Neuroscience
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MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores connected by a 22-atom linker. Intrathecal (i.t.) administration of MMG22 to inflamed mice has been reported to produce fmol-range antinociception in the reversal of LPS-induced hyperalgesia. MMG22 reduced hyperalgesia in the spared nerve injury (SNI) model of neuropathic pain at 10 days after injury but not at 30 days after injury, perhaps related to the inflammation that occurs early after injury but subsequently subsides. ⋯ We propose that MMG22 induces the formation of a MOR-mGluR5 heteromer through selective interaction with the upregulated NR2B subunit of activated NMDAR, in view of the 4600-fold reduction of i.t. MMG22 antinociception by the selective NR2B antagonist, Ro25-6981. A possible explanation for the substantially reduced potency for MMG22 in the SNI model is discussed.
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Walking is an important function which requires coordinated activity of sensory-motor neural networks. Noninvasive brain stimulation (NIBS) is a safe neuromodulatory technique with motor function-improving effects. This study aimed to determine the effect of different types of NIBS interventions explored in randomized controlled trials on gait in healthy young and older adults. ⋯ NIBS is a promising approach to improve gait in healthy young and older adults. Anodal tDCS over the motor areas and DLPFC, and tACS over the cerebellum have shown positive effects on gait.
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Previous work in the suprachiasmatic nucleus (SCN), the locus of the principal circadian clock, has shown that the activation state of the ERK/MAPK effector p90 ribosomal S6 kinase (RSK) is responsive to photic stimulation and is modulated across the circadian cycle. These data raise the prospect that RSK signaling contributes to both SCN clock timing and entrainment. Here, we found marked expression of the three main RSK isoforms (RSK1/2/3) within the SCN of C57/Bl6 mice. ⋯ To test the potential contribution of RSK signaling to SCN pacemaker activity, slice cultures from a per1-Venus circadian reporter mouse line were chronically treated with SL0101. Suppression of RSK signaling led to a significant lengthening of the circadian period (∼40 min), relative to vehicle-treated slices. Together, these data reveal that RSK functions as a signaling intermediate that regulates light-evoked clock entrainment and the inherent time keeping properties of the SCN.
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Years before Alzheimer's disease (AD) is diagnosed, patients experience an impaired sense of smell, and β-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause β-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of β-amyloid that occurs in human AD, we investigated the progressive accumulation of β-amyloid across the brain using a conditional mouse model that overexpresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. ⋯ We also observe reduced OB volumes in these mice when hAPP expression begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore conclude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of β-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of β-amyloid-related AD progression.
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Chemotherapy-induced peripheral neuropathy is one of the most common side effects of anticancer therapy. It is anticipated that chemotherapies with different mechanisms of action may affect somatosensory neurons differently. This study aimed to explore similar and differential etiologies of oxaliplatin- and paclitaxel-induced neuropathy by comparing the transcriptomes of dorsal root ganglia (DRGs). ⋯ However, 28 out of 29 terms were oppositely modulated. This study suggests that distinct mechanisms underly paclitaxel- and oxaliplatin-induced neuropathy. Paclitaxel might directly affect somatosensory neurons while oxaliplatin primarily targets dividing cells and immune cells.