Neuroscience
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The chemogenetic procedure DREADD (designer receptor exclusively activated by designer drugs) is an inventive way to selectively affect g-coupled protein receptors. In theory, DREADD receptors are only activated by administering inert compounds, primarily clozapine N-oxide (CNO). Research has shown that CNO does not cross the blood-brain barrier, and CNO is converted back to clozapine and N-desmethylclozapine (N-Des) in the brain. ⋯ The source of the DA and glutamate could be caused by activation of projection neurons or local effects. The data replicate findings that CNO is not an inert compound and that interpretation of CNO-activated DREADD findings should be done with caution. The data indicate that low ('safe') doses of CNO still have neurochemical effects and that controlling for the actions of clozapine/N-Des in CNO-DREADD studies has many concerns.
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Vanillin has been reported to reduce hippocampal neuronal death in rat models of global cerebral ischemia. However, the immunoregulatory mechanism of vanillin in ischemic stroke is still unclear. To investigate the role of vanillin in a mouse model of ischemic stroke, we administered vanillin to mice after transient middle cerebral artery occlusion (tMCAO) by tail vein injection. ⋯ Similar effects were observed using the in vitro LPS-stimulated microglia cell model. Moreover, the reduced expression of proinflammatory cytokines in the vanillin group was related to TLR4/NF-κB signaling. Taken together, the findings suggest that vanillin decreased microglial activation by inhibiting the TLR4 /NF-κB signaling pathway, which reduced expression of proinflammatory cytokines IL-1β and TNF-α, and finally reduced the infarct volume and improved motor function in tMCAO mice.
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Intracerebral hemorrhage (ICH) is a hemorrhagic stroke with a high mortality and disability rate. Neurological impairment after ICH is closely associated with neuronal axon damage. Serine/threonine-protein kinase p21 activated kinase 1 (PAK1) participates in cytoskeletal remodeling and regulates the F-actin and G-actin ratio in neuronal axons, but the function of PAK1 after ICH remains unclear. ⋯ Knockdown of PAK1 increased the live/dead cell ratio and promoted neurons survival. Our study showed that PAK1 is involved in ICH early secondary brain injury by affecting F-actin/G-actin ratio through the PAK1/LIMK1/cofilin pathway. PAK1 may be an essential target for early secondary brain injury intervention after ICH.
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Early-life stress (ELS) has long-term consequences, including an increased risk for drug abuse and psychiatric disorders later in life, which is higher in women than in men. The consequences of ELS include heightened sensitivity to stressful events. Here, we hypothesized that ELS changes the stress sensitivity of dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) and orexin (OXA) neurons in the lateral hypothalamus (LH), that are crucial for the control of motivated behaviors. ⋯ Furthermore, an increase in spine head diameter of VTA neurons and a concurrent decrease in dendritic spine density in dorsal VTA were observed. We also showed that MS changed the stress sensitivity of OXA neurons selectively in the dorsomedial hypothalamus (DMH), which is implicated in arousal and the stress response. These findings show the long-lasting consequences of ELS and indicate the selective, regional sensitivity of structures involved in the control of arousal, motivational behaviors and the stress response to ELS.
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Previous studies have demonstrated patients with autism spectrum disorder (ASD) are accompanied by alterations of spontaneous brain activity in gray matter. However, whether the alterations of spontaneous brain activity exist in white matter remains largely unclear. In this study, 88 ASD patients and 87 typical controls (TCs) were included and regional homogeneity (ReHo) was calculated to characterize spontaneous brain activity in white matter. ⋯ Compared with TCs, the ASD group showed significantly decreased ReHo in the left superior corona radiata and left posterior limb of internal capsule, and decreased ReHo in the left anterior corona radiata with a trend level of significance. In addition, significantly weaker structural-functional coupling was observed in the left superior corona radiata and left posterior limb of internal capsule in ASD patients. Taken together, these findings highlighted abnormalities of white matter's regional spontaneous brain activity in ASD, which may provide new insights into the pathophysiological mechanisms of this disorder.