IMPACT OF EARLY-LIFE STRESS ON MITOCHONDRIAL FUNCTION IN THE MPFC-HP-AM NEURONAL CIRCUIT: A GENDER-SPECIFIC STUDY IN ADULT RATS

• Grant number: 25/13247-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: September 15, 2025
• End date: September 14, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Carolina Demarchi Munhoz
• Grantee: Robbert Mota Pereira
• Supervisor: Marco Andrea Riva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Università degli Studi di Milano, Italy
• Associated to the scholarship: 23/13386-6 - Effect of acute restraint stress on mitochondrial function and its repercussions on late anxiety-like behaviors and extinction of aversive memory in adult male and female rats subjected to maternal separation, BP.DR

Abstract

Stress is a vital physiological response for survival, but excessive exposure can increase the risk of developing psychiatric disorders. The hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role in the stress response, mediating the release of glucocorticoid hormones (GCs) that modulate gene expression and influence cognition, emotion, mood, and immunity. During offspring neurodevelopment, factors like inadequate nutrition and maternal care can cause enduring modifications that impact neuroendocrine homeostasis and lead to vulnerability to mood disorders. Early-life stress (ELS), including maternal separation (MS), affects physiology and behavior, leading to changes in glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC) and hippocampus (HP). Overall, stressful stimuli increase energy demand in the brain due to the activation of areas involved in the stress response. Interestingly, studies have shown that after GR activation, the complex GCs-GR can not only act on nuclear transcription but also translocate to mitochondria and exhibit mitochondrial genomic action. Second messengers linked to stress responses modify the expression of genes responsible for processes such as biogenesis, dynamics, and mitochondrial function or alter reactive oxygen species (ROS) production. Thus, although distinct, these pathways can act in a complementary manner to modulate mitochondrial activity in response to different stress conditions. Experimental models demonstrate that the brain networks involved in cognitive control and emotional reactivity, such as the medial prefrontal cortex (mPFC), HP, and amygdala (AM), are particularly vulnerable to oxidative stress, which can affect emotional regulation following stress. Therefore, this study aims to investigate the effects of ELS induced by MS on indicators of mitochondrial function and morphology in neuronal populations of the mPFC, HP, and AM circuit of male and female Wistar rats subsequently exposed to stress in adulthood. (AU)