RESUMEN
Maintaining appropriate levels of fear memory specificity is crucial for individual's survival and mental health, whereas overgeneralized fear commonly occurs in neuropsychiatric disorders, including posttraumatic stress disorder and generalized anxiety disorder. However, the molecular mechanisms regulating fear memory specificity remain poorly understood. The medial prefrontal cortex (mPFC) is considered as a key brain region in fear memory regulation. Previous transcriptomic studies have identified that plexin-A1, a transmembrane receptor critical for axon development, was downregulated in the mPFC after fear memory training. In this study, we identified that learning-induced downregulation of the mRNA and protein levels of plexin-A1 specifically occurred in the inhibitory but not excitatory neurons in the infralimbic cortex (IL) of mPFC. Further studies of plexin-A1 by virus-mediated over-expression of functional mutants selectively in the IL inhibitory neurons revealed the critical roles of plexin-A1 for regulating memory specificity and anxiety. Moreover, our findings revealed that plexin-A1 regulated the distribution of glutamic acid decarboxylase 67, a GABA synthetase, which in turn modulated the activity of IL and its downstream brain regions. Collectively, our findings elucidate the molecular modifier of IL inhibitory neurons in regulating memory specificity and anxiety, and provide candidates for developing therapeutic strategies for the prevention or treatment of a series of fear generalization-related neuropsychiatric disorders.
Asunto(s)
Miedo , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal , Receptores de Superficie Celular/metabolismo , Animales , Moléculas de Adhesión Celular , Extinción Psicológica/fisiología , Miedo/fisiología , Masculino , Ratones , Proteínas del Tejido Nervioso/genética , Neuronas , Corteza Prefrontal/fisiologíaRESUMEN
The release of neuropeptides from dense core vesicles (DCVs) modulates neuronal activity and plays a critical role in cognitive function and emotion. The granin family is considered a master regulator of DCV biogenesis and the release of DCV cargo molecules. The expression of the VGF protein (nonacronymic), a secreted neuropeptide precursor that also belongs to the extended granin family, has been previously shown to be induced in the brain by hippocampus-dependent learning, and its downregulation is mechanistically linked to neurodegenerative diseases such as Alzheimer's disease and other mood disorders. Currently, whether changes in translational efficiency of Vgf and other granin mRNAs may be associated and regulated with learning associated neural activity remains largely unknown. Here, we show that either contextual fear memory training or the administration of TLQP-62, a peptide derived from the C-terminal region of the VGF precursor, acutely increases the translation of VGF and other granin proteins, such as CgB and Scg2, via an mTOR-dependent signaling pathway in the absence of measurable increases in mRNA expression. Luciferase-based reporter assays confirmed that the 3'-untranslated region (3'UTR) of the Vgf mRNA represses VGF translation. Consistently, the truncation of the endogenous Vgf mRNA 3'UTR results in substantial increases in VGF protein expression both in cultured primary neurons and in brain tissues from knock in mice expressing a 3'UTR-truncation mutant encoded by the modified Vgf gene. Importantly, Vgf 3'UTR-truncated mice exhibit enhanced memory performance and reduced anxiety- and depression-like behaviors. Our results therefore reveal a rapid, transcription-independent induction of VGF and other granin proteins after learning that are triggered by the VGF-derived peptide TLQP-62. Our findings suggest that the rapid, positive feedforward increase in the synthesis of granin family proteins might be a general mechanism to replenish DCV cargo molecules that have been released in response to neuronal activation and is crucial for memory function and mood stability.
Asunto(s)
Neuronas , Péptidos , Animales , Cognición , Hipocampo , Memoria , RatonesRESUMEN
BACKGROUND: This study investigated the effects of the intracoronary injection of nicorandil and tirofiban on myocardial perfusion and short-term prognosis in elderly patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). METHODS: Seventy-eight STEMI patients with age >65 years who underwent emergency PCI were consecutively enrolled. These patients received conventional PCI and were randomly divided into a control group and a treatment group (n=39 per group). The control group received an intracoronary injection of tirofiban followed by a maintenance infusion for 36 hours after surgery. The treatment group received intracoronary injection of tirofiban and nicorandil, and then intravenous infusion of tirofiban and nicorandil 36 hours after surgery. The following parameters were measured: TIMI grade, corrected TIMI frame count (cTFC), TIMI myocardial perfusion grade (TMPG), ST-segment resolution (STR) rate 2 hours post-operatively, resolution of ST-segment elevation (STR) at 2 hours postoperatively, peak level of serum CK-MB, left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) at 7-10 days postoperatively, and major adverse cardiac events (MACEs) in-hospital and within 30 days post-operatively. RESULTS: Compared with the control group, more patients in the treatment group had TIMI 3 and TMPG 3, and STR after PCI was significantly higher. The treatment group also had significantly lower cTFC, lower infarction relative artery (IRA), lower peak CK-MB, and no reflow ratio after PCI. The treatment group had significantly higher LVEDD and LVEF but lower incidence of MACEs than the control group. CONCLUSION: The intracoronary injection of nicorandil combined with tirofiban can effectively improve myocardial reperfusion in elderly STEMI patients after emergency PCI and improve short-term prognoses.
RESUMEN
OBJECTIVE: To evaluate the efficacy and safety of pemetrexed and nedaplatin followed by pemetrexed maintenance therapy in advanced lung adenocarcinoma. METHODS: A total of 53 advanced lung adenocarcinoma patients hospitalized between July 2013 and June 2016 with a performance status ≤2 were enrolled in this study. All patients received 4-6 cycles of combination chemotherapy comprising pemetrexed (500 mg/m2 dL) and nedaplatin (80 mg/m2 dL). Each chemotherapy cycle consisted of 21 days. After the efficacy of the combination chemotherapy was assessed, patients with stable disease, partial remission, or complete remission received pemetrexed maintenance therapy (500 mg/m2 dL) until disease progression or intolerable side effects occurred. Each pemetrexed maintenance therapy cycle was 28 days. RESULTS: After completion of the pemetrexed and nedaplatin combination chemotherapy, 26 (49.1%), 15 (28.3%), and 12 (22.6%) patients exhibited partial remission, stable disease, and progressive disease, respectively. Complete remission was not achieved in any patient. Therefore, the response and disease control percentages were 49.1% and 77.4%, respectively. A total of 38 patients were further administered pemetrexed maintenance chemotherapy for an average of 9.8 cycles. The median progression-free survival and overall survival of the 38 patients receiving the pemetrexed maintenance therapy were 9.3 (95% confidence interval: 8.6-10) months and 16.3 (95% confidence interval: 14.5-18.2) months, respectively. The major adverse effects included bone marrow suppression and gastrointestinal reactions, which were well tolerated. CONCLUSIONS: Combination chemotherapy based on pemetrexed and nedaplatin is effective for the treatment of advanced lung adenocarcinoma with a high tolerance by patients. In addition, pemetrexed maintenance therapy of advanced lung adenocarcinoma is safe and effective for the treatment of advanced lung adenocarcinoma following pemetrexed and nedaplatin combination chemotherapy.