Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have su...Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have supported a protective role of ketamine against stress-induced depressive behavior.However,the effect of ketamine on fear generalization remains unclear.In this study,we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model.The mice were given a single sub-anesthetic dose of ketamine(30 mg/kg,i.p.)1 h before,1 week before,immediately after,or 22 h after fear conditioning.The behavioral measure of fear(indicated by freezing level)and synaptic protein expression in the basolateral amygdala(BLA)and inferior-limbic pre-frontal cortex(IL-PFC)of mice were examined.We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization,and the effect was dose-dependent and lasted for at least 2 weeks.The fear-generalized mice showed a lower level of brainderived neurotrophic factor(BDNF)and a higher level of GluN2B protein in the BLA and IL-PFC,and this was reversed by a single administration of ketamine.Moreover,the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC,but had no effect when infused into the BLA.Infusion of ANA-12(an antagonist of the BDNF receptor TrkB)into the BLA or ILPFC blocked the effect of ketamine on fear generalization.These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.展开更多
基金supported by grants from the National Natural Science Foundation of China(81530061 and 81471829)the Pearl River Nova Program of Guangzhou(201610010154)the Natural Science Foundation of Guangdong Province China(2017A030313095).
文摘Fear memories are critical for survival.Nevertheless,over-generalization of these memories,depicted by a failure to distinguish threats from safe stimuli,is typical in stress-related disorders.Previous studies have supported a protective role of ketamine against stress-induced depressive behavior.However,the effect of ketamine on fear generalization remains unclear.In this study,we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model.The mice were given a single sub-anesthetic dose of ketamine(30 mg/kg,i.p.)1 h before,1 week before,immediately after,or 22 h after fear conditioning.The behavioral measure of fear(indicated by freezing level)and synaptic protein expression in the basolateral amygdala(BLA)and inferior-limbic pre-frontal cortex(IL-PFC)of mice were examined.We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization,and the effect was dose-dependent and lasted for at least 2 weeks.The fear-generalized mice showed a lower level of brainderived neurotrophic factor(BDNF)and a higher level of GluN2B protein in the BLA and IL-PFC,and this was reversed by a single administration of ketamine.Moreover,the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC,but had no effect when infused into the BLA.Infusion of ANA-12(an antagonist of the BDNF receptor TrkB)into the BLA or ILPFC blocked the effect of ketamine on fear generalization.These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.
