Brain-Body Institute, St. Joseph's Healthcare, Hamilton, ON, Canada.
Department of Biology, McMaster University, Hamilton, ON, Canada.
Sci Rep. 2021 Oct 26;11(1):21130. doi: 10.1038/s41598-021-00615-w.
The vagus nerve relays mood-altering signals originating in the gut lumen to the brain. In mice, an intact vagus is required to mediate the behavioural effects of both intraluminally applied selective serotonin reuptake inhibitors and a strain of Lactobacillus with antidepressant-like activity. Similarly, the prodepressant effect of lipopolysaccharide is vagus nerve dependent. Single vagal fibres are broadly tuned to respond by excitation to both anti- and prodepressant agents, but it remains unclear how neural responses encode behaviour-specific information. Here we demonstrate using ex vivo experiments that for single vagal fibres within the mesenteric neurovascular bundle supplying the mouse small intestine, a unique neural firing pattern code is common to both chemical and bacterial vagus-dependent antidepressant luminal stimuli. This code is qualitatively and statistically discernible from that evoked by lipopolysaccharide, a non-vagus-dependent antidepressant or control non-antidepressant Lactobacillus strain and are not affected by sex status. We found that all vagus dependent antidepressants evoked a decrease in mean spike interval, increase in spike burst duration, decrease in gap duration between bursts and increase in intra-burst spike intervals. Our results offer a novel neuronal electrical perspective as one explanation for mechanisms of action of gut-derived vagal dependent antidepressants. We expect that our ex vivo individual vagal fibre recording model will improve the design and operation of new, extant electroceutical vagal stimulation devices currently used to treat major depression. Furthermore, use of this vagal antidepressant code should provide a valuable screening tool for novel potential oral antidepressant candidates in preclinical animal models.
迷走神经将源自肠道腔的情绪改变信号传递到大脑。在小鼠中，需要完整的迷走神经来介导腔内应用选择性 5-羟色胺再摄取抑制剂和具有抗抑郁活性的乳杆菌菌株的行为效应。同样，脂多糖的促抑郁作用依赖于迷走神经。单一迷走神经纤维广泛调节为兴奋反应，对抗抑郁和促抑郁药物都有反应，但尚不清楚神经反应如何编码行为特异性信息。在这里，我们使用离体实验证明，对于供应小鼠小肠的肠系膜神经血管束中的单个迷走神经纤维，化学和细菌依赖迷走神经的抗抑郁管腔刺激的共同特征是独特的神经发射模式。这种编码在质量和统计学上可与脂多糖、非迷走神经依赖的抗抑郁或对照非抗抑郁乳杆菌菌株以及不受性别状态影响的编码区分开来。我们发现，所有依赖迷走神经的抗抑郁药都引起平均尖峰间隔减少、尖峰爆发持续时间增加、爆发之间的间隙持续时间减少以及爆发内尖峰间隔增加。我们的结果提供了一种新的神经元电观点，作为肠道来源的迷走神经依赖抗抑郁药作用机制的一种解释。我们预计，我们的离体单个迷走神经纤维记录模型将改进目前用于治疗重度抑郁症的新型、现有的电刺激迷走神经刺激设备的设计和操作。此外，这种迷走神经抗抑郁编码的使用应该为新型潜在的口服抗抑郁候选药物在临床前动物模型中提供有价值的筛选工具。
