Neuroscience
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Cognitive dysfunction on chronic exposure to hypobaric hypoxia has been attributed to a myriad of survival and degenerative factors. Downregulation of Trkβ and compromised survival signaling has been ascribed as a major contributing factor for hypoxic neurodegeneration. The mechanisms leading to downregulation of Trkβ in hypoxia, however, remain to be elucidated. ⋯ Selective inhibition of signaling intermediate MLK2 by CEP11004 and inhibition of extra-synaptic NMDAR during hypoxic stress prevented Trkβ downregulation in the hippocampus of hypoxic rats. Administration of Kaempferol also inhibited phosphorylation of E47 and hypoxia-induced downregulation of Trkβ. The present study establishes the role of extra-synaptic NMDAR in hypoxia-induced downregulation of Trkβ and the efficacy of Kaempferol in inhibiting extra-synaptic NMDAR-mediated signaling.
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It is generally believed that oxidative stress and neuroinflammation are implicated in the pathogenesis of Parkinson's disease (PD). Reduced nicotinamide adenine dinucleotide phosphate (NADPH) has been demonstrated to have potent neuroprotective effects against oxidative stress. In the present research, we investigated if NADPH could offer neuroprotection by inhibiting glia-mediated neuroinflammation induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mechanism contributing to PD pathogenesis. ⋯ These effects were diminished by TNF-α neutralizing antibody and NADPH. NADPH reduced motor dysfunction and the loss of dopaminergic (DA) cells induced by MPTP. Therefore, the present study demonstrates that NADPH protects DA neurons by inhibiting oxidative stress and glia-mediated neuroinflammation both in vitro and in vivo, thus suggesting a potential of clinical application for PD and other neurodegenerative diseases.
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Tinnitus alters auditory-somatosensory plasticity in the cochlear nucleus (CN). Correspondingly, bimodal auditory-somatosensory stimulation treatment attenuates tinnitus, both in animals and humans (Marks et al., 2018). Therefore, we hypothesized that tinnitus is associated with altered somatosensory innervation of the CN. ⋯ Tinnitus-associated ipsilateral upregulation of VGLUT2-positive projections likely derives from somatosensory projections to the GCD and AVCN. This upregulation may underlie the neurophysiological hallmarks of tinnitus in the CN. Reversing the increased ipsilateral glutamatergic innervation in the CN is likely a key mechanism in treating tinnitus.
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Motor function can be modulated by transcranial alternating current stimulation (tACS) in alpha, beta, and high-gamma frequencies. However, few studies have investigated tACS-induced behavioral changes in combination with endogenous oscillatory neural activity in detail. Herein, we investigated the effect of tACS on motor learning capacity and endogenous oscillatory neural activity. ⋯ Oscillation analysis revealed a significant increase in beta-band power after 70-Hz tACS but not in the other stimulation groups. Our finding that capacity for motor learning and endogenous oscillatory beta activity were modulated in parallel after 70-Hz tACS suggests that 70-Hz tACS may increase the motor learning capacity by cross-modulating beta oscillatory activity. Because high gamma and beta oscillatory activity have been shown to reflect the activity of excitatory and inhibitory interneuron, our results may derive from the modulation of excitatory and inhibitory interneurons in M1 by 70-Hz tACS.
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Hepatic ischemia reperfusion (HIR) has been found to induce hippocampus injury and cognitive dysfunction. The N-methyl-d-aspartate (NMDA) receptor subunit 2A (NR2A) is an important factor mediating excitotoxicity and neurons injury, and autophosphorylation of Src can up-regulate tyrosine phosphorylation of NR2A to improve its activity. However, the role of Src and NR2A in HIR-induced hippocampus injury in young mice remains unknown. ⋯ Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-6 were increased after reperfusion of 3 days, while PP2 and NVP-AAM077 treatment didn't attenuate the changes. And no difference was found in serum TNF-α, IFN-γ, IL-6 concentrations as well as the levels of Src, p-Src, NR2A, p-NR2A, PSD95 among the four groups after reperfusion of 1 month. In summary, HIR can lead to hippocampus injury and long-term cognitive dysfunction, and Src-PSD95-NR2A pathway plays an important role in the process.