Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli 1 , 2 . Internal emotional states, such as fear, also persist following exposure to an inciting stimulus 3 , but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice 4 – 7 . Optogenetic activation of these neurons, referred to here as VMHdm SF1 neurons, elicits defensive behaviours that outlast stimulation 5 , 8 , which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdm SF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdm SF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdm SF1 neurons. Microendoscopic calcium imaging of VMHdm SF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex 9 , 10 , contribute to a persistent emotional state. Persistent neural activity in the mouse hypothalamus encodes aversive emotional states related to specific threatening stimuli.

中文翻译：

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持续防御状态的刺激特异性下丘脑编码

皮层、海马和运动网络中的持续神经活动被描述为对短暂遇到的刺激 1、2 的工作记忆进行调解。内部情绪状态，例如恐惧，在暴露于刺激性刺激 3 后也会持续存在，但尚不清楚该过程是否涉及缓慢的神经动力学。表达核受体蛋白 NR5A1（也称为 SF1）的下丘脑腹内侧 (VMHdm/c) 的背内侧和中央细分中的神经元对于小鼠对捕食者的防御反应是必要的 4 – 7。这些神经元（这里称为 VMHdm SF1 神经元）的光遗传学激活会引发比刺激 5、8 更持久的防御行为，这表明诱导了持续的恐惧或焦虑内部状态。在这里，我们表明，为了应对自然主义的威胁刺激，小鼠中的 VMHdm SF1 神经元表现出持续数十秒的活动。这种持续的活动与开放场试验中的持续防御行为相关，并且是必需的，并且依赖于 VMHdm SF1 神经元的神经递质释放。急性切片中的刺激和钙成像显示 VMHdm SF1 神经元之间存在局部兴奋性连接。VMHdm SF1 神经元的显微内窥镜钙成像显示，群体水平的持续活动反映了单个细胞之间的异质动力学。出乎意料的是，不同的威胁刺激方式持续激活了不同但重叠的 VMHdm SF1 亚群。计算模型表明，单独的反复兴奋和缓慢作用的神经调节剂都不能解释维持刺激同一性的持续活动。我们的研究结果表明，下丘脑中特定于刺激的缓慢神经动力学在时间尺度上比皮层中的工作记忆长几个数量级 9 、 10 ，有助于持续的情绪状态。小鼠下丘脑中持续的神经活动编码与特定威胁刺激相关的厌恶情绪状态。