Currently, there are no effective therapeutic targets for the treatment of chronic cerebral hypoperfusion(CCH)-induced cerebral ischemic injury. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are discovered as the inducers of neurogenesis and angiogenesis. We previously made a nanofiber membrane (NFM), maintaining a long-term release of VEGF and bFGF up to 35 days, which might make VEGF and bFGF NFM as the potential protective agents against cerebral ischemic insult. In this study, the effects of VEGF and bFGF delivered by NFM into brain were investigated as well as their underlying mechanismsin a rat model of CCH. VEGF + bFGF NFM application increased the expressions of tight junction proteins, maintained BBB integrity, and alleviated vasogenic cerebral edema. Furthermore, VEGF + bFGF NFM sticking enhanced angiogenesis and elevated CBF. Besides, VEGF + bFGF NFM treatment inhibited neuronal apoptosis and decreased neuronal loss. Moreover, roofing of VEGF + bFGF NFM attenuated microglial activation and blocked the launch of NLRP3/caspase-1/IL-1β pathway. In addition, VEGF + bFGF NFM administration prevented disruption to the pre/postsynaptic membranes and loss of myelin sheath, relieving synaptic injury and demyelination. Oligodendrogenesis, neurogenesis and PI3K/AKT/mTOR pathway were involved in the treatment of VEGF + bFGF NFM against CCH-induced neuronal injury and hypomyelination. These findings supported that VEGF + bFGF NFM application constitutes a neuroprotective strategy for the treatment of CCH, which may be worth further clinical translational research as a novel neuroprotective approach, benifiting indirect surgical revascularization.

The transmembrane 63 (TMEM63) family of proteins are originally identified as homologs of the osmosensitive calcium-permeable (OSCA) channels in plants. Mechanosensitivity of OSCA and TMEM63 proteins are recently demonstrated in addition to their proposed activation mechanism by hyper/hypo-osmolarity. TMEM63 proteins exist in all animals, with a single member in Drosophila (TMEM63) and three members in mammals (TMEM63 A/B/C). In humans, monoallelic variants of TMEM63A have been reported to cause transient hypomyelination during infancy, or severe hypomyelination and global developmental delay. Heterozygous variants of TMEM63B are found in patients with intellectual disability and abnormal motor function and brain morphology. Biallelic variants of TMEM63C are associated with hereditary spastic paraplegias accompanied by mild or no intellectual disability. Physiological functions of TMEM63 proteins clearly recognized so far include detecting food grittiness and environmental humidity in Drosophila, and supporting hearing in mice by regulating survival of cochlear hair cells. In this review, we summarize current knowledge about the activation mechanisms and biological functions of TMEM63 channels, and provide a concise reference for researchers interested in investigating more physiological and pathogenic roles of this family of proteins with ubiquitous expression in the body.

How neuronal signaling affects brain myelination remains poorly understood. We show dysregulated neuronal RHEB-mTORC1-DLK1 axis impairs brain myelination. Neuronal Rheb cKO impairs oligodendrocyte differentiation/myelination, with activated neuronal expression of the imprinted gene Dlk1. Neuronal Dlk1 cKO ameliorates myelination deficit in neuronal Rheb cKO mice, indicating that activated neuronal Dlk1 expression contributes to impaired myelination caused by Rheb cKO. The effect of Rheb cKO on Dlk1 expression is mediated by mTORC1; neuronal mTor cKO and Raptor cKO and pharmacological inhibition of mTORC1 recapitulate elevated neuronal Dlk1 expression. We demonstrate that both a secreted form of DLK1 and a membrane-bound DLK1 inhibit the differentiation of cultured oligodendrocyte precursor cells into oligodendrocytes expressing myelin proteins. Finally, neuronal expression of Dlk1 in transgenic mice reduces the formation of mature oligodendrocytes and myelination. This study identifies Dlk1 as an inhibitor of oligodendrocyte myelination and a mechanism linking altered neuronal signaling with oligodendrocyte dysfunction.

UNASSIGNED: Social interaction is a fundamental human need. Social isolation (SI) can have negative effects on both emotional and cognitive function. However, it is currently unclear how age and the duration of SI affect emotion and recognition function. In addition, there is no specific treatment for the effects of SI.
UNASSIGNED: The adolescence or adult mice were individually housed in cages for 1, 6 or 12 months and for 2 months to estabolish SI mouse model. We investigated the effects of SI on behavior in mice at different ages and under distinct durations of SI, and we explored the possible underlying mechanisms. Then we performed deep brain stimulation (DBS) to evaluate its influences on SI induced behavioral abnormalities.
UNASSIGNED: We found that social recognition was affected in the short term, while social preference was damaged by extremely long periods of SI. In addition to affecting social memory, SI also affects emotion, short-term spatial ability and learning willingness in mice. Myelin was decreased significantly in the medial prefrontal cortex (mPFC) and dorsal hippocampus of socially isolated mice. Cellular activity in response to social stimulation in both areas was impaired by social isolation. By stimulating the mPFC using DBS, we found that DBS alleviated cellular activation disorders in the mPFC after long-term SI and improved social preference in mice.
UNASSIGNED: Our results suggest that the therapeutic potential of stimulating the mPFC with DBS in individuals with social preference deficits caused by long-term social isolation, as well as the effects of DBS on the cellular activity and density of OPCs.

The neurodevelopmental toxicity of anesthetics has been confirmed repeatedly, and esketamine is now widely used in pediatric surgeries. Oligodendrocyte precursor cells (OPCs) evolved into mature oligodendrocytes (OLs) and formed myeline sheath during the early brain development. In this study, we investigated whether esketamine exposure interrupted development of OPCs and induced hypomyelination in rats. Further we explored the roles of PI3K/Akt phosphorylation in OPCs development and myelination. Sprague Dawley rats with different ages (postnatal day (P) 1, 3, 7 and 12) were exposed to 40mg/kg esketamine. Progesterone treatment was given (16 mg/kg per day for 3 days) 24 h after esketamine exposure via the intraperitoneal route. Corpus callosum tissues were collected at P8 or P14 for western blot and immunofluorescence analyses. Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) expression and CC1+ OLs number in corpus callosum. Esketamine exposure at P7 not only aggravated the mature OLs apoptosis, also decreased the OPCs proliferation and differentiation, which was related with dephosphorylation of PI3K/Akt. Progesterone was able to promote OPCs differentiation and ameliorate esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation. Stage-dependent abnormality of OPCs/OLs after esketamine leads to the esketamine-induced hypomyelination. Esketamine interrupted OPCs evolution via PI3K/Akt signaling pathway, which can be ameliorated by progesterone.

Oligodendrocyte (OL) myelination is a critical process for the neuronal axon function in the central nervous system. After demyelination occurs because of pathophysiology, remyelination makes repairs similar to myelination. Proliferation and differentiation are the two main stages in OL myelination, and most factors commonly play converse roles in these two stages, except for a few factors and signaling pathways, such as OLIG2 (Oligodendrocyte transcription factor 2). Moreover, some OL maturation gene mutations induce hypomyelination or hypermyelination without an obvious function in proliferation and differentiation. Herein, three types of factors regulating myelination are reviewed in sequence.

Very preterm infants who survive are at high risk of white matter injury (WMI). With a greater understanding of the pathogenesis of WMI, the gut microbiota has recently drawn increasing attention in this field. This review tries to clarify the possible mechanisms behind the communication of the gut bacteria and the immature brain via the gut-brain axis. The gut microbiota releases signals, such as microbial metabolites. These metabolites regulate inflammatory and immune responses characterized by microglial activation, which ultimately impact the differentiation of pre-myelinating oligodendrocytes (pre-OLs) and lead to WMI. Moreover, probiotics and prebiotics emerge as a promising therapy to improve the neurodevelopmental outcome. However, future studies are required to clarify the function of these above products and the optimal time for their administration within a larger population. Based on the existing evidence, it is still too early to recommend probiotics and prebiotics as effective treatments for WMI.

Spinal cord injury (SCI) can cause secondary brain changes, leading to hypomyelination in the dorsolateral prefrontal cortex (dlPFC). Some studies have shown that notch signaling pathway activation can regulate oligodendrocyte maturation and myelination. The aim of this study was to investigate whether inhibition of the Notch signaling pathway can alleviate hypomyelination in the dlPFC caused by SCI. Moreover, we further investigated whether the changes in myelination in the dlPFC are associated with neuropathic pain following SCI. We established a mouse model of SCI and observed the changes in mechanical and thermal hyperalgesia. Western blotting and immunofluorescence were used to analyze the changes in myelination in the dlPFC. The results indicated the existence of a relationship between activation of the Notch signaling pathway and hypomyelination in the dlPFC and confirmed the existence of a relationship between hypomyelination in the dlPFC and decreases in mechanical and thermal hyperalgesia thresholds. In conclusion, these results suggested that the Notch signaling pathway is activated after SCI, leading to hypomyelination in the dlPFC, and that DAPT can inhibit the Notch signaling pathway and improve mechanical and thermal hyperalgesia thresholds. Our findings provide a new target for the treatment of neuropathic pain caused by SCI.

Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia-ischemia and inflammation in premature infants. The activation of A2B adenosine receptor (A2BAR) is shown to involve into inflammation, ischemia, and other typical stress reactions, but its exact function in PVL has not been clarified. We gained initial insight from PVL mouse model (P9) by the induction of hypoxia-ischemia with right carotid ligation followed by exposure to hypoxia and intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS). The results showed that treatment of PSB-603, an A2BAR selective antagonist, greatly ameliorated cerebral ischemic injury by increasing bodyweights, reducing infarct volume, brain injury,inflammation andcontributing to long-term learning memory functionalrecoveryof the PVL mice. Meanwhile, PSB-603 treatment suppressed neurons apoptosis as characterized byreducing of Caspase-3 level, inhibited microglia activation and attenuated hypomyelination through promoting MBP expression and oligodendrocytes differentiation. A2BAR inhibition also augmented PKC expression, the activity of PKC downstream signaling molecules were then explored. Erk expression and Creb phosphorylation exhibited upregulation in PSB-603 treatment group compared with the control group. Hypoxia Inducible Factor-1α (HIF-1α), a direct target of hypoxia, which is a key regulator of adenosine signaling by binding to the A2BAR promoter to induce expression of A2BAR, was shown to be decreased by PSB-603. Taken together, A2BAR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway.

UNASSIGNED: Astrocyte A1/A2 phenotypes may play differential role in the pathogenesis of periventricular white matter (PWM) damage in septic postnatal rats. This study aimed to determine whether melatonin (MEL) would improve the axonal hypomyelination through shifting A1 astrocytes towards A2.
UNASSIGNED: One-day-old Sprague-Dawley rats were divided into control, LPS, and LPS+MEL groups. Immunofluorescence was performed to detect C1q, IL-1α, TNF-α, IBA1, GFAP, MAG, C3 and S100A10 immunoreactivity in the PWM of neonatal rats. Electron microscopy was conducted to observe alterations of axonal myelin sheath in the PWM; moreover, myelin protein expression was assessed using in situ hybridization. The effects of MEL on neurological function were evaluated by behavioral tests. In vitro, A1 astrocytes were induced by IL-1α, C1q and TNF-α, and following which the effect of MEL on C3 and S100A10 expression was determined by Western blot and immunofluorescence.
UNASSIGNED: At 1 and 3 days after LPS injection, IBA1+ microglia in the PWM were significantly increased in cell numbers which generated excess amounts of IL-1α, TNF-α, and C1q. The number of A1 astrocytes was significantly increased at 7-28d after LPS injection. In rats given MEL treatment, the number of A1 astrocytes was significantly decreased, but that of A2 astrocytes, PLP+, MBP+ and MAG+ cells was increased. By electron microscopy, ultrastructural features of axonal hypomyelination were attenuated by MEL. Furthermore, MEL improved neurological dysfunction as evaluated by different neurological tests. In vitro, MEL decreased the C3 significantly, and upregulated expression of S100A10 in primary astrocytes subjected to IL-1α, TNF-α and C1q treatment. Importantly, JAK2/STAT3 signaling pathway was found to be involved in modulation of A1/A2 phenotype transformation.
UNASSIGNED: MEL effectively alleviates PWMD of septic neonatal rats, which is most likely through modulating astrocyte phenotypic transformation from A1 to A2 via the MT1/JAK2/STAT3 pathway.