contribute to later development of depressive outcomes. The mouse model of ELA mimics this pathology.
Studies in humans have shown that depressive disorder is often associated with olfactory disturbance. Odors play a major role in social interactions and food intake. Thus, any alteration of odor perception and more particularly of the pleasant odorants will have consequences on daily pleasures, aggravating depressive symptoms. Our project aims at understanding the impact of ELA on the perception of pleasant odorants in female and male mice. As it has recently been shown that the positive hedonic value of odors is encoded in the olfactory system and the reward circuitry, we will specifically analyze the neural activity of these two circuits using cellular imagery, optogenetics, fine neural morphology analysis and fiberphotometry.
Furthermore, it has been shown in humans and mice that olfactory training can restore odor perception and improve emotional behavior. In this context, we will develop a remediation strategy using odor training and test whether this treatment can rescue olfactory hedonics and restore altered activity in the olfactory and reward systems as well as dopamine release in ELA mice.
We will extend results in humans by studying the influence of ELA on pleasant odor perception, brain connectivity within the mesocorticolimbic pathway and dopamine release. We will also investigate the influence of ELA on clinical response to a remediation strategy combining odor and noninvasive brain stimulation (rTMS) in patients with depression. We hypothesize that stimulating DA release with both odorants and rTMS will increase beneficial effects of rTMS on depressive symptoms as well as odor hedonics judgment and brain connectivity of regions involved in dopamine transmission.
This project will allow determining how the neural networks responsible for pleasant odorant perception lose their capacity to create a positive emotion after ELA and by studying the effect of olfaction-based therapy.