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The role of glucocorticoids and the vagus nerve afferences on the neuronal activity and plasticity of central circuits and their implications for stress-induced anxiety in rats

Grant number: 18/19599-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): May 01, 2019
Effective date (End): April 30, 2021
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Carolina Demarchi Munhoz
Grantee:Leonardo Santana Novaes
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Stress-related disorders, such as anxiety, depression, and post-traumatic stress disorder (PTSD), are recurrent causes of occupational absence in Brazil. Both acute restraint stress and transient elevation of glucocorticoid (GC) levels induce anxiety behaviors as well as dendritic branching within the basolateral complex of the amygdala (BLA) of rodents. The BLA is one fundamental structure regulating fear- and anxious-related behaviors. We have recently shown a crucial role for glucocorticoid receptor (GR) signaling in BLA in the anxiety-like behavior, both during and after acute restraint stress. In addition to the long-lasting anxiety-like behavior, we found that the same stressor promotes a deficit in the extinction of fear memories, another PTSD-like symptom. We also observed functional alterations in BLA and medial prefrontal cortex (mPFC), another critical brain area for fear-related behavior and memory. Under stressful conditions, besides the rapid release of GC by the adrenal glands, the vagus nerve responds to elevations in epinephrine and signals the Central Nervous System (CNS), leading to the release of norepinephrine (NE) in limbic structures, such as the amygdala and mPFC. This increase of NE in the CNS may be related to behavioral effects associated to stress, such as anxiety and fear memory. Accordingly, this project aims to investigate how acute restraint stress modify the amygdalar and prefrontal circuits underlying its behavioral effects. Our central hypothesis states that endocrine signals, notably GC and norepinephrine, mediate the stress-induced modifications of these neural circuits. To achieve our goals, we will make use of tools such as optogenetics, pharmacogenetics, and virally mediated modulation of receptors expression