CE14 - Physiologie et physiopathologie

Vulnerability to Brain Disorders: Role of Past Stressful Events – STRESS

Submission summary

Past stressful events can lead to sustained accumulation of reactive oxygen species (ROS). Our hypothesis is that ROS accumulation creates favorable grounds for the development of neurological disorders and co-morbidities (depression and cognitive deficits). We have shown that half of the rats exposed to social defeat (first hit) become vulnerable, i.e. they develop a depression-like profile and cognitive deficits following a second hit. Social defeat results in a sustained decrease in serum BDNF levels (which can be used as a predictive biomarker) in the vulnerable population, whilst BDNF levels recover in non-vulnerable animals. In parallel, there is an accumulation of ROS in vulnerable animals. We have found that low BDNF levels prevent the proper activation of the transcription factor Nrf2, which controls anti-oxidant defense mechanisms, resulting in ROS accumulation. Treatments with antioxidants or BDNF mimetics abolish vulnerability. The goal of this project is to understand what controls BDNF levels, how does BDNF control Nrf2, and what are the functional consequences of ROS accumulation?
What controls BDNF levels? We have discovered a drastic reorganization of the microbiome in vulnerable animals. Since microbiome metabolites can control BDNF production, we will test causality with fecal transplants from vulnerable to non-vulnerable animals, and vice versa. In case of success, we will use metabolomics to identify the actors of BDNF control.
How does BNDF control Nrf2? We have found that BDNF acts in a non-canonical way, in a TrkB and p75-independent manner. We will establish how BDNF diffuses through the plasma membrane and controls Nrf2 levels.
Functional consequences. Hippocampal networks display high levels of ROS in vulnerable animals. Parvalbumin GABA neurons are particularly affected, which could result in altered gamma oscillations, which may contribute to cognitive deficits. We will test the state of glutamatergic and GABAergic pathways in the CA1 region with in vitro electrophysiology. Using high density silicon probe recordings, we will determine whether hippocampal rhythms and cell firing patterns are altered in anesthetized and freely moving animals. To test for causality, we will treat the animals with antioxidants. Finally, we will determine whether sleep patterns are disrupted in vulnerable animals, since sleep fragmentation is associated with low BDNF levels.
The project is highly innovative, building on a very fruitful collaboration between the two laboratories. We do not claim to explain all vulnerability phenotypes. The mechanisms we are unravelling may be applicable to sub-populations of patients, which is central in the context of personalized medicine. Importantly, past and future work allows us to propose novel predictive biomarkers of vulnerability (serum BDNF is already part of a clinical trial) and propose therapeutic solutions that may be translated to the patient. Both teams are strongly embedded in a clinical environment, and we are negotiating a patent with a pharmacological society to obtain an exclusive license of exploitation of antioxidant compound to treat vulnerability to depression in patients. In addition to clinical transfer, the project bears a high potential for a paradigm shift, with the demonstration that the microbiome controls BDNF levels and that BDNF can diffuse through the membrane to control antioxidant defense mechanisms.

Project coordination

Christophe BERNARD (Institut de Neurosciences des Systèmes)

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

UPDESCARTES-UMRS 1124 Laboratoire Toxicité Environnementales, Cibles Thérapeuthiques et Signalisation Cellulaire
INS Institut de Neurosciences des Systèmes

Help of the ANR 515,533 euros
Beginning and duration of the scientific project: December 2019 - 42 Months

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