Stimulus-specific hypothalamic encoding of a persistent defensive state.
Stimulus-specific hypothalamic encoding of a persistent defensive state.
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DOI：
10.1038/s41586-020-2728-4
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Anderson DJ
中科院分区：
文献类型：
--
作者：
Kennedy A;Kunwar PS;Li LY;Stagkourakis S;Wagenaar DA;Anderson DJ
持续的神经活动已被描述为在皮层，海马和运动网络介导的短暂遇到的刺激的工作记忆。内部情绪状态，如恐惧，在暴露于刺激刺激物后也会表现出持久性，但是否涉及缓慢的神经动力学还没有得到很好的研究。下丘脑腹内侧区（VMHdm/c）背内侧和中央亚区的SF 1 +/Nr 5a 1+神经元在对捕食者的防御反应中是必需的。VMHdmSF 1神经元的光遗传激活激发了比刺激更持久的防御行为，这表明诱导了持续的内部恐惧或焦虑状态。在这里，我们表明，在响应自然的威胁刺激，VMHdmSF 1神经元表现出持续数十秒的持续活动。这种持续的活动与持续的防御行为在旷场试验中是相关的，并且是持续的防御行为所必需的，并且依赖于VMHdmSF 1神经元的神经递质释放。急性切片的刺激和钙成像实验显示VMHdmSF 1神经元之间的局部兴奋性连接。VMHdmSF 1神经元的显微内窥镜钙成像显示，在群体水平上的持续活动反映了单个细胞之间的异质性动力学。出乎意料的是，不同但重叠的VMHdmSF 1亚群持续激活不同形式的威胁刺激。计算模型表明，无论是经常性的兴奋，也不是缓慢作用的神经调节剂单独可以占持久的活动，保持刺激的身份。我们的研究结果确定刺激特定的下丘脑缓慢的神经动力学，在时间尺度上的数量级长于支持工作记忆的皮层，作为一个贡献机制的基础上持续的情绪状态。(238字）
Persistent neural activity has been described in cortical, hippocampal, and motor networks as mediating working memory of transiently encountered stimuli. Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus, but whether slow neural dynamics are involved is not well-studied. SF1+/Nr5a1+ neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) are necessary for defensive responses to predators. Optogenetic activation of VMHdmSF1 neurons elicits defensive behaviours that outlast stimulation, suggesting the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 neurons exhibit persistent activity lasting many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behavior in an open-field assay, and was dependent on neurotransmitter release from VMHdmSF1 neurons. Stimulation and calcium imaging experiments in acute slices revealed local excitatory connectivity between VMHdmSF1 neurons. Microendoscopic calcium imaging of VMHdmSF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different modalities of threatening stimuli. Computational modeling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results identify stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that supporting working memory in the cortex, as a contributing mechanism underlying a persistent emotion state. (238 words)
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