Fear Extinction Induced By Activation Of PKA Ameliorates Anxiety-Like Behavior In PTSD Mice

Background: Posttraumatic stress disorder(PTSD)is a neuropsychiatric disorder secondary to stressful trauma.Delayed onset and long-term persistence after individual experiences an unusually traumatic event.The condition of PTSD is complex and the prognosis is poor,which seriously affects the mental health and mental state of patients.Prolonged exposure(PE)therapy,designed to promote fear memory extinction is an effective treatment for PTSD.The cyclic adenosine 3,5-monophosphate(c AMP)/protein kinase A(PKA)signaling pathway regulates emotional and stress responses primarily by mediating cell division,synaptic plasticity,and protein transcription,making it a potential target for the treatment of neurological disorders.Previous studies have suggested that the c AMP/PKA signaling pathway may be involved in regulating fear extinction.In addition,it has also been shown that synaptic plasticity in the hippocampus is closely associated with fear extinction.In this study,we screened the signaling pathways involved in fear extinction impairment by bioinformatics analysis and investigated the effects of exogenous activation of PKA on fear extinction in PTSD mice and the related molecular mechanisms.This provides a new way to enhance the efficacy of PE therapy.Objective: To investigate the effects of exogenous activation of PKA on fear extinction and anxiety-like behavior in PTSD mice.Based on Brain-derived neurotrophic factor(BDNF)/Tropomyosin-related kinase B(Trk B)and calpain1-protein kinase B(AKT)/mammalian target of rapamycin(mTOR)signaling pathways,we investigated the mechanism of activation of PKA to enhance the ability of extinction learning in mice.Methods: A bioinformatic approach was first used to screen for differentially expressed genes in the blood of PTSD patients.A single prolonged stress(SPS)-induced PTSD model was established,and the obtained differential genes were further validated in the hippocampus of PTSD mice.The role of the two key targets in fear extinction in mice was explored by inhibiting the activation of PKA in normal mice or knocking down the expression of calpain1 in their hippocampus.The effects of rolipram(ROL)or methylglucamine cyclic adenosine monophosphate(M-c AMP,MCP)on fear extinction and anxiety-like behavior in PTSD mice were then assessed.Then based on the BDNF/Trk B and calpain1-AKT/mTOR signaling pathways in the hippocampus,the mechanism of PKA activation enhancing the extinction learning ability of mice was explored.Finally,the effect of intranasal application of ROL on PTSD-like behavior in mice was further examined.Results: The results of bioinformatics analysis revealed abnormalities in c AMP/PKA,AKT-mTOR and calcium signaling pathway transduction in the sera of PTSD patients.These results were also confirmed in the hippocampus of PTSD mice.In addition,inhibition of PKA activation or reduction of calpain1 expression in the hippocampus enhanced the generalization of fear memory in normal mice.activation of PKA by ROL or MCP promoted the abrogation of fear memory and improvement of anxiety-like behavior in PTSD mice and improved the conduction of hippocampal BDNF/Trk B and calpain1-AKT/mTOR signaling pathways.Finally,intranasal administration of ROL also exerted an effect of promoting fear memory extinction and improving anxiety-like behavior in PTSD mice.Conclusions: Exogenous activation of PKA promotes the abrogation of fear memory and improves anxiety-like behavior in PTSD mice,possibly by promoting the transduction of BDNF/Trk B and calpain1-AKT/mTOR signaling pathways.This study demonstrates that PKA activation can be used as an adjunct to PE treatment.