Genomic glucocorticoid receptor effects guide acute stress-induced delayed anxiety and basolateral amygdala spine plasticity in rats.

Abstract

Anxiety, a state related to anticipatory fear, can be adaptive in the face of environmental threats or stressors. However, anxiety can also become persistent and manifest as anxiety-and stress-related disorders, such as generalized anxiety or post-traumatic stress disorder (PTSD). In rodents, systemic administration of glucocorticoids (GCs) or short-term restraint stress induces anxiety-like behaviors and dendritic branching within the basolateral complex of the amygdala (BLA) ten days later. Additionally, increased arousal-related memory retention mediated by elevated GCs requires concomitant noradrenaline (NE) signaling, both acting in the BLA. It is unknown whether GCs and NE play a role in the delayed acute stress-induced effects on behavior and BLA dendritic plasticity. Here, inhibiting corticosterone (CORT) elevation during two hours of restraint stress prevents stress-induced increases in delayed anxiety-like behavior and BLA dendritic spine density in rats. Also, we show that the delayed acute stress-induced effects on behavior and morphological alterations are critically dependent on genomic glucocorticoid receptor (GR) actions in the BLA. Unlike CORT, the pharmacological enhancement of NE signaling in the BLA was insufficient to drive delayed anxiety-related behavior. Nonetheless, the delayed anxiety-like behavior ten days after acute stress requires NE signaling in the BLA during stress exposure. Therefore, we define the essential roles of two stress-related hormones for the late stress consequences, acting at two separate times: CORT, via GR, immediately during stress and NE, via beta-adrenoceptors, during the expression of delayed anxiety. Significance StatementThe dysregulation in orchestrating and finetuning major stress-related neural circuitries leads to enhanced reactivity and other altered ways of coping with threatening situations, predisposing humans to multiple psychiatric disorders, including anxiety and PTSD. Given the tremendous burden of affective disorders, we must advance our understanding of stress neurobiology and translate this into improved treatments. Here we showed that the absence of neuronal genomic GR signaling in the BLA prevented delayed effects on anxiety-like behavior and dendritic spine density ten days after stressor exposure. We also demonstrate that CORT, via GR and immediately at stress and NE, via beta-adrenoceptors, during the expression of delayed behavior contribute to the late stress consequences.