基础科研：无心工作，只想放假！《Cell》：都是神经元的“锅”

2021-12-21 生物探索网络

该研究揭示了岛叶参与调控动力的具体的神经环路机制。

“距离年假还有多少天了，只有50天了！”“今天怎么才周二啊，距离周末还有好久啊。”诸如此类的对话可能是打工人的每日必聊。进入“工地”，打开电脑，登录微信，就算开启了“带薪摸鱼”的一天。一顿操作猛如虎，最后进度只有5%。

为什么大家无法专心工作呢？美国冷泉港实验室李波研究团队的最新研究很好地解答了大家的疑惑。近日，该团队将成果“Agenetically defined insula-brainstem circuit selectively controls motivationalvigor ”发表于《Cell》。研究发现岛叶皮层深层神经元（aIC^Fezf2）到脑干孤束核的神经环路在调控动力中发挥重要作用，揭示了岛叶皮层神经元介导动力行为的神经基础。通俗地讲，不想工作，没有动力，不是你的错，这个“锅”得由神经元来背。

19世纪早期，德国神经解剖学家JohannChristian Reil首次命名岛叶皮层，随后研究又发现这一脑区不仅参与处理味觉等感觉信息，也具有调控情感和认知行为的功能。当岛叶受损或出现功能异常，则可能导致动力下降，还与抑郁症等心理和精神疾病密切相关。虽然先前研究表明，岛叶可能参与调控动力相关的行为，然而其具体的神经环路基础目前尚不清楚。

在本次研究中，研究人员标记了小鼠岛叶皮层深层表达Fezf2基因的神经元，再通过体钙成像观察这群神经元的钙活动变化。一组小鼠经过训练后，它们一听见特定的声音刺激时，就会进行舔舐，从而收到蔗糖奖赏。通过调节行为学参数或改变小鼠的生理状态（渴水程度、奖赏多少或限盐），研究人员进一步调控小鼠获取奖赏动力的强弱，实验结果显示许多神经元对不同的条件刺激表现出兴奋性或抑制性反应，且条件刺激诱发的舔舐在两个区块中是相当的。

为了明确aIC^Fezf2神经元和动机行动之间的关系，研究人员试图在预期期间用光遗传学专门抑制这些神经元。他们在aIC^Fezf2神经元中选择性地表达了光敏神经元抑制剂GtACR2或mCherry（作为对照），小鼠接受了“GO/NO-GO联想任务”。GtACR2小鼠的光刺激在 “GO”试验中导致了预期舔舐的急剧减少，而在“NO-GO”试验中未受影响，但这是因为在这些试验中舔舐的情况很少。mCherry组小鼠均未受影响。有趣的是，一旦GtACR2小鼠在 “连续舔舐”任务中开始舔舐，光刺激对正在进行的舔舐行为没有影响。因此，抑制AaIC^Fezf2神经元会降低获得奖励所需的预期舔舐，但不影响舔舐行为的运动能力，也就是说神经元调控不会影响小鼠舔舐的能力，但会影响它们完成这些行为的动力。

行动活力和动机状态与神经元活动

此前的研究已经发现，位于岛叶皮层深层的锥体神经元会直接投射至脑干。研究人员追踪神经元的下游神经环路，发现其中一个特异的投射脑区是位于脑干的孤束核（NTS）（传统上，孤束核充当大脑传递味觉信息的中继站）。在接下来的研究中，利用通过光遗传操控，他们测试了先前观察到的aIC^Fezf2神经元的功能是否是通过aICFezf2神经元到孤束核的环路实现的。RFR（小鼠在滚轮上跑动，以获取奖赏）和GO/NO-GO联想任务的结果共同表明，aIC^Fezf2神经元到孤束核的活动能促进 “需求”，但不会影响人体正常状态或自动产生行为。这证明了aIC^Fezf2神经元的激活功能确实是由上述神经环路来执行，抑制或激活这一神经环路，可以减弱或增强个体的动力。进一步的实验发现操控这一环路的神经活动并不会影响小鼠的进水量、摄食量，以及对于奖赏的价值编码。

岛叶Fezf2神经元到孤束核的神经环路示意图

此外，他们还发现岛叶Fezf2神经元到孤束核的神经环路对动力的调节作用受个体内在状态、外在奖赏刺激的价值大小以及学习经验影响。当小鼠处于温饱状态、奖赏刺激价值小或者小鼠还未学会获得奖赏时，光遗传激活这一环路对动力行为的调控能力很弱。最后，研究人员通过同时进行光遗传激活实验和光纤记录伏隔核的多巴胺信号发现，增强Fezf2神经元到孤束核神经环路的活性，可以增加多巴胺在伏隔核的释放。

aIC^Fezf2到孤束核的神经环路促进NAc多巴胺释放

总而言之，该研究揭示了岛叶参与调控动力的具体的神经环路机制。调控岛叶到孤束核的神经环路可以减弱或增强个体动力，而不影响其他方面，这与传统控制动力的神经环路存在显著区别。这一发现可能为成瘾、抑郁症等相关精神疾病的治疗提供了一个全新的方向和探索路径。

End

参考资料：

[1]https://doi.org/10.1038/nrn894

[2]https://doi.org/10.1016/j.cell.2021.11.019

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2022-05-19 维他命

#CEL#

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2022-10-29 zhaozhouchifen

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2022-08-01 szhvet

#基础科研#

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2021-12-24 13a460c3m30暂无昵称

不想工作

69 0
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2021-12-22 xinxin088

#放假#

39 0
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2021-12-21 海阔天空Sin

厉害！

54 0

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基础科研：无心工作，只想放假！《Cell》：都是神经元的“锅”