Neuroscience
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Neonatal handling, an experimental model of early life experiences, is known to affect hypothalamic-pituitary-adrenal (HPA) axis function, thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. AMPA receptors (AMPARs) mediate fast synaptic transmission at excitatory glutamatergic synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPARs are composed of four types of subunits, designated as AMPA glutamate receptor subunits (GluA1, GluA2, GluA3 and GluA4), which combine to form tetramers. ⋯ Furthermore, we observed that neonatal handling induced in both sexes decreases of GluA2 mRNA in the dorsal hippocampus, as well as in the somatosensory and occipital cortex, of GluA3 mRNA in most hippocampal areas, amygdaloid complex and cortical regions studied, and of GluA4 mRNA in the ventral hippocampus. These results show that glutamatergic transmission is markedly affected by an early experience. The neonatal handling-induced alterations in AMPAR subunit composition are in line with the increased brain plasticity, the more effective HPA axis function, and in general the more adaptive behavioral phenotype known to characterize the handled animals.
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Many types of injury such as seizure, ischemia, and oxidative stress cause upregulation of the p75 neurotrophin receptor (p75(NTR)) in brain neurons, where it promotes apoptosis, however the mechanism by which p75(NTR) is regulated under these conditions is not well understood. Proinflammatory cytokines such as interleukin-1β (IL-1β) are highly produced under these injury conditions and, in particular, are expressed rapidly in the rat hippocampus after seizure. IL-1β is known to increase neuronal vulnerability under many conditions, although it does not directly induce neuronal death. ⋯ Here, we show that IL-1β infusion into the brain induces p75(NTR) in neurons of the CA1 area of the hippocampus. While IL-1β induction of p75(NTR) is not sufficient to induce cell death, we demonstrate that IL-1β primes the neurons by recruiting p75(NTR) and its coreceptor sortilin to the cell surface, making the neurons more vulnerable to subsequent challenge by proNGF. These results suggest a mechanism by which IL-1β exacerbates neuronal death following injury.
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Our previous study has shown that aging and hypertension may alter apparent diffusion coefficient (ADC) and cerebral blood flow (CBF) and increase ischemic susceptibility in the non-ischemic rat brain. The present study wishes to further investigate whether aging and hypertension may influence cerebral diffusion/perfusion and increase ischemic susceptibility in the ischemic brain. Brain magnetic resonance (MR) imaging was examined 1day before and 1 and 7days after bilateral common carotid artery occlusion. ⋯ At day 1 post-operation, CBF reduced and ADC/CBF ratio elevated significantly in the parietal cortex of the rats with infarction when compared to the rats without infarction (CBF: ROC, P=0.002; BLR, P=0.017. ADC/CBF ratio: ROC, P=0.001; BLR, P=0.018). Our results demonstrated that pre-operation ADC and post-operation CBF and ADC/CBF ratio can be used as good MR markers in the prediction of ischemic susceptibility after cerebral hypoperfusion.
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Loss-of-function in the Parkin protein is thought to play a part in causing neuronal cell death in patients with Parkinson's disease. This study explores the effect of Parkin degradation, via the overexpression of nucleus accumbens 1 (NAC1), on cell viability. It was found that NAC1 and Parkin are co-localized within the cell and interact with one another, leading to a decrease in Parkin levels. ⋯ Interestingly, mutation in the POZ/BTB domain (Q23L) of NAC1 disrupts the co-localization and interaction of NAC1 with Parkin and it further abrogates the proteasome inhibition-induced toxicity. We further observed that co-transfection of the mutant form of NAC1 with Parkin reversed the proteasome activity and 20S proteasome protein levels. These results indicate a novel interaction between NAC1 and Parkin that leads to neuronal cell death, a main characteristic in Parkinson's disease.
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Progesterone is a known anticonvulsant, with its inhibitory effects generally attributed to its secondary metabolite, 5α,3α-tetrahydroprogesterone (THP), and THP's enhancement of GABAA receptor activity. Accumulating evidence, however, suggests that progesterone may have non-genomic actions independent of the GABAA receptor. In this study, we explored THP/GABAA-independent anticonvulsive actions of progesterone in a mouse model of hippocampal kindling and in mouse entorhinal slices in vitro. ⋯ Carbamazepine mimicked the effects of progesterone with finasteride pretreatments in decreasing cortical discharges and motor seizures, whereas midazolam produced effects similar to progesterone alone or THP in decreasing hippocampal ADs and motor seizures. In brain slices, progesterone at 1μM inhibited entorhinal epileptiform potentials in the presence of picrotoxin and finasteride. We suggest that progesterone may have THP/GABAA-dependent and independent anticonvulsive actions in the hippocampal-kindled mouse model.