Background:Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective:To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods:Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro. Olfaction was assessed through the habituation/dishabituation test. Results:Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro. Conclusion:Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.

中文翻译：

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与嗅觉功能障碍相关的体内淀粉样蛋白β给药后梨状和延髓活性/兴奋性/偶联的改变

背景：气味检测和辨别方面的缺陷是阿尔茨海默病 (AD) 的过早症状，与嗅球 (OB) 和梨状皮层 (PCx) 的病理体征相关。类似的嗅觉功能障碍已经在过度产生淀粉样蛋白-β (Aβ) 的 AD 转基因小鼠中表征，这可以通过免疫学和药理学方法降低 Aβ 水平来预防，这表明嗅觉功能障碍取决于 Aβ 积累和 Aβ 驱动的 OB 和/ 或 PCx，以及它们的激活。不过，这种可能性之前并没有直接测试过。目的：表征 Aβ 对 OB 和 PCx 兴奋性/偶联和嗅觉的影响。方法：Aβ低聚溶液（含低聚物、单体、和原纤维）或其载体在 OB 和 PCx 兴奋性和同步性前两周通过脑室内和脑切片的现场记录进行评估。从 OB 到 PCx 的突触传递也在体外进行了评估。通过习惯/去习惯测试评估嗅觉。结果：Aβ 不影响外侧嗅觉传导到 PCx，但减少气味习惯和交叉习惯。这种嗅觉功能障碍与体内 PCx 和 OB 网络活动能力的降低有关。此外，Aβ 也降低了 PCx-OB 活动之间的一致性。最后，Aβ 治疗加剧了体外 PCx 中 4-氨基吡啶诱导的兴奋。结论：我们的结果表明，Aβ 诱导的嗅觉功能障碍涉及嗅觉通路不同水平的一组复杂的病理变化，包括 PCx 兴奋性的改变及其与 OB 的耦合。这些病理变化可能导致 AD 中的嗅觉减退。