Neuroscience
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Alcoholism is a relapsing disorder with limited treatment options, in part due to our limited understanding of the disease etiology. We have recently shown that increased ethanol-seeking in a behavioral model of relapse in a rat model of alcoholism was associated with increased oligodendrogenesis which was positively correlated with platelet/endothelial cell adhesion molecule (PECAM-1) expression in the medial prefrontal cortex (mPFC). The current study investigated whether newly born oligodendrocytes form close physical associations with endothelial cells expressing PECAM-1 and whether these changes were accompanied by altered blood-brain barrier (BBB) integrity. ⋯ Furthermore, voluntary wheel running during abstinence enhanced SMI-71 expression in endothelial cells, indicating protection against abstinence-induced reduction in BBB integrity. Taken together, these results suggest that ethanol experience and abstinence disrupts homeostasis in the oligo-vascular niche in the mPFC. Reversing these mechanisms may hold the key to reducing propensity for relapse in individuals with moderate to severe alcohol use disorder.
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Amyloid-β (Aβ) production and clearance in the brain is a crucial focus of investigations into the pathogenesis of Alzheimer disease. Imbalance between production and clearance leads to accumulation of Aβ. The important Aβ-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), and defective enzyme expression may facilitate Aβ deposition in sporadic late-onset AD patients. ⋯ NEP expression in cultured astrocytes was suppressed by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), and reduced NEP expression was accompanied by an increase of NEP release into the extracellular space (culture medium). Moreover, culture medium from EGCG-treated astrocytes facilitated the degradation of exogenous Aβ. These results suggest that EGCG may have a beneficial effect on AD by activating ERK-and PI3K-mediated pathways in astrocytes, thus increasing astrocyte secretion of NEP and facilitating degradation of Aβ.
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The post-stroke angiogenic response is accompanied by changes of tight junctions (TJs) of the blood-brain barrier (BBB). However, the precise dynamic change of TJ proteins (TJPs) in the different stages of stroke-induced vascular remodeling and the molecules mediating these processes have yet to be fully defined. To investigate the temporal relationship between changes in TJPs, the pro-angiogenic factor α5β1 integrin and the anti-permeability factor Ang1 in cerebral vessels following cerebral ischemic stroke, male C57Bl/6 mice were subject to 90min of ischemia by temporary occlusion of the middle cerebral artery followed by reperfusion and their brains analyzed 0, 1, 2, 4, 7 and 14days post-ischemia. ⋯ In the penumbra, Ang1 expression was induced, peaking at the same time point as α5β1 expression. Consistent with these findings, oxygen glucose deprivation/reperfusion induced expression of α5β1 and Ang1 on brain endothelial cell (BEC) in a similar manner in vitro, which correlated closely with BEC proliferation and increased expression of TJPs. Our results demonstrate that in the post-ischemic penumbra, a tight temporal correlation exists between the angiogenic markers α5β1 and Ang1 and the TJPs, suggesting a potential role for Ang1 and α5β1 in promoting BBB integrity following ischemic stroke.
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Visceral pain in inflammatory and functional gastrointestinal conditions is a major clinical problem. The exact mechanisms underlying the development of pain, during and after visceral inflammation are unknown. However, clinical and pre-clinical evidence suggests plasticity within the spinal cord dorsal horn is a contributing factor. ⋯ Conversely, several measures of intrinsic excitability were altered in a manner that would decrease SDH network excitability following colitis. We propose that during inflammation, sensitization of colonic afferents results in increased signaling to the SDH. This is accompanied by plasticity in SDH neurons whereby their intrinsic properties are changed to compensate for altered afferent activity.
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Sestrin 2 (SESN2) is a stress-inducible protein that protects tissues from oxidative stress and delays the aging process. However, its role in maintaining the functional and structural integrity of the cochlea is largely unknown. Here, we report the expression of SESN2 protein in the sensory epithelium, particularly in hair cells. ⋯ Hair cell death occurred by caspase-8 mediated apoptosis. Compared to C57BL/6J control mice, Sesn2 KO mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages, suggesting that loss of SESN2 function provokes the immune response. Together, these results suggest that Sesn2 plays an important role in cochlear homeostasis and immune responses to stress.