Neuroscience
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Adolescent binge drinking renders young drinkers vulnerable to alcohol use disorders in adulthood; therefore, understanding alcohol-induced brain damage and associated cognitive dysfunctions is of paramount importance. Here we investigated the effects of binge-like adolescent intermittent ethanol (AIE) exposure on nonspatial working memory, behavioral flexibility and cholinergic alterations in the nucleus accumbens (NAc) in male and female rats. On postnatal days P25-57 rats were intubated with water or ethanol (at a dose of 5 g/kg) on a 2-day-on/2-day-off cycle and were then tested in adulthood on social recognition and probabilistic reversal learning tasks. ⋯ During probabilistic reversal learning, AIE-treated male and female rats showed behavioral inflexibility as indicated by a higher number of trials needed to complete three reversals within a session, longer response latencies for lever selection, and for males, a higher number of errors as compared to water-treated rats. AIE exposure also reduced the number of cholinergic interneurons in the NAc in males and females. These findings indicate AIE-related pathologies of accumbal cholinergic interneurons and long lasting cognitive-behavioral deficits, which may be associated with cortico-striatal hypofunction.
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The subfornical organ (SFO) is forebrain sensory circumventricular organ, characterized by lack of a blood-brain barrier. Neurons of the SFO can detect circulating molecules such as peptide hormones and communicate this information to regulatory centers behind the blood-brain barrier, thus playing a critical role in homeostatic processes including regulation of energy balance, hydromineral balance and cardiovascular control. The SFO contains two subregions defined by neuronal expression of molecular markers: the dorsolateral peripheral or shell SFO (sSFO) neurons express calretinin, and the ventromedial core (cSFO) neurons express calbindin D28K. ⋯ This study used a gold nanoparticle-conjugated RNA fluorescent probe on dissociated SFO neuron cultures and patch clamp electrophysiology to characterize the intrinsic electrophysiological properties of cSFO and sSFO neurons. Our studies revealed that neurons originating from the core region exhibited significantly more action potential bursting, while neurons from non-core regions exhibited more tonic firing neurons, albeit at a higher overall frequency. The difference in activity is correlated with a more depolarized resting membrane potential and a higher density of voltage gated Na+ currents.
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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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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.