Molecular and biomarker impact of innovative therapeutic modalities in mice models of depression.

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for international co-supervised PhDs.

The call for international co-supervised PhDs aims to provide an exceptional opportunity for talented young researchers to have an international doctoral training. The candidates may be local (AMU master’s student) or external (from other French or foreign universities). 

This project is one of the two proposed projects. Check our website for details.

State of the art: Major depression constitutes a heavy toll on mental health and society in terms of disabilities and economic cost as, globally, an estimated 5% of adults suffer from depression according to the World Health Organization. Even though antidepressants (AD) targeting monoamines (SSRIs/SNRIs) are among the most widely prescribed drugs, two-third of patients do not respond to first-line AD. Moreover, ADs have a long delay of action, leaving the patient to suffer for weeks, if not months. While ketamine is proposed as an alternative in treatment-resistant patients, it exhibits serious side-effects, thus highlighting the urgent need to search for new drugs and strategies with improved response rate and faster action, and without major risks.

Objectives: This project focuses on testing two promising drugs/strategies: a) treatment combination of classical SSRI with TDE, an inhibitor of the ERK activation of the transcription factor Elk-1 (targets alternative stress/depression pathways) (Apazoglou et al. NMED, 2018; additional preliminary results), b) cannabidiol, a non-addictive phytocannabinoid (preliminary results). We will I) Evaluate rapidity and synergy of beneficial action; II) Clarify their multiscale impact on depressive brain pathology; III) Investigate their biomarker “footprint” based on brain exosomes (small extracellular vesicles (EVs) with great biomarker potential); IV) Study identified targets in a human cohort of AD response (ANTARES; promotion APHM).

Methods: As chronic stress and sleep disturbances are risk factors for major depression, we will use stress and sleep deprivation-based depressive mouse models (males and females). Depressive-like and anxiety-like behavior, as well as cognition will be assessed longitudinally to evaluate delay-of-onset-of-action and response rate. Brain analysis will include molecular, proteomic, RNA-Seq and neurostructural analyses. In addition, brain exosomes (EVs) will be extracted from plasma and brain samples, purified and stratified for cell-type origin. EVs analysis includes Nanotracking particle analysis (NTA) and multi-omics, including proteome and non-coding RNAs (microRNAs and circular RNAs). A statistical multivariate analysis will permit identification of a combination of protein/RNA species whose level of expression in a defined subcellular fraction is associated to rapid recovery/better efficacy. Homologues of these RNAs will be profiled by RT-qPCR on total RNAs from the human blood samples of the ANTARES cohort https://www.neuron-eranet.eu/projects/ANTaRES/.

Expected results: a) Proof-of-concept for novel antidepressant strategies with quicker and better action; b) identification of underlying molecular mechanisms; c) clarification of their impact on brain biomarkers (exosomes).

Feasibility: ANTARES CPP n°: 2022-A00352-41, part of the project is covered by ANR grant STRATAGEM (ANR-23-CE17-0053)

Co-supervised PhD; complementarity of the laboratories: Dr Ibrahim: animal and human transcriptomics, high-throughput sequencing as well as RT-qPCR and statistical multivariate analysis. Professor Dalla: Stress-driven male/female models of depression, neuropsychopharmacology, sEVs in brain pathology.

Within Aix Marseille Université, NeuroMarseille brings together 8 research laboratories and NeuroSchool, a graduate school in neuroscience, to increase the attractiveness of the university, international collaborations, interdisciplinarity, links with the clinical and industrial worlds and the integration of students into professional life. 

Launched in July 2018, NeuroSchool unifies and harmonizes the training of the third year of the Bachelor of Life Sciences (Neuroscience track), the Master's and the PhD in Neuroscience. 

• Master's degree from a non-French university in neuroscience or related field
• Fluent in English

Background in brain analyses e.g. behavioral, nucleic acid analysis; authorized to work with mice; academic background in the psychopathology of psychiatric disorders.