Neuroscience
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Anxiety is considered an important protracted abstinence symptom that can aggravate craving and relapse risk in opioid addicts. Although the insular cortex (IC) has been reported to be a key brain region in mediating emotional and motivational alterations induced by drug consumption and withdrawal, the role of IC in anxiety related to protracted abstinence remains elusive. ⋯ Bilateral lesion of the medial IC, but not the anterior or posterior IC with ibotenic acid (IBO) alleviated the anxiety-like behavior. (3) Expression of Wnt7a in the medial IC was significantly increased after 28 days of withdrawal, and specific down-regulation of Wnt7a with AAV-shWnt7a also alleviated the anxiety-like behavior. The findings reveal the medial IC is involved in mediating anxiety-like behavior related to morphine protracted abstinence, in which Wnt7a plays a critical role.
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The perirhinal cortex (PRH) is considered a crucial cortical area for familiarity memory and electrophysiological studies have reported the presence of visual familiarity encoding neurons in PRH. However, recent evidence has questioned the existence of these neurons. ⋯ However, the PRH showed no response modulation with respect to familiarity under a variety of different conditions or retention delays. These results indicate that the PRH does not contribute to familiarity/novelty encoding using passively exposed visual stimuli.
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Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterized by progressive cognitive dysfunction. Aquaporin 9 (AQP9) is an aquaglyceroporin membrane channel shown biophysically to conduct water, glycerol, and other small solutes. In our study, we reported for the first time an age-associated decrease in AQP9 mRNA and protein expressions in both hippocampus and cerebral cortex of APPswe/PS1dE9 (Tg) AD mice at 3, 6 and 10 months of age. ⋯ Pre-treatment with AQP9 small interfering RNA led to a more severe neurotoxicity in PC12 cells in response to Aβ1-40. Furthermore, we corroborated that the active participation of AQP9 in AD progression is associated with Aβ-induced apoptosis both in vitro and in vivo. Taken together, our results reveal an important role of AQP9 in Aβ-induced pathogenesis of AD which deserves further investigation.
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Apolipoprotein E4 (apoE4), one of the three apoE isoforms, is the strongest factor for raising the risk for late-onset Alzheimer's disease (AD) and has been proposed to play a major role in AD pathogenesis. Amyloid-peptide β 42 (Aβ42) has also been proposed to affect neuronal degeneration and AD pathogenesis, possibly by interacting with apoE. Previous studies have shown that the functions of apoE forms can be dictated by their structural and biophysical properties. ⋯ Structural and thermodynamic analyses showed that all three apoE4 mutants have significantly increased α-helical and decreased β-sheet content, have reduced portion of hydrophobic surfaces exposed to the solvent and have a reduced conformational stability during chemical denaturation. Overall, our data highlight a pathogenic role of apoE4 that could be linked to the capacity of the protein to form oligomeric species especially in the presence of Aβ42 and to induce cytotoxicity. Carboxyl-terminal residues L279, K282 or Q284 appear to be involved in the conformation of apoE4 that may underlie the protein's functional properties related to neurotoxicity.
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Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). ⋯ Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.