Neuroscience
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A significant number of women suffer from depression during pregnancy and the postpartum period. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat maternal depression. While maternal stress and depression have long-term effects on the physical and behavioural development of offspring, numerous studies also point to a significant action of developmental exposure to SSRIs. ⋯ Primary results show that developmental fluoxetine exposure, regardless of prenatal stress, decreases circulating levels of corticosterone and reduces the expression of the glucocorticoid receptor (GR), and its coactivator the GR interacting protein (GRIP1), in the hippocampus. Interestingly, these effects occurred primarily in male, and not in female, adolescent offspring. Together, these results highlight a marked sex difference in the long-term effect of developmental exposure to SSRI medications that may differentially alter the capacity of the hippocampus to respond to stress.
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Hepatic encephalopathy (HE) is a potentially fatal complication of acute liver failure, associated with severe neurological dysfunction and coma. The brain's innate immune cells, microglia, have recently been implicated in the pathophysiology of HE. To date, however, only ex vivo studies have been used to characterize microglial involvement. ⋯ Conversely, both microglial activation and motility are unchanged during AHE, despite the mice developing pathologically increased plasma ammonia and severe neurological dysfunction. Our study indicates that microglial activation does not contribute to the early neurological deterioration observed in either HE or AHE. The late microglial activation in HE may therefore be associated with terminal BBB opening and brain edema, thus exacerbating the progression to coma and increasing mortality.
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Recent study from our laboratory has indicated that microinjection of glutamate into the nucleus tractus solitarius (NTS) facilitates the cardiac-somatic reflex induced by pericardial capsaicin. Further, N-methyl-d-aspartate (NMDA) receptors and metabotropic glutamate receptors (mGluRs) mediate this function. However, the roles of the individual receptor subtypes or subunits in modulating cardiac nociception are unknown. ⋯ In contrast, intra-NTS microinjection of a selective mGluR8 agonist, (S)-3, 4-dicarboxyphenylglycine (DCPG, at 6 and 8 nmol), significantly increased the EMG response above control levels. This effect was eliminated by intra-NTS MSOP and by vagal deafferentation. These data suggest that group III mGluRs and mGluR7 in the NTS display an inhibitory effect, while mGluR8 displays a facilitatory effect in modulating cardiac nociception, and this facilitatory effect is dependent on vagal afferents.
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Acute treatment of stroke with histone deacetylase (HDAC) inhibitors has been shown to reduce ischemic cell damage; however, it is unclear whether delayed treatment with HDAC inhibitors will contribute to the brain repair and plasticity. In the present study, we investigated the effects of delayed treatment of stroke with a pan HDAC inhibitor, valproic acid (VPA), on white matter injury and neurogenesis during stroke recovery. ⋯ VPA treatment also increased the expression of glutamate transporter 1 (GLT1) in the ischemic boundary after stroke, and increased acetylated histone H4 expression in neuroblasts and the number of new neurons in striatal ischemic boundary region. This study provides new evidence that the delayed VPA treatment enhances white matter repair and neurogenesis in ischemic brain, which may contribute to improved functional outcome.
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Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood-brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and -9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). ⋯ We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP-2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons during acute stroke injury.