Neuroscience
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N-Acetyl cysteine, a glutathione precursor, has been shown to benefit patients with Alzheimer's disease and reduce the symptoms of traumatic brain injury in soldiers. Parkinson's and Alzheimer's disease are both characterized by stress from protein misfolding, or proteotoxicity. We have developed a high-throughput model of proteotoxicity by treating neuroblastoma N2a cells with the proteasome inhibitor MG132 and performing three independent assays for viability. ⋯ Consistent with the chaperone functions of Hsp70, VER 155008 also prevented the reduction in ubiquitin-conjugated proteins by N-acetyl cysteine. These data reveal a new role for N-acetyl cysteine: this compound may reduce misfolded protein levels and ameliorate proteotoxicity through heat shock proteins. These findings broaden the potential mechanisms of action for this dietary supplement in neurodegenerative proteinopathies.
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Brain-derived neurotrophic factor (BDNF) is critically involved in synaptic plasticity and neurotransmission. Our lab has previously found that BDNF activation of neurotrophic tyrosine kinase, receptor, type 2 (TrkB) is required for fear memory formation and that GABAA receptor (GABAAR) subunits and the GABAA clustering protein gephyrin are dynamically regulated during fear memory consolidation. We hypothesize that TrkB-dependent internalization of GABAARs may partially underlie a transient period of amygdala hyperactivation during fear memory consolidation. ⋯ Our data with anisomycin suggest that BDNF may rapidly induce gephyrin protein degradation, with subsequent gephyrin synthesis occurring. Together, these findings suggest that gephyrin may be a key factor in BDNF-dependent GABAAR regulation in the amygdala. This work may inform future studies aimed at elucidating the pathways connecting BDNF, GABAA systems, gephyrin, and their role in underlying amygdala-dependent learning.
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Cholinergic interneurons, which provide the main source of acetylcholine (ACh) in the striatum, control the striatal local circuits and deeply involve in the pathogenesis of neurodegenerative diseases. Glycogen synthase kinase-3 (GSK-3) is a crucial kinase with diverse fundamental functions and accepted that deregulation of GSK-3 activity also plays important roles in diverse neurodegenerative diseases. However, up to now, there is no direct proof indicating whether GSK-3 activation is responsible for cholinergic dysfunction. ⋯ Furthermore, we proved that cellular ChAT distribution was dependent on low phosphorylation level of NFs. Nevertheless, the cholinergic dysfunction in the striatum failed to induce significant neuronal number reduction. In summary, our data demonstrates the link between GSK-3 activation and cholinergic dysfunction in the striatum and provided beneficial evidence for the pathogenesis study of relevant neurodegenerative diseases.
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In rodents, olfactory bulbectomy (OBX) results in several behavioral and biochemical changes, useful as a screening model for antidepressants. Recent evidences suggest that quercetin; a bioflavonoid exhibits a variety of behavioral effects including anxiolytic, antidepressant, etc. Since microglia are commonly implicated in the neuroinflammation cascade of depression, we hypothesized that quercetin might involve microglial inhibition pathway in its antidepressant-like effects. ⋯ After a surgical recovery period of 2weeks, treatment with quercetin (40, 80mg/kg; per oral (p.o.) p.o., 14days) significantly prevented OBX-induced behavioral, biochemical, molecular and histopathological alterations. Further, combination of sub effective doses of quercetin (20, 40mg/kg; p.o.) with minocycline (25mg/kg; p.o.) significantly potentiated their protective effects as compared to their effects alone. Based on our results, we propose that microglial inhibitory pathway might be involved in the neuroprotective effects of quercetin and suppression of oxidative-nitrosative stress mediated neuroinflammation-apoptotic cascade associated with OBX rat model of depression.
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Brain machine interfaces (BMI) have become important in systems neuroscience with the goal to restore motor function in paralyzed patients. We assess the current ability of BMI devices to move objects. The topics discussed include: (1) the bits of information generated by a BMI signal, (2) the limitations of including more neurons for generating a BMI signal, (3) the superiority of a BMI signal using single cells versus electroencephalography, (4) plasticity and BMI, (5) the selection of a neural code for generating BMI, (6) the suppression of body movements during BMI, and (7) the role of vision in BMI. We conclude that further research on understanding how the brain generates movement is necessary before BMI can become a reasonable option for paralyzed patients.