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

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 effects on BLA dendritic plasticity and behavior. Here, we show that inhibiting corticosterone (CORT) elevation during the two-hour restraint stress prevents stress-induced increases in delayed anxiety-like behaviors and BLA dendritic spine density in rats. Also, we show that acute stress’s behavioral and morphological delayed effects are critically dependent on glucocorticoid receptor (GR) genomic 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 10 days after acute stress requires NE signaling in the BLA at the time it is expressed. Therefore, we define essential roles for two stress-related hormones acting at two different times, for the late stress consequences: CORT, via GR, immediately at stress; NE, via beta-adrenoceptors, during the expression of delayed behavior. Significance Statement The dysregulation in orchestrating and finetuning major stress-related neural circuitries leads to enhanced reactivity and other altered ways of coping with threatening situations. These predispose 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 GR genomic signaling in the BLA prevented delayed effects on dendritic spine density and anxiety-like behavior ten days after stressor exposure. We also define essential roles for two stress-related hormones acting at two different times, for the late stress consequences: CORT, via GR, immediately at stress; NE, via beta-adrenoceptors, during the expression of delayed behavior.