ABSTRACT Peroxisome proliferator‑activated receptor gamma coactivator‑1α (PGC‑1α), a key metabolic regulator, is implicated in astrocyte function, but its specific role during fear memory retrieval and in posttraumatic stress disorder (PTSD) pathogenesis remains unclear. Here, using the single‐prolonged stress mice model, we demonstrated a significant downregulation of PGC‑1α specifically within hippocampal astrocytes, concomitant with reduced astrocyte density, attenuated intracellular Ca2+ signaling, and impaired activity‑dependent ATP release. Targeted knockdown of hippocampal astrocytic PGC‑1α in vivo was sufficient to potentiate fear memory retrieval. This behavioral enhancement was associated with a loss of complex astrocyte morphology, further suppression of ATP release, aberrant hippocampal neuronal activity, and a marked decrease in connexin 43 (CX43) expression. Notably, pharmacological inhibition of CX43‑based gap junctions mimicked this pro‑fear phenotype in control animals. Conversely, interventions either via chemogenetic activation of astrocytes or administration of PGC‑1α agonists effectively normalized fear memory responses and rescued CX43 levels in PTSD mice. Crucially, the therapeutic benefit of chemogenetic astrocyte activation was abolished when PGC‑1α was concomitantly knocked down. Collectively, our results demonstrate that PGC‐1α deficiency in hippocampal astrocytes underlies enhanced fear memory retrieval in PTSD model mice, highlighting the potential of astrocyte‑targeted strategies for preventing and treating PTSD.

OBJECTIVES:To explore the effect of electroacupuncture (EA) on fear memory extinction in single prolonged stress (SPS) mice and the potential mechanism involving astrocytes. METHODS:Thirty-six male C57BL/6J mice were randomly divided into the control, SPS model, EA treatment, paroxetine positive drug (PRX), Saline and CNO group. In Saline and CNO group, chemical genetic virus was used to inhibit the hippocampal astrocytes. Except for control group, the other groups were subjected to SPS modeling. After 7 days, the EA, Saline and CNO group were treated with EA at Baihui and Zusanli, while PRX group was given paroxetine solution for 10 days. Fear conditioning test and elevated plus maze test were used to evaluate fear memory extinction and anxiety-like behaviors, and the CNO group was administered CNO 30 minutes before the tests start. Immunofluorescence staining was used to observe the changes in the number and morphology of hippocampal astrocytes, and hippocampal expressions of GFAP and CX43 proteins were detected using Western blotting. RESULTS:In the mouse models with SPS, EA intervention significantly reduced the freezing time during fear re-exposure for 3-15 min and in the fear extinction phase. EA intervention also significantly increased the extinction coefficient, time spent in the open arms, the mean fluorescence intensity of GFAP, the number of astrocyte branches 50 μm from the soma, and the expression of CX43 proteins in the hippocampus of SPS mice. CONCLUSIONS:EA at Baihui and Zusanli improves fear memory extinction and anxiety-like behaviors in SPS mice by activating hippocampal astrocytes.

The study aimed to optimize the processing conditions of Gardeniae Fructus with ginger juice (GFPG) and confirm its therapeutic effects and pharmacological mechanisms on cholestatic liver injury. Processing conditions were optimized using response surface methodology (RSM) and thermal analysis, focusing on geniposide content as a key active compound. Variables included processing time, moistening time, and the solid-liquid ratio. Optimal conditions were: ginger juice to Gardeniae Fructus ratio of 8:1 (w/v), processing temperature of 208 °C, moistening time of 3 hours, and processing time of 5 minutes. Pharmacological mechanisms were analyzed through network pharmacology, molecular docking, and experimental validation using alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury in mice and lipopolysaccharide (LPS)-stimulated RAW264.7 cell models. In vivo, GFPG extract alleviated ANIT-induced cholestatic liver injury by improving liver function markers (AST, ALT, TBA, TBIL, DBIL) and modulating TLR4/NF-κB, FXR/PPAR-α, and PI3K/AKT/GSK-3β pathways. In vitro, it reduced LPS-induced production of inflammatory mediators (NO, TNF-α, IL-6, IL-1β) through TLR4/NF-κB pathway inhibition. This study established optimal processing methods for GFPG using RSM and thermal analysis, providing robust quantitative parameters. GFPG demonstrated significant therapeutic effects in cholestatic liver injury models, indicating its potential as a candidate for developing treatments for cholestatic hepatitis.

BACKGROUND:Pyridaben, a commonly employed pyridazinone insecticide, is extensively utilized in safeguarding crops against insects and mites. Pyridaben is known to impede mitochondrial complex I activity, inducing mitochondrial impairment, which subsequently culminates in cellular hypoxia, cessation of glycolysis, swift lactic acid buildup, and the onset of lactic acidosis. Prolonged exposure to pyridaben has been demonstrated to elicit deleterious effects on neuronal cells. Furthermore, pyridaben has been associated with the manifestation of cardiotoxicity, leading to abnormal cardiac function. CASE PRESENTATION:A 55-year-old Male was expeditiously transported to our medical facility thirty minutes subsequent to ingesting 10 mL of pyridaben. Upon admission, the patient exhibited symptoms of vomiting and coma. Within the next half-hour, he progressed to hypotonic hypoxemia and hypotension as a result of pyridaben intoxication. With the implementation of prompt gastric lavage, oral administration of activated charcoal, respiratory and circulatory support, as well as continuous renal replacement therapy (CRRT), the patient was ultimately discharged successfully without any lingering sequelae. CONCLUSION:This case report delineates a rare occurrence of acute human poisoning stemming from contact with novel synthetic pesticides. The document elucidates the clinical manifestations observed and the efficacious administration of supportive therapeutic interventions.

The extracellular acidic microenvironment plays a pivotal role in driving tumor initiation and sustaining its malignant progression. Therefore, understanding its regulatory mechanism is crucial for the treatment of liver cancer. Acid-sensing ion channel 1a (ASIC1a) serves as the primary acid sensor, transmitting the extracellular low pH signal into the cell to initiate downstream signaling pathways. In this study, we have investigated the pathogenic role of ASIC1a in liver cancer and elucidated its molecular mechanism. Our findings suggest that ASIC1a facilitates the proliferation of liver cancer cells and enhances their malignant characteristics in the acidic microenvironment. Relevantly, this deleterious characteristic was notably repressed upon the inhibition of ASIC1a activity. Transcription factor 7 acts as a crucial mediator, transmitting the activation signals from ASIC1a to upregulate c-Myc expression, thereby promoting the proliferation of liver cancer cells. In conclusion, our results provide new insights into how the extracellular acidic microenvironment contributes to the advancement of liver cancer.

A longed lack of control over harmful stimuli can lead to learned helplessness (LH), a significant factor in depression. However, the cellular and molecular mechanisms underlying LH, and eventually behavioral despair, remain largely unknown. The deleted in colorectal cancer (dcc) gene is associated with the risk of depression. However, the therapeutic potential and regulation mechanism of DCC in behavioral despair are still uncertain. In this study, we showed that depressive stimulators, including LH, lipopolysaccharide, and unpredictable chronic mild stress, triggered an elevation in DCC expression in the medial prefrontal cortex (mPFC). Additionally, elevated DCC expression in the mPFC was crucial in inducing behavioral despair, as evidenced by the induction of behavioral despair in normal mice and exacerbation of behavioral despair in LH mice upon DCC overexpression. By contrast, neutralizing DCC activity ameliorated LH-induced behavioral despair. Importantly, we elucidated that pathological DCC expression was attributable to the excessive excitation of CaMKII+ neurons in a manner dependent on the calpain-mediated degradation of SCOP and aberrant phosphorylation of the ERK signaling pathway. In addition, the increase in DCC expression led to a decreased excitability threshold in CaMKII+ neurons in the mPFC, which was supported by the observation that the ligand netrin 1 increased the frequency of action potential firing and of spontaneous excitatory postsynaptic currents in CaMKII+ neurons. In conclusion, our data indicate that LH triggers the excessive excitation of CaMKII+ neurons and activation of calpain-SCOP/ERK signaling to promote DCC expression, and DCC represents a crucial target for the treatment of LH-induced behavioral despair in male mice.

Introduction: Huangqin decoction (HD) is a traditional Chinese medicine used for complementary therapy of liver cancer. However, its molecular mechanism of action is still unclear. Methods: After determining the active ingredients and targets of HD and identifying the genes related to liver cancer, a protein-protein interaction (PPI) network of the overlapping genes. The Metascape platform was used to perform gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis and the PubChem database, SwissADME database, PyMOL software, and AutoDock software were used to perform molecular docking. The Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA ) database were used to evaluate the expression levels, survival analysis, and pathological stage. The Cancer Genome Atlas (TCGA) database was used to extract the clinical and RNA-seq data of liver cancer patients. The R packages were used to analyse clinical data. Results: Network pharmacology and molecular docking revealed the potential molecular mechanisms of HD in the treatment of liver cancer. The active components of HD were quercetin, kaempferol, wogonin, baicalein, naringenin, formononetin, isorhamnetin, and medicarpin. HD modulated the expression of AKT1, TP53, TNF, IL6, CTNNB1, VEGFA, and ESR1. Conclusion: HD treats liver cancer in a multi-component, multi-target, and multi-pathway manner. Our findings encourage further studies on the mechanisms underlying the therapeutic effects of HD in liver cancer. The proofof-concept approach enable future studies on the molecular mechanisms of traditional Chinese medicine and contribute to the development of novel therapeutic targets.

Major depressive disorder (MDD) is a prevalent mental disorder that significantly impacts social and psychological function, but no effective medication is currently available. Circular RNAs (circRNAs) have been reported to participate in the pathogenesis of MDD which are envisioned as promising therapeutic targets. However, nonviral-based delivery strategies targeting circRNA against MDD are not thoroughly investigated. Here, it is identified that circATF7IP is significantly upregulated in plasma samples and positively correlated with 24-Hamilton Depression Scale (HAMD-24) scores of MDD patients. Synergistic amine lipid nanoparticles (SALNPs) are designed to deliver siRNA targeting circATF7IP (si-circATF7IP) into the hippocampus brain region by intranasal administration. Intranasal delivery of SALNP-si-circATF7IP successfully alleviated the depressive-like behaviors in the LPS-induced mouse depression model via decreasing CD11b + CD45 dim microglia population and pro-inflammatory cytokine productions (TNF-α and IL-6). These results indicate that the level of circATF7IP positively correlates with MDD pathogenesis, and SALNP delivery of si-circATF7IP via intranasal administration is an effective strategy to ameliorate LPS-induced depressive-like behaviors.

ETHNOPHARMACOLOGICAL RELEVANCE:According to traditional Chinese medicine (TCM) theory, post-traumatic stress disorder (PTSD) is a kind of depression syndrome, and its occurrence is related to deficiencies of the heart and kidney. Polygonatum cyrtonema Hua replenishes Qi and blood and tonifies the five zang organs, so it is widely used in TCM as a prescription for the treatment of depression syndrome. The polysaccharides in P. cyrtonema Hua (PSP) are the main active components of the herb, but the effects of PSP on PTSD and the mechanisms remain unclear.AIM OF THE STUDY:To investigate the preventive effect of PSP on PTSD-like behaviors and to determine the mechanisms.METHODS:We used behavioral tests to evaluate PTSD-like behaviors in mice. Synaptic changes were assessed by transmission electron microscopy. Hematoxylin-eosin staining was used to assess pathological changes to the hippocampus, and immunofluorescence staining was used to observe changes in astrocytes. Serum corticosterone (CORT), cytokine, and hippocampal oxidation-related indicator levels were evaluated by ELISA. We detected the expression levels of synaptic, oxidative, and inflammation-related proteins in the hippocampus by western blotting.RESULTS:Single prolonged stress (SPS)-modeled mice exhibited significant PTSD-like phenotypes, including increased fear memory acquisition and anxiety-like behaviors. These behavioral changes were prevented by PSP administration. Compared to controls, SPS modeling increased serum CORT, cytokine, and hippocampal malondialdehyde levels; decreased superoxide dismutase activity; and caused losses in pyramidal neurons, astrocytes, and synapses in the CA1 region. At the molecular level, the expression of brain-derived neurotrophic factor, postsynaptic density protein 95, nuclear factor erythroid 2-related factor 2 (Nrf2), phospho-tyrosine kinase receptor B, activity-regulated cytoskeleton-associated protein, heme oxygenase-1 (HO-1), and GluA1 decreased in SPS mice compared with the control group, while the expression of NOD-like receptor protein 3 (NLRP3), GluN2B, and apoptosis-associated speck-like protein increased in SPS mice. Treatment with PSP counteracted these abnormal changes. Importantly, ML385, an Nrf2 inhibitor, blocked PSP's ability to ameliorate PTSD behaviors and abnormal protein expression. The NLRP3 inhibitor MCC950 reduced the PTSD-like behaviors and normalized protein expression in SPS mice.CONCLUSION:PSP prevents SPS-induced PTSD-like behaviors and synaptic damage by regulating oxidative stress and NLRP3-mediated inflammation, probably in an Nrf2/HO-1 signaling pathway-dependent manner.

Headings ethnopharmacological relevance: Anshen Dingzhi prescription (ADP), which was first published in the masterpiece of traditional Chinese Medicine in the Qing Dynasty, "Yi Xue Xin Wu" (1732 CE), is documented to interrupt panic-related disorders. However, the mechanism of its action is still not clear. Aim of the study: This study aims to investigate the effects of ADP on post-traumatic stress disorder (PTSD)-like behaviors and explore the mechanism from perspective of sirtuin1 (SIRT1)-peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha)-dependent mitochondrial function. Materials and methods: The changes of SIRT1-PGC-1 alpha signal and mitochondrial function were evaluated in the hippocampus of mice receiving single prolonged stress (SPS). Later, the roles of this signaling pathway played in fear memory generalization and anxiety-like behavior in SPS mice was investigated using two agonists of this signaling pathway. On this basis, the effects of ADP (36.8 mg/kg) with definite therapeutic effects, on mitochondrial function were investigated and further confirmed by a SIRT1 inhibitor. Finally, the possible components of ADP targeting PGC-1 alpha were monitored through bioinformatics. Results: Compared with control mice, SIRT1-PGC-1 alpha signal in the hippocampus was impaired in SPS mice, accompanied with dysfunction of mitochondria and abnormal expression of synaptic proteins. The agonists of SIRT1-PGC-1 alpha signal, ZLN005, as well as resveratrol improved the behavioral changes of mice caused by SPS, reversed the decline of proteins in SIRT1-PGC-1 alpha signal, mitochondrial dysfunction, and the abnormal expression of synaptic proteins. The fingerprint was established for the quality control of ADP. At a dose of 36.8 mg/kg, ADP could prevent fear memory generalization and anxiety-like behavior in SPS mice. Mechanically, ADP promoted SIRT1-PGC-1 alpha signal and repaired mitochondrial function. Importantly, SIRT1 inhibitor, selisistat eliminated the ameliorative effects of ADP on behavioral and mitochondrial function. Through molecular docking simulation, the brain-entering components of ADP, including malkangunin, Rg5, fumarine, frutinone A, celabenzine, and inermin had high binding energy with PGC-1 alpha. Conclusion: Dysfunction of SIRT1-PGC-1 alpha-dependent mitochondrial function is attributed to SPS-triggered fear generalization and anxiety-like behavior, and ADP could improve PTSD-like behaviors likely through activating this signaling pathway.

Memory refers to the imprint accumulated in the brain by life experiences and represents the basis for humans to engage in advanced psychological activities such as thinking and imagination. Previously, research activities focused on memory have always targeted neurons. However, in addition to neurons, astrocytes are also involved in the encoding, consolidation, and extinction of memory. In particular, astrocytes are known to affect the recruitment and function of neurons at the level of local synapses and brain networks. Moreover, the involvement of astrocytes in memory and memory-related disorders, especially in Alzheimer's disease (AD) and post-traumatic stress disorder (PTSD), has been investigated extensively. In this review, we describe the unique contributions of astrocytes to synaptic plasticity and neuronal networks and discuss the role of astrocytes in different types of memory processing. In addition, we also explore the roles of astrocytes in the pathogenesis of memory-related disorders, such as AD, brain aging, PTSD and addiction, thus suggesting that targeting astrocytes may represent a potential strategy to treat memory-related neurological diseases. In conclusion, this review emphasizes that thinking from the perspective of astrocytes will provide new ideas for the diagnosis and therapy of memory-related neurological disorders.

Ethnopharmacological relevance: Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum, Sanyeqing) has been used in the prevention and treatment of repetitive Febrile seizures (FS) over the centuries in China. Aim of the study: T. hemsleyanum exerts wide pharmacological action, which has been widely used for treating various diseases, including infantile febrile seizure. However, the systematic study on this herb's material basis and the functional mechanism is lacking. This study intended to systematically elucidate the mechanism of T. hemsleyanum against febrile seizures. Materials and methods: The efficacy of T. hemsleyanum was estimated by using a hot bath as a model of FS, the onset and duration of seizure, morphological structure changes of hippocampal neurons as well as magnetoencephalography were applied to evaluate the effects. Meanwhile, the bioactive components of T. hemsleyanum responsible for the therapeutic effect of T. hemsleyanum on FS were identified by UPLC-MS/MS. Then we systematically elucidated the mechanism of T. hemsleyanum based on metabonomics, transcriptomics, network pharmacological and experimental validation. Results: In a hyperthermia-induced FS model of rats, T. hemsleyanum significantly increased the seizure latency and decreased seizure duration, alleviating the abnormal delta and gamma band activity during epileptic discharge. Furthermore, ten chemical components of ethanol extracts from T. hemsleyanum were identified by UPLC-MS/MS, including quercetin, kaempferol, and procyanidin B1 and so on, which was consistent with the network pharmacology prediction. The serum metabolomics indicated that T. hemsleyanum mainly acts on inflammation regulation and neuroprotection by the glycerophospholipid metabolism pathway. Ninety-two potential targets of T. hemsleyanum on FS were identified by network pharmacology, and TNF, IL-6, and IL-1 beta were considered the pivotal targets. In the hippocampus transcriptomics, 17 KEGG pathways were identified after T. hemsleyanum treatment compared with the FS model group, among which 15 pathways overlapped with those identified by network pharmacology, and the PKC-delta/caspase-1 signaling pathway was a critical node. Finally, in vivo experiments also verified T. hemsleyanum inhibited the activation of microglia and resulted in a significant reduction in the level of PKCd, NLRC4, caspase-1, IL-1 beta, IL-6 and TNF- a in hippocampus of FS rats. Conclusions: Our study suggested that the therapeutic effect of T. hemsleyanum on FS might be regulated by inhibiting the neuroinflammation, thus exerting an anticonvulsant effect in vivo, and the mechanism might be related to regulating the PKC-d/caspase-1 signaling pathway.

As substitutes for bisphenol A (BPA), bisphenol analogs (BPs) have raised concerns due to their frequent environmental detection and unclear safety. Here, the cytotoxicity, endocrine disruption, neurotoxicity, aryl hydrocarbon receptor (AhR) activity, and genotoxicity of nine BPs and BPA were evaluated in three types of cell lines. Over half of the tested BPs exhibited greater cytotoxicity than BPA, with IC50 values showing a linear correlation with LogKow (R²=0.69). All tested BPs exhibited at least one endocrine-disrupting effect, notably estrogenic, which was observable even at 0.01-0.1 μM. Importantly, BPAF and BPAP exposure had widespread endocrine-suppressing effects. Moreover, all BPs (except BPP) and BPA increased SH-SY5Y cells apoptosis at 1-10 μM. Only BPF and BPP significantly increased 7-ethoxyresorufin-O-deethylase levels, highlighting their notable effects on AhR activity. BPAF significantly induced DNA damage at 1.25 μM, whereas BPA, BPF, and BPP induced damage at 20, 25, and 25 μM, respectively. Finally, ToxPi, a weighted scoring system, was used to rank the comprehensive toxicity of BPs, with 7 of 9 BPs showing higher scores than BPA. Collectively, BPs generally exhibited stronger comprehensive toxicity compared with BPA, emphasizing the urgent need for further research to confirm their potential health implications.

BACKGROUND:Dysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. METHODS:We investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples. RESULTS:Increased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues. CONCLUSIONS:We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.

Aralianudaside A, a triterpene saponin with an unusual skeleton of pentacyclic triterpenoid, along with a new triterpene glycoside and six known compounds were obtained from the buds of Aralia elata. Their structures were determined through extensive spectral analysis, including HRESIMS, IR, 1D and 2D NMR, glycolysis and GC. All compounds were evaluated for anti-airway inflammatory activity in lipopolysaccharides (LPS)-induced airway epithelial cells (16HBE), compounds 1, 3, 5, 7 and 8 significantly decreased the expression of pro-inflammatory cytokines IL-1β and IL-4.

Polygonatum cyrtonema polysaccharide (PCP) was subjected to simulated gastrointestinal digestion, followed by in vitro fermentation using human gut microbiota organisms. The results indicated that PCP did not degrade under simulated salivary conditions; however, a certain increase in reducing sugars and monosaccharides, and a slight reduction in the molecular weight of PCP in the gastrointestinal tract were observed, suggesting the partial degradation of PCP. During in vitro fermentation, a large proportion of PCP was degraded by the gut microbiota in fecal samples from both healthy and obese people. The utilization of PCP by the gut microbiota resulted in the generation of abundant short-chain fatty acids (SCFAs), leading to a reduction in environmental pH and stimulation of the proliferation of beneficial bacteria, such as Collinsella and Dialister, while impeding the growth of detrimental bacteria like Flavonifractor. The gut microbiota of healthy individuals exhibited greater efficiency in utilizing PCP compared to that of obese individuals. PICRUSt prediction analysis indicated that the regulation of the gut microbiota by PCP was mainly linked to carbohydrate, amino acid, energy, and lipid metabolic pathways. These results suggested that PCP may promote host health by modulating the gut microbiota and exhibiting potential prebiotic properties.

高等教育质量监测国家数据平台已成为高校完善教学质量监控体系的重要依托.结合学校质量监测数据采集与分析工作的系统实践,梳理依托平台多维数据促进高校协同育人、科学管理、预警调控等方面的经验与启示,能够为高校基于国家数据平台全面提升教学质量提出策略与建议.

Prolonged exposure (PE) therapy aiming to promote fear extinction is a useful treatment for post-traumatic stress disorder (PTSD). However, the mechanisms underlying fear extinction and effective methods used to promote fear extinction in PTSD are still lacking. In this study, we displayed dysfunctions of cyclic adenosine 3,5-monophosphate (cAMP)-protein kinase A (PKA), protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and calcium signaling in peripheral serum of PTSD patients using bioinformatics analysis. Later, we confirmed the dysfunctions of cAMP-PKA, AKT/mTOR and calcium signaling in the hippocampus of PTSD mice. Moreover, the reduction of calpain1 in the hippocampus enhanced fear memory acquisition. Single activation of PKA by systemic application of rolipram (ROL) or meglumine cyclic adenylate (M-cAMP) before re-exposure promoted fear extinction and improved anxiety-like behavior in PTSD mice. Moreover, systemic application of ROL before re-exposure improved hippocampal brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling and calpain1/AKT/mTOR signaling. Interestingly, the effects of activation of PKA could be partially blocked by TrkB antagonist, ANA-12 and mTOR inhibitor, RAPA. Finally, intranasal administration of ROL could also adjust the abnormality of fear memory and improve anxiety-like behaviors in PTSD mice. Collectively, activation of PKA could promote fear extinction, which correlated with the reduction of anxiety-like behavior. The mechanisms were related to the BDNF/TrkB and calpain1/AKT/mTOR signaling pathways. PKA activation might be a useful complementary therapy for PE in the symptom elimination of PTSD.