The role of microglia in the mitochondrial damage and mood disorders promoted by chronic restraint stress in C57BL/6 mice.

• Grant number: 18/17991-3
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): July 01, 2019
• Effective date (End): May 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal researcher: Carolina Demarchi Munhoz
• Grantee: Nilton Barreto dos Santos
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

According to recent studies, mood disorders such as depression, anxiety, and post-traumatic stress disorder comprise a health problem in the modern world, affecting 15% of the population. In addition, less than half of the patients treated with antidepressants show an improvement in symptoms. Furthermore, patients diagnosed with depression have high levels of circulating pro-inflammatory cytokines such as IL-6, IL-1b, and TNF-alpha. Moreover, animal studies have shown increased inflammation, mitochondrial damage, and microglial activation after different types of stress. Therefore, to elucidate the mechanisms involved in the pathophysiology of these disorders, as well as in the development of new and more effective therapies, this project aims to investigate the function of glucocorticoids and their receptors on mitochondrial activity in glial and neuronal cells at the onset of depressive behavior. For this, C57BL/6 mice (WT or with glucocorticoid receptor deletion in myeloid cells) will be submitted to chronic restraint stress. Twenty-four hours after the last stress, the animals will be submitted to different behavioral tests to evaluate anxiety- (Elevated Plus Maze) and depressive-like behaviors (Tail Suspension, Splash test). They will be euthanized and their brain will be removed and used to produce enriched primary cultures of neurons. The cultured cells will be treated with the conditioned medium from LPS-treated microglia for evaluation of mitochondrial activity and release of cytokines. Subsequently, the myeloid cells of both groups will be transplanted intravenously into recipient animals (WT), which will be challenged or not with LPS and subjected to the same behavioral tests. With this project, we thus aim to elucidate how microglia and inflammation contribute to mitochondrial dysfunction and the onset of mood symptoms, as well as to establish new therapeutic targets for the treatment of these diseases.