Aberrant Amygdala-dependent Fear Memory in Corticosterone-treated Mice

• Published in: Neuroscience 2018-09, Vol.388, p.448-459
• Main Authors: Inagaki, Ryo, Moriguchi, Shigeki, Fukunaga, Kohji
• Format: Article
• Language: English
• Subjects: amygdala; CaMKII; corticosterone; fear memory; long-term potentiation
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2018.08.004

•Chronic corticosterone-treated mice exhibit impaired amygdala-dependent fear memory.•Corticosterone treatment increased Ca2+/calmodulin-dependent kinase autophosphorylation in the basolateral amygdala.•Long-term potentiation was markedly enhanced in the basolateral amygdala of chronic-corticosterone-treated mice.•Increased synaptic plasticity in the basolateral amygdala may underlie abnormal fear memory in corticosterone-treated mice. Anxiety disorder is a major psychiatric disorder characterized by fear, worry, and excessive rumination. However, the molecular mechanisms underlying neural plasticity and anxiety remain unclear. Here, we utilized a mouse model of anxiety-like behaviors induced by the chronic administration of corticosterone (CORT) to determine the exact mechanism of each region of the fear circuits in the anxiety disorders. Chronic CORT-treated mice showed a significant increase in anxiety-related behaviors as assessed by the elevated plus maze, light–dark, open-field, and marble-burying tasks. In addition, chronic CORT-treated mice exhibited abnormal amygdala-dependent tone-induced fear memory but normal hippocampus-dependent contextual memory. Consistent with amygdala hyperactivation, chronic CORT-treated mice showed significantly increased numbers of c-Fos-positive cells in the basolateral amygdala (BLA) after tone stimulation. Long-term potentiation (LTP) was markedly enhanced in the BLA of chronic CORT-treated mice compared to that of vehicle-treated mice. Immunoblot analyses revealed that autophosphorylation of Ca2+/calmodulin-dependent protein kinase (CaMK) IIα at threonine 286 and phosphorylation of cyclic-adenosine-monophosphate response-element-binding protein (CREB) at serine 133 were markedly increased in the BLA of chronic CORT-treated mice after tone stimulation. The protein and mRNA levels of brain-derived neurotrophic factor (BDNF) also significantly increased. Our findings suggest that increased CaMKII activity and synaptic plasticity in the BLA likely account for the aberrant amygdala-dependent fear memory in chronic CORT-treated mice.