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Stress-induced anxiety-like behaviors: glucocorticoid signaling in neuronal hyperexcitability and mitochondrial dysfunction within the basolateral amygdala complex

Grant number: 19/00908-9
Support type:Regular Research Grants
Duration: June 01, 2019 - May 31, 2021
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Carolina Demarchi Munhoz
Grantee:Carolina Demarchi Munhoz
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Fernando Rodrigues de Moraes Abdulkader ; Leonardo Santana Novaes ; Niels Olsen Saraiva Câmara ; Nilton Barreto dos Santos

Abstract

Anxiety-related disorders are common among psychiatric patients and are widely present in studies focusing on stress. In addition to the long-lasting anxiety behavior, impaired extinction of learned fear is associated with the development of post-traumatic stress disorder, one of the most debilitating stress-related disorder. The amygdala is a fundamental brain structure essential for behavioral manifestations of emotional content, and electrical stimulation of the basolateral amygdala (BLA) promotes anxiety-like behavior in rats. In addition, in recent years, several studies have been suggesting a broader role for mitochondria than that related to energy production in the cell. In this way, this organelle is no longer only associated with the control of energy metabolism and has been gaining notoriety in central functions, such as cerebral homeostasis, neuroplasticity, and adaptation to stress. Because the complexity of such phenomena, it is urgent the need to understand the correlation among stress, BLA neuronal excitability, neuronal mitochondrial biogenesis, and anxiety; and how the activation of glucocorticoid receptors coordinates these events and modulates the extinction of learned fear. Thus, considering the role of glucocorticoids in the stress response and its fast and long-lasting (plastics) effects on the central nervous system, the study of these mechanisms is particularly relevant for the understanding of fear and anxiety-related pathologies. The goals of this project are 1) to verify, using viral vectors, whether both restraint stress-induced long-lasting anxiety and the impairment in contextual fear extinction are dependent on the increase of neuronal excitability (SK2-HSV) in the BLA as well as its relationship to the increased GR nuclear activity (HSV-GRE-Sk2) and whether they are related to changes in the intercommunication with other structures such as the medial prefrontal cortex and hippocampus, equally important for these behavioral phenomena; 2) to understand whether there is any change in the mitochondrial biogenesis in BLA cells whose electrophysiological activity was modified by stress; and 3) whether the modulation of mitochondrial biogenesis in BLA neurons modifies the course of behavioral responses associated with stress. We feel that this project significantly advances in the understanding of stress-associated disorders and can offer structural and molecular substrates as therapeutic targets that will serve as basis for the cure and, equally important, the identification of biomarkers that would help predict the prognosis of such malady, such as the posttraumatic stress disorder. (AU)