Neuroscience
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Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) have been implicated in the trafficking of postsynaptic glutamate receptors, including N-methyl-d-aspartate (NMDA)-subtype glutamate receptors (NMDARs) that are critical for nociceptive plasticity and behavioral sensitization. However, the components of SNAREs complex involved in spinal nociceptive processing remain largely unknown. Here we found that SNAP25, syntaxin4, VAMP2 and Munc18-1 were localized at postsynaptic sites and formed the complex in the superficial lamina of spinal cord dorsal horn of rats. ⋯ Disruption of the molecular interaction between SNAP25 with its SNARE partners by using a blocking peptide derived from the C-terminus of SNAP25 effectively repressed the surface and synaptic accumulation of GluN2B-containing NMDARs in CFA-injected rats. This peptide also alleviated inflammatory mechanical allodynia and thermal hypersensitivity. These data suggested that SNAREs complex assembly in spinal cord dorsal horn was involved in the inflammatory pain hypersensitivity through promoting NMDAR synaptic trafficking.
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Repetitive transcranial magnetic stimulation (rTMS) treatment is widely accepted as an evidence-based treatment option for depression and anxiety. However, the underlying mechanism of this treatment maneuver has not been clearly understood. The chronic unpredictable mild stress (CUMS) procedure was used to establish depression and anxiety-like behavior in rats. ⋯ Following Nrf2 silencing, the antidepressant and anxiolytic-like effect produced by rTMS was abolished. Moreover, the elevated Nrf2 nuclear translocation, and the reduced production of TNF-α, iNOS, IL-1β, and IL-6 in hippocampus mediated by rTMS, were reversed by Nrf2 knockdown. Together, these results reveal that the Nrf2-induced anti-inflammation effect is crucial in regulating antidepressant-related behaviors produced by rTMS.
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Ethanol is one of the most widely used drugs - with many psychoactive effects, including anxiolysis. The deleterious effects on brain function and general health of chronic and high-level ethanol use are well-studied. However, the neurophysiology of acute low dose ethanol has not been systematically investigated. ⋯ We conclude low dose ethanol has weak but detectable effects on neocortical and hippocampal theta oscillations. These effects may underlie positive cognitive and behavioural outcomes reported in the literature using low dose ethanol. The double dissociation of slope and y-intercept specific changes relating to different methods of hippocampal theta elicitation presents the potential to probe multiple mechanisms contributing to anxiolytic effects on theta and so hippocampal function.
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Recent work has suggested that 5α-reduced metabolites of testosterone may contribute to the neuroprotection conferred by their parent androgen, as well as to sex differences in the incidence and progression of Alzheimer's disease (AD). This study investigated the effects of inhibiting 5α-reductase on object recognition memory (ORM), hippocampal dendritic morphology and proteins involved in AD pathology, in male 3xTg-AD mice. Male 6-month old wild-type or 3xTg-AD mice received daily injections of finasteride (50 mg/kg i.p.) or vehicle (18% β-cyclodextrin, 1% v/b.w.) for 20 days. ⋯ Hippocampal amyloid β levels were substantially higher in 3xTg-AD females compared to both vehicle and finasteride-treated 3xTg-AD males. Site-specific Tau phosphorylation was higher in 3xTg-AD mice compared to sex-matched wild-type controls, increasing slightly after finasteride treatment. These results suggest that 5α-reduced neurosteroids may play a role in testosterone-mediated neuroprotection and may contribute to sex differences in the development and severity of AD.
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Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. ⋯ Finally, Pam3Csk4 and zymosan increased the [Ca2+]i in DRG neurons from wild-type mice. However, the enhancement of [Ca2+]i was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.