Post-traumatic stress disorder(PTSD)is a severe mental disorder that significantly impacts an indi-vidual's health,with its primary symptom being fear-based memories.In the pathological state of PTSD,fear-based memo-ries are prolonged and intensified by certain physiological mechanisms.Therefore,expediting the extinction of fear-based memories and preventing their excessive consolidation are crucial for successful treatment.Recently,researchers have dis-covered that ketamine,beyond its role as an anesthetic,also plays a substantial part in regulating fear-based memories.This paper aims to elucidate the role of ketamine in modulating conditioned fear-based memories across various time frames and brain regions,as well as the associated molecular mechanisms.Furthermore,it seeks to clarify the specificity of dif-ferent molecular mechanisms in distinct time frames of fear-based memories and assess whether ketamine could be a prima-ry medication for treating PTSD.

Post-traumatic stress disorder(PTSD)is a severe mental disorder that significantly impacts an indi-vidual's health,with its primary symptom being fear-based memories.In the pathological state of PTSD,fear-based memo-ries are prolonged and intensified by certain physiological mechanisms.Therefore,expediting the extinction of fear-based memories and preventing their excessive consolidation are crucial for successful treatment.Recently,researchers have dis-covered that ketamine,beyond its role as an anesthetic,also plays a substantial part in regulating fear-based memories.This paper aims to elucidate the role of ketamine in modulating conditioned fear-based memories across various time frames and brain regions,as well as the associated molecular mechanisms.Furthermore,it seeks to clarify the specificity of dif-ferent molecular mechanisms in distinct time frames of fear-based memories and assess whether ketamine could be a prima-ry medication for treating PTSD.

OBJECTIVE To prep are Legumain enzyme and mitochondrial double-stage targeted harmine （HM） liposome （KA@HM-LPS）and preliminary evaluate its pharmaceutical properties ，in vitro antitumor effect and biocompatibility. METHODS Firstly，the preparation and homogenization methods of KA@HM-LPS was screened ，and prepared liposomes were characterized. Secondly，the serum stability ，in vitro release rate ，hemolysis percentage of KA@HM-LPS and cell survival rate under KA@BLPS were determines respectively. Finally ，the cell surivival rate ，mitochondrial targeting and inhibitory effects on cell migration and invasion of KA@HM-LPS were determined. RESULTS KA@HM-LPS was prepared by the thin-film dispersion method ，with encapsulation efficiency of （90.50 ± 0.62）％ . The extrusion moulding method was selected as homogenization method of KA@HM-LPS. The particle size ，polydispersity index ，and Zeta potential of KA@HM-LPS were （211.40±11.67）nm，0.316± 0.014 and（－14.20±0.49）mV，respectively. In 37 ℃，10％ FBS，the particle size of KA@HM-LPS kept stable after 12 h. In vitro release curve of KA@HM-LPS in 20％ plasma conformed to Weibull distribution and had the property of sustained release. When HM concentration was 160 μg/mL，the hemolysis percentage of KA@HM-LPS was （4.23±0.19）％，which was much lower than that of free HM ，with safety. When the mass concentration of KA@BLPS reaches 400 μg/mL，the survival rate of LO 2 cells was （94.40 ± 6.12）％ ，and the biocompatibility was good. Cell test results in vitro showed that ，inhibitory effect of KA@HM-LPS on liver cancer cells with overexpression of Legumain enzyme （LGMN -SK-Hep-1） was significantly higher than that of normal liver cancer cells SK-Hep- 1； compared with SK-Hep-1，LGMN +-SK-Hep-1 cells had a higher uptake efficiency of the liposome ；KA@HM-LPS could significantly inhibit the migration and invasion of LGMN +- SK-Hep-1 cells. CONCLUSIONS KA@HM-LPS is prepared successfully ，which can effectively inhibit the migration and invasion of liver cancer cells with Legumain enzyme overexpression ，and improve the blood compatibility of HM.