Exploring Exercise-Induced Molecular Pathways for Novel Stroke Therapeutics

The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD contracts for students with a master's degree in a non-French university and for  international co-supervised PhDs.

This project is one of the proposed projects. Not all proposed projects will be funded, check our website for details.

State of the art: Ischemic stroke is a major cause of death and disability worldwide, with increasing prevalence. Exercise provides systemic benefits and has gained interest as a therapeutic approach. The search for "exercise mimetics"—bioactive compounds replicating exercise effects—has strongly intensified, but not after stroke. Exercise triggers complex molecular changes, acting as a multi-targeted therapy beyond most drugs, with effects depending on the type of exercise. For example, aerobic exercise enhances brain-derived neurotrophic factor (BDNF) expression, promoting brain plasticity, memory, and neuron survival. BDNF-mimicking drugs are being explored for individuals unable to exercise. However, administration of a single agent remains insufficient to improve recovery. Indeed, multi-drug therapies better improve neurological outcomes after stroke. It is therefore important to continue the search for therapeutic targets. Omics techniques (proteomics) help uncover exercise-activated molecular pathways depending on the exercise type, thereby identifying novel preclinical therapeutic targets. The link between the most significant expressed proteins with functional recovery (behavior) will be performed. In vitro measurements will then be planned to find out direct molecular interaction between identified proteins and expression in neurotrophic factors.

Methods: Four groups of middle-aged males and females Wistar rats (n=8 per group and sex): Sham (no ischemia)/tMCAO (transient middle cerebral artery occlusion) without exercise/MICT (moderate-intensity training) after tMCAO/HIIT (high-intensity training) after tMCAO. tMCAO procedure: A 1h30 right tMCAO will be performed. Neurological test (nMSS): Conducted to assess lesion severity. Incremental treadmill exercise test (D2, D7, D14 post-tMCAO): Evaluates aerobic gains and defines individualized running speed for translational relevance^24,26,27. MICT and HIIT treadmill sessions (D3–D14): Based on lactate threshold. Barnes Maze Task (BMT): Learning and memory test, measuring running speed, traveled distance, and location. Molecular analysis (D15): Proteomics in ipsi- and contralesional prefrontal cortex, hippocampus, gastrocnemius muscles, and serum exosomes (INMED and CRCM), with ELISA and Western blot confirming expression changes in key proteins.

Objectives: To define novel molecular pathways after 2 weeks of different aerobic training regimens in stroke-induced rats using omics approaches in brain, blood serum (exosomes) and muscles levels along with behavioral analysis. By defining the molecular pathways involved in exercise-induced recovery, this project will help discover molecules mimicking beneficial effects of exercise.

Expected results: (1) Validation of exercise-mimetic drug candidates: Identification of therapeutic targets replicating exercise effects on post-stroke recovery. (2) Identification of key proteins in serum/brain tissues linked to functional improvement. (3) Efficacy of MICT and HIIT in rehabilitation programs.

Feasibility:  APAFIS #11519. Suitable devices and technical expertise in the team.

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

A motivated neuroscience or biomedical student with expertise in omics techniques. Required skills: 1) Animal models & behavioral analysis (cognitive function, locomotion analysis). 2) Molecular & cellular biology techniques: proteomics or Western blotting or ELISA. 3) Data analysis & bioinformatics. 4) Skills in exercise physiology.