Neuroplasticity at the basolateral amygdala complex, anxiety-like behavior, and extinction memory circuitries mediated by glucocorticoids via GR.

Author(s)

Letícia Morais Bueno de Camargo

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2023-08-02

Examining board members

Carolina Demarchi Munhoz; Eliana Hiromi Akamine; Fábio Cardoso Cruz; Raquel Vecchio Fornari

• Advisor: Carolina Demarchi Munhoz

Abstract

The increasing occurrence of stressors in everyday life, especially in large cities and the increased incidence of anxiety disorders and post-traumatic stress disorder (PTSD) have attracted attention from the World Health Organization (WHO). However, the neurobiological mechanisms involved in this stress-PTSD relationship are still partially known. In rats, acute restraint stress and its consequent increased glucocorticoids (GCs) release, corticosterone (CORT) in rodents, promote anxiety-like behavior after 10 days, through dendritic remodeling in the basolateral complex of the amygdala (BLA), hippocampus, and medial prefrontal cortex (mPFC). Still, it is known that this CORT increase improves the aversive memories consolidation and promotes extinction memory impairment in this same time window. Highly involved in mnemonic processes, glutamatergic signaling is altered by CORTs action via GR, with increased AMPA and NMDA traffic in the presynaptic membranes of the mPFC-hippocampusBLA neurocircuitry. As is evident, these relationships occur time-dependently, making neuroplasticity due to stress and CORT increase an essential focus of study. From this, we investigated, in mice, changes in neuronal activations and glutamatergic signaling in this neurocircuitry, resulting from the action of GCs via GR after acute stress, and the occurrence of anxiety-like behavior and/or aversive memory extinction deficit. For this, we standardized an acute stress model in male mice and evaluated, 72 hours later, whether it would induce anxiety-like behavior, extinction impairment, or aversive memory renewal and which brain structures on the mPFC-hippocampus-BLA circuitry would have their neuronal activities changed. A single acute social defeat stress (SD1) session augmented CORT release, and although it did not promote anxiety-like or greater risk assessment behaviors in the elevated plus maze (EPM), it altered aversive memory processing. SD1 promoted stress-enhanced fear learning (SEFL), since their freezing percentages did not return to their baseline patterns even with an equal extinction gain compared to the control and the SD-repeated stress (SD3) groups. In addition, the SD1 group also showed this memory renewal, similar to what is observed and configures one of the main challenges of exposure therapy applied in PTSD patients. The differentiated extinction processing in this stressed group is related to a hypoactivation of the CA1, CA3, and DG subregions of the ventral hippocampus, together with a hypoactivation laterality effect at the right CA2. No quantitative changes were observed in BLA activation, predominantly in the lateral rather than basal subregion. But it is still unclear whether the neurons activated in these regions are primarily glutamatergic or another type. These results indicate that prior exposure to SD acute stress in mice promotes a late increased aversive memory acquisition and on its renewal, even if it is already extinct, a process highly dependent on the hippocampal dorsal CA2 and ventral CA1, CA3, and DG. (AU)

• FAPESP's process: 18/15982-7 - Neuroplasticity in the basolateral complex of amygdala and on anxiety and extinction memory circuit mediated by glucocorticoids via GR
• Grantee: Letícia Morais Bueno de Camargo
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)