Neuroscience
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Abnormal buildup of the microtubule associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) and various tauopathies. The mechanisms by which pathological tau accumulates and spreads throughout the brain remain largely unknown. Previously, we demonstrated that a restoration of the major astrocytic glutamate transporter, GLT1, ameliorated a buildup of tau pathology and rescued cognition in a mouse model of AD. ⋯ To mimic glutamate-induced aberrant excitatory input in neurons, repeated depolarization of neurons via transgenic TrpA1 was applied to the adult Drosophila optic nerves, and we examined the change of tau deposits. Repeated depolarization significantly increased the accumulation of tau in these neurons. We propose that increased neuronal excitatory activity exacerbates tau-mediated neuronal toxicity and behavioral deficits.
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Acid-sensing ion channels (ASICs) are associated with many pathophysiological processes, such as neuronal death during ischemic stroke, epileptic seizure and nociception. However, there is a dearth of ASIC-specific therapeutic blockers. Here we report that quercetin, a plant flavonoid, which is known for its neuroprotective effect, reversibly inhibits homomeric rat ASIC1a, ASIC2a and ASIC3 with an IC50 of about 2µM. ⋯ Computational analysis revealed that quercetin binds to the channel in a cavity at the central vestibule, lined by several charged residues like Q276, R369, E373 and E416 in ASIC1a. Mutation of Arg369 to Ala or Glu416 to Gln abolished the inhibitory effect of quercetin on rat ASIC1a completely, while Glu373 to Gln showed reduced sensitivity. Our results raise the possibility of using quercetin for targeting ASICs in vivo.
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Spinal cord injury (SCI) is a devastating condition with few effective treatments. Resveratrol, a polyphenolic compound, has exhibited neuroprotective effects in many neurodegenerative diseases. However, the explicit effect and mechanism of resveratrol on SCI is still unclear. ⋯ Expression of SIRT1, p-AMPK, Beclin-1, LC3-B, and Bcl-2 was elevated in resveratrol-treated animals, whereas expression of p62, Cleaved Caspase-3, Caspase-9, and Bcl-2 associated X protein (Bax) was inhibited. Immunofluorescence analysis of primary neurons treated with resveratrol alone or in combination with Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) revealed that treatment with the inhibitors blocks the increased LC3-B expression in cells and increases the portion of TUNEL-positive cells. Taken together, these results suggest that resveratrol exerts neuroprotective effects on SCI by regulating autophagy and apoptosis mediated by the SIRT1-AMPK signaling pathway.
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Preparation for postural instability engages cortical resources that serve to optimize compensatory balance responses. Engagement of these cortical resources in cognitive dual-task activities may impact the ability to appropriately prepare and optimize responses to instability. The purpose of this study was to determine whether cognitive dual-task activities influenced cortical activity preceding and following postural instability. ⋯ Performance of the cognitive task delayed and reduced the magnitude of the initial gastrocnemius response. The findings indicate that pre- and post-perturbation cortical activity is affected by a cognitive distractor when postural instability is temporally predictable. Distraction also influences associated muscle responses.
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Mild-to-severe traumatic brain injury (TBI) is frequently associated with prolonged dysfunction of reward circuitry, including motivation and salience, which suggests alterations of dopamine (DA) processing within the core and shell of the nucleus accumbens (NAC). Using fast-scan cyclic voltammetry in a rodent model of traumatic brain injury, we found that stimulus-evoked DA release is distinct in the core and shell of the NAC, with the shell being less responsive to tonic stimulation and more sensitive to the number of pulses when phasic stimulation is applied. ⋯ Taken together, these data support behavior and anatomical studies suggesting the NAC core and striatum may subserve parallel functions, whereas the shell is distinct. These data offer a unique window on how different neurological systems respond to TBI and may help explain affective and cognitive changes that are seen.