Rationale:
Brain-derived neurotrophic factor (BDNF) is a key mediator in the development of chronic pain. Sortilin is known to interact with proBDNF and regulate its activity-dependent secretion in cortical neurons. In a rat model of inflammatory pain with intraplantar injection of complete Freund's adjuvant (CFA), we examined the functional role of proBDNF-sortilin interaction in dorsal root ganglia (DRG).
Methods:
Expression and co-localization of BDNF and sortilin were determined by immunofluorescence. ProBDNF-sortilin interaction interface was mapped using co-immunoprecipitation and bimolecular fluorescence complementation assay. The analgesic effect of intrathecal injection of a synthetic peptide interfering with proBDNF-sortilin interaction was measured in the CFA model.
Results:
BDNF and sortilin were co-localized and their expression was significantly increased in ipsilateral L4/5 DRG upon hind paw CFA injection.
In vivo
adeno-associated virus-mediated knockdown of sortilin-1 in L5 DRG alleviated pain-like responses. Mapping by serial deletions in the BDNF prodomain indicated that amino acid residues 71-100 supported the proBDNF-sortilin interaction. A synthetic peptide identical to amino acid residues 89-98 of proBDNF, as compared with scrambled peptide, was found to interfere with proBDNF-sortilin interaction, inhibit activity-dependent release of BDNF
in vitro
and reduce CFA-induced mechanical allodynia and heat hyperalgesia
in vivo
. The synthetic peptide also interfered with capsaicin-induced phosphorylation of extracellular signal-regulated kinases in ipsilateral spinal cord of CFA-injected rats.
Conclusions:
Sortilin-mediated secretion of BDNF from DRG neurons contributes to CFA-induced inflammatory pain. Interfering with proBDNF-sortilin interaction reduced activity-dependent release of BDNF and might serve as a therapeutic approach for chronic inflammatory pain.
Background
Both the clinical and preclinical studies have suggested embryonic or infant exposure to ketamine, a general anesthetic, pose a great threat to the developing brain. However, it remains unclear how ketamine may contribute to the brain dysfunctions.
Methods
A mouse model of prenatal exposure to ketamine was generated by i.m. injection and continuous i.p. infusion of pregnant mice. Open field test and elevated plus maze test were used to analyze the behavioral alterations induced by ketamine. Immunostaining by c-Fos was used to map the neuron activity. Chemogenetic modulation of the neurons was used to rescue the abnormal neuron activity and behaviors.
Results
Here we show that mice prenatally exposed to ketamine displayed anxiety-like behaviors during adulthood, but not during puberty. C-Fos immunostaining identified abnormal neuronal activity in Bed Nucleus of the Stria Terminalis, the silencing of which by chemogenetics restores the anxiety-like behaviors.
Conclusions
Taken together, these results demonstrate a circuitry mechanism of ketamine-induced anxiety-like behaviors.
Susceptible genetic polymorphisms and altered expression levels of protein kinase C (PKC)-encoding genes suggest overactivation of PKC in autism spectrum disorder (ASD) development. To delineate the pathological role of PKC, we pharmacologically stimulated its activity during the early development of zebrafish. Results demonstrated that PKC hyper-activation perturbs zebrafish development and induces a long-lasting head size deficit. The anatomical and cellular analysis revealed reduced neural precursor proliferation and newborn neuron formation. β-Catenin that is essential for brain growth is dramatically degraded. Stabilization of β-catenin by gsk3β inhibition partially restores the head size deficit. In addition, the neuropathogenic effect of developmental PKC hyper-activation was further supported by the alterations in the behavioral domain including motor abnormalities, heightened stress reactivity and impaired habituation learning. Taken together, by causally connecting early-life PKC hyper-activation to these neuropathological traits and the impaired neurogenesis, these results suggest that PKC could be a critical pathway in ASD pathogenesis.
This paper proposes VDStream, a new effective method, to discover arbitrary shape clusters over variable density data streams. The algorithm can reduce the influence of history data and effectively eliminate the interference of noise data. When the density of data streams changes, VDStream can dynamically adjust the parameters of density to find precise clusters. Experiments demonstrate the effectiveness and efficiency of VDStream.
As to classification problem, this paper puts forward the combinatorial optimization least squares support vector machine algorithm (COLS-SVM). Based on algorithmic analysis of COLS-SVM and improves on it, the improved COLS-SVM can be used on individual credit evaluation. As to regression problem, appropriate kernel function and parameters were selected based on the analysis of support vector regression (SVR) algorithm. This paper proposes the forecasting model of coal mine ground-water-level based on SVR algorithm and improves on it. In another regression problem, it improves on successive overrelaxation for support vector regression (SORR) algor...
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