专家点评Cell | 突破！曹鹏团队揭示大脑启动“恶心-呕吐”反应的神经机制

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关键词：揭示Cell神经

资讯来源：BioArt

发布时间： 2022-11-02

点评 | 段树民（中科院院士），罗敏敏（北京脑科学与类脑研究中心），王立铭（深圳湾实验室）、袭荣文（北京生命科学研究所）

根据世界卫生组织的统计，全世界每年约6亿人因摄入被病原污染的食物而发生食物中毒，导致约42万人死亡 【1】 。食物中毒后，大脑启动恶心（nausea）和呕吐（vomiting）等一系列防御反应。通过呕吐，人体将摄入的有毒食物排出消化道，避免病原进一步侵入身体。通过恶心这一厌恶性情绪，大脑可以对有毒食物的特征形成长期的记忆，从而避免以后再次摄入有毒食物。可见，“恶心-呕吐”反应是遭遇病原入侵后人体产生的一类自我保护的防御反应，对生存有着极为重要的意义。

恶心和呕吐也是癌症化疗的主要副作用，具有重要的临床意义 【2】 。化疗药物可以杀死快速分裂的肿瘤细胞，但对正常细胞也有很强的杀伤作用。摄入体内的化疗药物被机体识别为“毒素”，并启动恶心和呕吐的防御反应，帮助机体尽快排出这些“毒素”。因此，接受化疗的癌症患者不得不遭受极为痛苦的“恶心-呕吐”副作用，必须服用大剂量的止吐药才能勉强熬过化疗过程。由于“恶心-呕吐”反应的具体机制不明，临床上可以使用的止吐药屈指可数。只有深度解析机体产生“恶心-呕吐”反应的精细机制，才有可能研发出更有效的化疗止吐药。

“恶心-呕吐”反应还发生在日常生活中。例如，在长途客运中,一些晕车晕船的乘客也会因为长时间的颠簸而出现“恶心-呕吐”反应。处于孕期的“准妈妈们”会出现不同程度的“恶心-呕吐”反应。这些情况下，我们需要安全性很高的止吐药来抑制过度的“恶心-呕吐”反应。

遗憾的是,在过去三十多年里，“恶心-呕吐”反应的机制研究一直举步维艰，因为领域内缺乏合适的动物模型和研究范式。 实验室常用的啮齿类动物（如小鼠和大鼠）并不能表现出呕吐行为。啮齿类动物无法吐出胃内的食物，被认为可能是因为消化道平滑肌不够发达 【3】 。前人只能用狗和雪貂等有呕吐行为的动物开展研究。他们发现切断膈下迷走神经可以有效阻断呕吐反应，说明呕吐依赖于胃肠道与大脑之间的“肠-脑”轴（gut-to-brain axis）。应用这些动物，前人还通过损毁和电刺激手段鉴定了参与呕吐反应的一些脑区 【4】 。通过药理学方法，发现5-HT₃R和NK₁R的拮抗剂可以有效抑制呕吐反应 【5】 。但是，这些模式动物缺乏与之匹配的分子遗传学工具，无法用于系统阐明大脑感知病原入侵启动“恶心-呕吐”反应的分子细胞和神经环路机制。

要想阐明大脑启动“恶心-呕吐”反应的机制，除了要有合适的动物模型和研究范式外，还需要解开三个长期未解的谜团。第一，胃肠道遭受病原入侵后，究竟是哪类肠道细胞把这一重要的情报交给了迷走神经？第二，迷走神经中负责与肠道“情报员”对接的感觉神经元具有怎样的身份和特征？第三，当大脑接到迷走神经传来的病原入侵的情报后，如何快速同步地启动恶心和呕吐等一系列防御反应？

2022年11月1日，北京生命科学研究所的曹鹏实验室在CELL上在线发表了题为 The gut-to-brain axis for toxin-induced defensive responses 的研究论文 【6】 。该研究建立了以小鼠为动物模型研究“恶心-呕吐”反应的新范式，并解开了上面的三个谜团，初步揭示了大脑感知病原入侵启动“恶心-呕吐”反应的分子细胞和神经环路机制。

在这个研究课题中，曹鹏团队系统地开展了“恶心-呕吐”反应的神经生物学机制研究 （图-1） 。首先，他们应用金黄色葡萄球菌产生的肠毒素（Staphylococcal enterotoxin）建立了小鼠食物中毒的研究范式。他们惊奇地发现，摄入肠毒素的小鼠虽然不能呕吐（vomiting），但能表现出“大张嘴”的干呕行为（retching-like behavior）（视频-1）。摄入的肠毒素也能引起小鼠类似“恶心”的厌恶性情绪，从而形成对含有肠毒素的饮料的条件性味觉回避（conditioned flavor avoidance）。因此，小鼠的条件性味觉回避和干呕行为分别模拟了人类食物中毒后引发的“恶心”和“呕吐”防御反应，可作为小鼠食物中毒的研究范式。

</section><section style="margin-bottom: 0px;line-height: 1.75em;text-align: center;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(136, 136, 136);font-size: 12px;">视频1</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><strong><br/></strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);">在肠道上皮中，存在着一类被称为“<strong>肠嗜铬细胞</strong></span><span style="font-size: 15px;color: rgb(136, 136, 136);">（enterochromaffin cell）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">”的肠道内分泌细胞。应用新建立的食物中毒研究范式，曹鹏团队发现肠嗜铬细胞在“恶心-呕吐”反应中扮演重要角色，可能是帮助大脑感知病原入侵的“情报员”。这类细胞合成了占机体90%的五羟色胺</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（5-HT）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">。当胃肠道遭受肠毒素入侵后，这类细胞可能被激活并大量释放五羟色胺。<strong>当敲除肠嗜铬细胞中合成五羟色胺的限速酶基因<em>Tph1</em>后，肠毒素引发的“恶心-呕吐”反应大大下降。</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><br/></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);">在肠嗜铬细胞周围分布着表达五羟色胺3型受体基因</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（<em>Htr3a+</em>）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">的迷走神经感觉末梢，通过响应五羟色胺来接收病原入侵的重要情报。这一情报通过迷走神经传送到脑干孤束核，被一群表达速激肽基因</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（<em>Tac1+</em>）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">的神经元接收到。研究者通过光遗传学</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（视频-2）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">和化学遗传学</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（视频-3）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">的方法激活这些孤束核<em>Tac1+</em>神经元，可以直接引发小鼠的干呕行为和条件性味觉回避。而失活这些神经元，或敲除<em>Tac1</em>基因，可以阻止病原入侵引发的干呕行为和条件性味觉回避。有趣的是，这些孤束核<em>Tac1+ </em>神经元兵分两路，一方面激活脑桥中的厌恶中枢</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（parabrachial nucleus）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">，产生与“恶心”相关的厌恶性情绪；另一方面激活延髓的呼吸中枢</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（ventral respiratory group）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">，可能通过调节其中负责膈肌和腹肌同时收缩的“干呕”神经元引发干呕的运动行为。</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><br/></span></section><section style="margin-bottom: 0px;margin-left: 8px;margin-right: 8px;"><iframe allowfullscreen="" class="video_iframe rich_pages" data-cover="http%3A%2F%2Fmmbiz.qpic.cn%2Fmmbiz_jpg%2FPlqGiacEDZrlLDmegZsW7baneCdicjRejiayJicrYXIViaXoF6ZCslgja9K837jqkq55CKEp9BOm60bsj6iakugicufgA%2F0%3Fwx_fmt%3Djpeg" data-mpvid="wxv_2645185844848361472" data-ratio="1.7391304347826086" data-src="https://mp.weixin.qq.com/mp/readtemplate?t=pages/video_player_tmpl&action=mpvideo&auto=0&vid=wxv_2645185844848361472" data-vidtype="2" data-w="640" frameborder="0" style="border-radius: 4px;"/></section><section style="margin-bottom: 0px;line-height: 1.75em;text-align: center;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(136, 136, 136);font-size: 12px;text-align: center;">视频2</span></section><section style="margin-bottom: 0px;margin-left: 8px;margin-right: 8px;"><iframe allowfullscreen="" class="video_iframe rich_pages" data-cover="http%3A%2F%2Fmmbiz.qpic.cn%2Fmmbiz_jpg%2FPlqGiacEDZrlLDmegZsW7baneCdicjRejiaNYcVXsyOw1nySrhkKjUG1ME7dl7llH8xeiaI90g1zH63CemyxncaOIA%2F0%3Fwx_fmt%3Djpeg" data-mpvid="wxv_2645186267147665410" data-ratio="1.7391304347826086" data-src="https://mp.weixin.qq.com/mp/readtemplate?t=pages/video_player_tmpl&action=mpvideo&auto=0&vid=wxv_2645186267147665410" data-vidtype="2" data-w="640" frameborder="0" style="border-radius: 4px;"/></section><section style="margin-bottom: 0px;line-height: 1.75em;text-align: center;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(136, 136, 136);font-size: 12px;text-align: center;">视频3</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><br/></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);">曹鹏团队进一步深入研究，发现这些分子细胞和神经环路机制也参与了化疗药物</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（doxorubicin）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">引发的“恶心-呕吐”副作用。这一发现暗示，化疗药物引发的“恶心-呕吐”副作用，可能是通过绑架进化上保守的“食物中毒”机制得以实现。审稿人认为，</span><span style="font-size: 15px;color: rgb(0, 122, 170);"><strong>这一成果开辟了“恶心-呕吐”反应的分子细胞机制和神经环路机制研究的新方向，有望为发展新型化疗止吐药提供新的靶点。</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><br/></span></section><section style="margin-bottom: 0px;white-space: normal;text-align: center;margin-left: 8px;margin-right: 8px;"><img class="rich_pages wxw-img" data-galleryid="" data-ratio="0.9745308310991957" data-s="300,640" src="https://zfz-oss.oss-cn-hangzhou.aliyuncs.com/temp/bcdb4a7f3c614441d70251544e542e9f.png" data-type="png" data-w="746"/></section><section style="margin-bottom: 0px;white-space: normal;line-height: 1.75em;text-align: center;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(136, 136, 136);font-size: 12px;">图-1 大脑感知毒素并启动“恶心-呕吐”反应的神经生物学机制</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><br/></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);">北京生命科学研究所曹鹏实验室的谢志勇</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（现任复旦大学脑转化研究院独立PI）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">、张现营、赵淼，以及生物岛实验室的霍立芳是研究论文的共同第一作者。曹鹏实验室其他成员</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（黄美珠、张双峰、程欣宇、谷华婷）</span><span style="font-size: 15px;color: rgb(63, 63, 63);">也对该研究做出了重要贡献。曹鹏博士、谢志勇博士、王凤超博士和尚从平博士是研究论文的共同通讯作者。</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(63, 63, 63);"><br/></span></section><section style="margin-bottom: 0px;white-space: normal;text-align: left;line-height: 1.5em;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(0, 122, 170);font-size: 12px;"><strong>原文链接：</strong></span></section><section style="margin-bottom: 0px;white-space: normal;text-align: left;line-height: 1.5em;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(0, 122, 170);font-size: 12px;"><strong>https://doi.org/10.1016/j.cell.2022.10.001</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><br/></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 14px;color: rgb(136, 136, 136);"><strong>曹鹏实验室热忱欢迎对科学研究有激情和斗志的研究生和博士后加入研究团队，一起探索大脑感知病原入侵引发防御反应的神经机制！！！</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><br/></section><section arial="" center="" gb="" helvetica="" neue="" normal="" rgb="" rotatez="" sans="" sans-serif="" sc="" style="padding: 10px;outline: 0px;letter-spacing: 0.544px;white-space: normal;font-family: -apple-system, system-ui, " ui="" yahei=""><span style="outline: 0px;font-size: 24px;">专家点评</span></section><section arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="margin-top: -1px;outline: 0px;color: rgb(34, 34, 34);letter-spacing: 0.544px;white-space: normal;font-family: -apple-system, system-ui, " ui="" yahei=""><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei=""><strong style="outline: 0px;"><span arial="" gb="" helvetica="" neue="" sans="" sans-serif="" sc="" style="outline: 0px;letter-spacing: 0.544px;font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">段树民</span></strong></span><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">（中科院院士）</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);">包括恶心呕吐在内的本能行为，往往表现为内分泌-自主神经系统所介导的内脏活动及感受的紊乱，并常常引起强烈的情绪反应。而焦虑、抑郁等负性情绪也常常引起内脏活动和感受的紊乱。由于研究手段的限制，内脏活动与情绪的关联机制一直没有得到很深入的研究。曹鹏实验室的工作为我们<strong>提供了很好的研究范例。</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><br/></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei=""><strong style="outline: 0px;"><span arial="" gb="" helvetica="" neue="" sans="" sans-serif="" sc="" style="outline: 0px;letter-spacing: 0.544px;font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">罗敏敏</span></strong></span><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">（北京脑科学与类脑研究中心资深研究员）</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><strong><br/></strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);">5-HT</span><span style="font-size: 15px;color: rgb(136, 136, 136);">（五羟色胺）</span><span style="font-size: 15px;color: rgb(0, 122, 170);">在人体多种生理过程中扮演了重要的角色。过去的研究集中探索5-HT对中枢神经系统的生理与行为功能。约90%的5-HT存在于胃肠道系统，被认为可能参与肠道的蠕动。曹鹏实验室的研究工作揭示了肠道嗜铬细胞的5-HT介导食物中毒后的“恶心-呕吐”反应。<strong>这一研究成果有力地推动了我们对5-HT生理功能的进一步理解。</strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><br/></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei=""><strong style="outline: 0px;"><span arial="" gb="" helvetica="" neue="" sans="" sans-serif="" sc="" style="color: rgb(171, 25, 66);outline: 0px;letter-spacing: 0.544px;font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">王立铭</span></strong></span><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">（深圳湾实验室资深研究员）</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><strong><br/></strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);">摄食是我们人类赖以生存的基本行为。我们需要持续寻找合适的食物来源、进食安全、充足且营养丰富的食物，以满足身体代谢的需要。但我们在摄取食物中能量和营养物质的同时，也可能不幸地摄入混杂于食物中的病原微生物。每年有上亿人因为摄入病原微生物而遭受食物中毒的折磨。有食物中毒经验的朋友都体验过恶心、呕吐和腹泻的痛苦。然而，这些反应其实对我们的机体具有重要的保护作用，利于尽快排出摄入的病原微生物，帮助以后避开类似的有毒食物。曹鹏实验室的这一研究，为我们清晰地解释了肠道中的病原如何被大脑感知，以及大脑如何发动恶心和呕吐的防御行为。</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><br/></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei=""><strong style="outline: 0px;"><span arial="" gb="" helvetica="" neue="" sans="" sans-serif="" sc="" style="color: rgb(171, 25, 66);outline: 0px;letter-spacing: 0.544px;font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">袭荣文</span></strong></span><span arial="" gb="" helvetica="" neue="" rgb="" sans="" sans-serif="" sc="" style="font-family: mp-quote, -apple-system-font, BlinkMacSystemFont, " ui="" yahei="">（北京生命科学研究所资深研究员）</span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);"><strong><br/></strong></span></section><section style="margin-bottom: 0px;line-height: 1.75em;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;color: rgb(0, 122, 170);">肠道内分泌细胞在肠道中发挥重要的感知和信号传递功能，可作用于邻近细胞和肠道神经元甚至远端其他器官，从而调控多种生理和病理过程。曹鹏团队及其合作者的这项工作进一步明确了肠道内分泌细胞在脑-肠轴介导的“恶心-呕吐”行为中的关键作用，提示其表达的相关受体发展为药物新靶点的潜在可能及＂脑病肠治＂的药物研发新思路。未来对肠道内分泌细胞的更多关注和深入研究或将带来更多惊喜。</span></section><section style="margin-bottom: 0px;text-align: left;line-height: 1.5em;margin-left: 8px;margin-right: 8px;"><br/></section><section style="line-height: 1.75em;margin-bottom: 0px;margin-left: 8px;margin-right: 8px;"><span style="color: rgb(136, 136, 136);font-size: 12px;">制版人：十一</span></section><section style="line-height: 1.75em;margin-bottom: 0px;margin-left: 8px;margin-right: 8px;"><span style="font-size: 15px;"><br/></span></section><section style="white-space: normal;max-width: 100%;box-sizing: border-box;letter-spacing: 0.544px;margin-bottom: 0px;margin-left: 8px;margin-right: 8px;overflow-wrap: break-word !important;"><section style="max-width: 100%;box-sizing: border-box;display: inline-block;vertical-align: top;overflow-wrap: break-word !important;"><section style="margin-left: -1px;max-width: 100%;box-sizing: border-box;width: 12px;height: 12px;border-top: 3px solid rgb(171, 25, 66);border-left: 3px solid rgb(171, 25, 66);transform: rotate(0deg);overflow-wrap: break-word !important;"><br/></section><section style="margin-top: -11px;margin-bottom: -11px;padding: 4px;max-width: 100%;box-sizing: border-box;border-width: 1px;border-style: solid;border-color: rgb(223, 223, 223);overflow-wrap: break-word !important;"><section style="padding-right: 6px;padding-left: 6px;max-width: 100%;box-sizing: border-box;border-width: 1px;border-style: solid;border-color: rgb(223, 223, 223);overflow-wrap: break-word !important;"><p style="max-width: 100%;box-sizing: border-box;min-height: 1em;overflow-wrap: break-word !important;"><strong style="max-width: 100%;box-sizing: border-box !important;overflow-wrap: break-word !important;"><span style="max-width: 100%;font-size: 15px;box-sizing: border-box !important;overflow-wrap: break-word !important;">参考文献</span></strong></p></section></section><section style="margin-right: -1px;margin-left: auto;max-width: 100%;box-sizing: border-box;width: 12px;height: 12px;border-bottom: 3px solid rgb(171, 25, 66);border-right: 3px solid rgb(171, 25, 66);transform: rotate(0deg);overflow-wrap: break-word !important;"><br style="max-width: 100%;box-sizing: border-box !important;overflow-wrap: break-word !important;"/></section></section></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">1. 世界卫生组织https://www.who.int/news-room/fact-sheets/detail/food-safety</span></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">2. Hesketh, P.J. (2008). Chemotherapy-induced nausea and vomiting. <em><strong>N. Engl. J. Med.</strong></em> 358, 2482-2494.</span></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">3. Horn, C.C. et al., (2013). Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study. <em><strong>PLoS One</strong></em> 8, e60537.</span></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">4. Babic, T., and Browning, K.N. (2014). The role of vagal neurocircuits in the regulation of nausea and vomiting.<em><strong> Eur. J. Pharmacol. </strong></em>722, 38-47.</span></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">5. Rojas, C., Raje, M., Tsukamoto, T., and Slusher, B.S. (2014). Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.<em><strong> Eur. J. Pharmacol.</strong></em> 722, 26-37.</span></section><section style="margin-bottom: 8px;white-space: normal;text-align: left;line-height: normal;margin-left: 8px;margin-right: 8px;"><span style="font-size: 12px;color: rgb(136, 136, 136);">6. Xie, Z. et al., (2022) The gut-to-brain axis for toxin-induced defensive responses. <em><strong>Cell</strong></em> https://doi.org/10.1016/j.cell.2022.10.001</span></section><section style="max-width: 100%;white-space: normal;text-align: center;margin-bottom: 8px;margin-left: 8px;margin-right: 8px;overflow-wrap: break-word !important;box-sizing: border-box !important;"><a data-linktype="1" href="https://mp.weixin.qq.com/s?__biz=MzA3MzQyNjY1MQ==&mid=2652589004&idx=4&sn=d391e0beef479ade335beb59276cd758&scene=21#wechat_redirect" imgdata="null" imgurl="" linktype="text" style="max-width: 100%;overflow-wrap: break-word !important;box-sizing: border-box !important;" tab="innerlink" target="_blank" textvalue="你已选中了添加链接的内容"><span class="js_jump_icon h5_image_link" data-positionback="static" style="max-width: 100%;inset: auto;overflow-wrap: break-word !important;box-sizing: border-box !important;"><img class="rich_pages wxw-img" data-backh="71" data-backw="562" data-cropselx1="0" 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