Neuroscience
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The transition from multipotent neural stem cells (NSCs) to terminally differentiated neurons is a multistep process, and the transition is finely regulated by transcription factors with basic helix-loop-helix (bHLH) motifs. Melatonin is an endogenous neurohormone with profound neurotrophic and neuroprotective effects both during the embryonic developmental stage and adulthood. The effects of melatonin on the differentiation of NSCs have been reported, and these effects may be responsible for its neuroprotective properties. ⋯ Increased H3K14 acetylation altered the chromatin state of the promoters of bHLH factors Neurogenin1 and NeuroD1 and activated their transcription; then, Neurogenin1 and NeuroD1 initiated and sustained the commitment to neuronal fates. As we know, CBP/p300 is an important class of histone acetyltransferases that acetylate histone H3K14, we found that melatonin activated the histone acetyltransferase activity of CREB-binding protein (CBP)/p300 via ERK signaling pathways. For the first time, we systematically showed the molecular mechanism of action of melatonin, which suggested that melatonin functions as a regulator of the acetylation-dependent gene expression network.
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PTPN11 is associated with regulation of growth factor signaling pathways in neuronal cells. Using SH-SY5Y neuroblastoma cells, we showed that adeno-associated virus (AAV)-mediated PTPN11 upregulation was associated with TrkB antagonism, reduced neuritogenesis and enhanced endoplasmic reticulum (ER) stress response leading to apoptotic changes. Genetic knock-down of PTPN11 on the other hand leads to increased TrkB phosphorylation in SH-SY5Y cells. ⋯ This study provides evidence of molecular interactions between PTPN11 and the TrkB receptor in SH-SY5Y cells. The results reinforce the role played by PTPN11 in regulating neurotrophin protective signaling in neuronal cells and highlight that PTPN11 dysregulation promotes apoptotic activation. Based on these findings we suggest that blocking PTPN11 could have potential beneficial effects to limit the progression of neuronal loss in neurodegenerative disorders.
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Local lesions caused by stroke may result in extensive structural and functional reorganization in the brain. Previous studies of this phenomenon have focused on specific brain networks. Here, we aimed to discover abnormalities in whole-brain networks and to explore the decoupling between structural and functional connectivity in patients with stroke. ⋯ Positive correlations between the nodal degree of the inferior parietal lobule and the Fugl-Meyer Assessment (FMA) score and between the nodal betweenness centrality of the posterior cingulate gyrus (PCG) and immediate recall were observed in patients with stroke. Most importantly, the strength of the structural-functional connectivity network coupling was decreased, and the coupling degree was related to the FMA score of patients, suggesting that decoupling may provide a novel biomarker for the assessment of motor impairment in patients with stroke. Thus, the topological organization of brain networks is altered in patients with stroke, and our results provide insights into the structural and functional organization of the brain after stroke from the viewpoint of network topology.
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Neurogenesis in the subventricular zone (SVZ) plays a vital role in neurologic recovery after stroke. However, only a small fraction of newly generated neuroblasts from the SVZ will survive long-term. Successful migration and survival of neuroblasts requires angiogenesis, lesion-derived chemo-attractants, and appropriate local microenvironments, which are partly regulated by the platelet-derived growth factor receptor (PDGFR) signaling pathway. ⋯ Crenolanib treatment increased the apoptosis of pericytes and decreased the pericyte/vascular coverage, but had no effects on apoptosis of astrocytes. We conclude that the PDGFR signaling pathway plays a vital role in the SVZ neurogenesis after stroke. It can also affect angiogenesis, lesion-derived chemo-attractants, and the local microenvironment, which are all important to stroke-induced neurogenesis.
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Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) induces rapid improvement of depressive symptoms in patients suffering from treatment-refractory major depressive disorder (MDD). It has been hypothesized that activation of the dopamine (DA) system contributes to this effect. To investigate whether DBS in the MFB affects DA release in the striatum, we combined DBS with fast-scan cyclic voltammetry (FSCV) in freely moving rats. ⋯ These findings suggest that effects of DBS in the MFB are mediated by an acute change in extracellular DA concentration, but more research is needed to further explore the potentially sustained duration of this effect. Together, our results provide both support and refinement of the hypothesis that MFB DBS activates the DA system: DBS induces an increase in overall ambient concentration of DA, but spontaneous or reward-associated more rapid, phasic DA dynamics are not enhanced. This knowledge improves our understanding of how DBS affects brain function and may help improve future therapies for depressive symptoms.