Neuroscience
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Transient hypofunction of NMDA receptors during brain maturation has been linked to cellular and behavioral alterations that mirror symptoms of schizophrenia. In line with this notion, neonatal administration of the non-competitive NMDA receptor antagonist, MK-801, mimics the negative and cognitive symptoms of schizophrenia. ⋯ As expected, behavioral impairments were consistently observed during the young adult stage (postnatal day 90), a period in which a steady deterioration of long-term depression and long-term potentiation was observed. Taken together, these results suggest that synaptic dysregulation precedes behavioral deterioration in a model that mimics the negative and cognitive symptoms of schizophrenia.
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Several studies have demonstrated the antitumor effect of doxazosin, an α1-adrenergic blocker, against glioma and breast, bladder and prostate cancers. Doxazosin is also being evaluated as a treatment for posttraumatic stress disorder (PTSD) and alcoholism, and α1-adrenergic blockers have been linked to neuroprotection in neurodegenerative disorders, such as Alzheimer's Disease (AD). Cancer and AD have an inverse relationship in many aspects, with several factors that contribute to apoptosis inhibition and proliferation being increased in cancers but decreased in AD. ⋯ On differentiated cells, doxazosin was less cytotoxic and increased p-EGFRTyr1048, p-AktSer473 and p-GSK-3βSer9 levels. Moreover, the drug was able to protect hippocampal slices from amyloid-β toxicity through prevention of GSK-3β activation and of Tau hyperphosphorylation. Therefore, our results show that doxazosin has antitumor activity against undifferentiated NB and is neuroprotective on an in vitro model of Alzheimer's disease.
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A common feature across neuropsychiatric disorders is inability to discontinue an action or thought once it has become detrimental. Reversal learning, a hallmark of executive control, requires plasticity within cortical, striatal and limbic circuits and is highly sensitive to disruption of N-methyl-D-aspartate receptor (NMDAR) function. In particular, selective deletion or antagonism of GluN2B containing NMDARs in cortical regions including the orbitofrontal cortex (OFC), promotes maladaptive perseveration. ⋯ Reversal impairment produced by corticohippocampal GluN2B deletion was paralleled by an aberrant increase in functional connectivity between the OFC and dS. These alterations in coordination were associated with alterations in local OFC and dS firing activity. These data demonstrate highly dynamic patterns of cortical and striatal activity concomitant with reversal learning, and reveal GluN2B as a molecular mechanism underpinning the timing of these processes.
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Age-related somatosensory processing appears to remain intact where tasks engage centrally- as opposed to peripherally-mediated mechanisms. This distinction suggests that insight into alterations in neural plasticity could be derived via metrics of vibrotactile performance. Such an approach could be used to support the early detection of global changes in brain health but current evidence is limited. ⋯ We also report, for the first time, that older adults displayed similar performance improvements to young adults, under conditions of dual-site adaptation (p = .948, d = 0.016). The findings support the argument that centrally-mediated mechanisms remain intact in the ageing population. Accordingly, dual-site adaptation data provide compelling new evidence of somatosensation in ageing that will contribute towards the development of an assessment tool to ascertain pre-clinical, age-related changes in the status of cortical function.
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Brachial plexus root avulsion (BPRA) results in the complete loss of motor function in the upper limb, mainly due to the death of spinal motoneurons (MNs). The survival of spinal MNs is the key to the recovery of motor function. Neuregulin-1 (Nrg1) plays fundamental roles in nervous system development and nerve repair. ⋯ In vitro studies on primary cultured mouse MNs showed that rNrg1β increased the survival rate in a dose-dependent manner, reaching a peak at 5 nM, which increased the survival rate and enhanced the pERK levels in MNs under H2O2-induced oxidative stress. In vivo studies revealed that rNrg1β improved the functional recovery of elbow flexion, promoted the survival of MNs, enhanced the re-innervation of biceps brachii, and decreased the muscle atrophy. These results suggest that Nrg1 may provide a potential therapeutic strategy for root avulsion.