Neuroscience
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Mitogen-activated protein kinases are signal transduction mediators that have been implicated in cell survival and cell death. This study characterized the activation of pathways in the hippocampus during reperfusion after global cerebral ischemia, as well as the influence of a regimen of hypothermia that reduces ischemic cell death in the hippocampus. Circulatory arrest was induced in rats by 8 min of asphyxia. ⋯ In contrast, active stress-activated protein kinase/c-Jun N-terminal kinase immunoreactivity was most intense in the CA3 and dentate gyrus regions. These data demonstrate that both extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun N-terminal kinase pathways are activated during the first 24h of reperfusion after global cerebral ischemia, and that hypothermia increases the activation of extracellular signal-regulated kinase relative to stress-activated protein kinase/c-Jun N-terminal kinase. Thus, an increase in extracellular signal-regulated kinase activation may be associated with improved neuronal survival after ischemic injury.
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Activation of primary afferent C fibers gives rise to spinal release of substance P and glutamate, and these mediators facilitate the cascade of nociceptive processing. We recently showed that intrathecal administration of nociceptin or orphanin FQ (hereafter called nociceptin) induced hyperalgesia to noxious thermal stimuli and allodynia to innocuous tactile stimuli applied to conscious mice. In the present study, we designed experiments to elucidate the pathways and mediators of nociceptin-evoked pain responses. ⋯ In contrast, the nociceptin-evoked allodynia, but not hyperalgesia, disappeared in N-methyl-D-aspartate receptor GluRvarepsilon1 subunit knockout mice. Both nociceptin-evoked hyperalgesia and allodynia were attenuated by morphine in a dose-dependent manner. Taken together, these results demonstrate that capsaicin-sensitive primary afferent fibers are involved not only in thermal hyperalgesia but also in tactile allodynia induced by nociceptin, but in different pathways; the former is mediated by substance P and the latter is mediated by glutamate through the N-methyl-D-aspartate receptor comprising the GluRvarepsilon1 subunit.
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Age-related changes in learning and memory are common in rodents. However, direct comparisons of the effects of aging on learning and memory in both males and females are lacking. The present study examined whether memory deteriorates with increasing age in C57BL/6NIA mice, and whether age-related changes in learning and memory are similar in both sexes. ⋯ Estrous cycling in females deteriorated significantly with increased age; all 25-month-old females had ceased cycling and 80% of 17-month-old females displayed either irregular or absent estrous cycling. This study is the first to directly compare age-related mnemonic decline in male and female mice. The results suggest that: (i) aged mice exhibit significant deficits in spatial and olfactory reference memory relative to young mice, whereas middle-aged mice exhibit only a moderate spatial memory deficit and; (ii) spatial reference memory decline begins at an earlier age in females than in males, a finding that may be related to the cessation of estrous cycling.
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The interpretation of task-induced functional imaging of the brain is critically dependent on understanding the relationship between observed blood flow responses and the underlying neuronal changes. However, the exact nature of this neurovascular coupling relationship remains unknown. In particular, it is unclear whether blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) responses principally reflect neuronal synaptic activity. ⋯ We found that mean N20-P22 amplitudes increased significantly with stimulus intensity in all subjects, as did fMRI BOLD percentage signal intensity change. Moreover, the intensity of the BOLD signal was found to correlate linearly with evoked potential amplitude in four of the five subjects studied. This suggests that the BOLD response correlates with synchronized synaptic activity, which is the major energy consuming process of the cortex.
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Organotypic cultures and ileal neuromuscular preparations were used to determine (i) whether endogenous release of opioids by electrical stimulation induces mu receptor endocytosis, and (ii) whether and under which conditions ligand-induced mu receptor endocytosis influences the responsiveness of neurons expressing native mu receptors. In longitudinal muscle-myenteric plexus preparations, electrical stimulation at 20 Hz induced a prominent endocytosis of mu receptors in enteric neurons, indicating endogenous release of opioids. ⋯ In contrast, there was no reduction of the inhibitory effect of morphine, which failed to induce mu receptor endocytosis, on neurogenic cholinergic response. These results provide the first evidence for the occurrence of mu receptor endocytosis in neurons by endogenously released opioids and show that agonist-dependent mu receptor endocytosis could serve as a mechanism to regulate mu opioid receptor responsiveness to ligand stimulation when the opioid receptor reserve is reduced.