A Lower-Brainstem Structure Coordinates Acquisition of Negative Experience
A Lower-Brainstem Structure Coordinates Acquisition of Negative Experience
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DOI：
10.1007/s12264-020-00504-8
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发表时间：
2020-04
影响因子：
5.6
通讯作者：
Lei Li
中科院分区：
文献类型：
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作者：
Lei Li
为了生存，动物必须快速处理厌恶或应激的事件，并评估和存储相关信息。积累的神经回路研究已经确定了在处理负面经历的过程中，关键的大脑核团，如杏仁核、外侧缰核(LHb)、中脑导水管周围灰质(PAG)、下丘脑腹内侧核、海马体等。然而，还需要更多的工作来确定这些大脑结构在应对这种经历时如何相互协调。最近发表在《科学》杂志上的一项研究题为《中缝中缝控制小鼠负面体验的获得》，该研究来自匈牙利科学院的Nyiri博士团队，为这个复杂而重要的问题提供了新的线索。利用特定细胞类型的神经元示踪、块面扫描免疫电子显微镜、体内和体外电生理学、光发生和化学发生操作以及行为任务，他们发现，中缝正中区(MRR，又称中缝正中核，Mnr)，特别是囊泡状谷氨酸转运体2(VGluT2)阳性神经元可能是协调负经验加工的关键枢纽。Szonyi等人对MRR中的5-羟色胺能神经元进行了研究。研究了一种以前被忽视的神经元类型-vGluT2神经元。这些神经元至少占所有MRR神经元的20%，分布于该区域的正中和旁正中部分。使用多通道记录和光基因标记，他们表明，MRR vGluT2-神经元对厌恶刺激(空气喷雾)有选择性地反应，对轻度厌恶发光二极管闪光的反应程度要小得多，而对水滴的奖励刺激没有反应。三组功能实验被用来破译MRR vGluT2-神经元在负面体验中的作用。首先，这些神经元在体内的急性光遗传躯体激活导致了显著的实时位置厌恶和条件性位置厌恶，并在配对后减少了饥饿小鼠对食物托盘奖励的鼻戳。其次，在体内，神经元胞体的化学激活导致了在社交测试和入侵者测试中的高度攻击性行为。此外，在蔗糖偏好试验中，3周的体细胞慢性化学激活可导致快感丧失。第三，MRR vGluT2神经元的光遗传激活触发了小鼠的运动和海马theta振荡。在一项使用延迟线索恐惧条件反射范式的功能丧失研究中，这些神经元在呈现不利刺激时的光遗传抑制减少了情境冻结行为和广义的条件性恐惧，表明它们在储存负面经历的记忆方面发挥了重要作用。Szonyi等人。不仅基于上述功能数据，而且基于它们对MRR vGluT2神经元输入和输出的坚实和详细的追踪，得出了结论：“MRR控制着小鼠负面经验的获得”。值得指出的是，使用块面扫描免疫电子显微镜来展示MRR vGluT2-神经元与其下游靶点形成的突触的细节是一个亮点。如图1(绿线)所示，MRR vGluT2-神经元接收
To survive, animals must process aversive or stressful events quickly, and evaluate and store the related information. Accumulating neural circuity studies have identified key brain nuclei, such as the amygdala, lateral habenula (LHb), periaqueductal grey (PAG), ventromedial hypothalamic nucleus, hippocampus, among others, in the processing of negative experiences [1, 2]. Yet more work is needed to determine how these brain structures coordinate with each other in coping with such experiences. A recent study published in Science entitled ‘‘Median raphe controls acquisition of negative experience in the mouse’’from Dr. Nyiri’s group at the Hungarian Academy of Sciences sheds new light on this complex and important question [3]. Using cell-type-specific neuronal tracing, block-face scanning immunoelectron microscopy, in vivo and in vitro electrophysiology, and optogenetic and chemogenetic manipulations together with behavioral tasks, they revealed that the median raphe region (MRR, also named median raphe nucleus, MnR), especially the vesicular glutamate transporter 2 (vGluT2)-positive neurons in the MRR may serve as a key hub for the coordination of negative experience processing. While the serotoninergic neurons in the MRR have been investigated, Szonyi et al. studied a previously neglected neuron type–vGluT2-neurons. These constitute at least20% of all MRR neurons, and are distributed both in the median and the paramedian parts of the region. Using multichannel recording and optogenetic tagging, they showed that MRR vGluT2-neurons respond selectively to an aversive stimulus (air puffs) and to a much lesser extent to mildly aversive light-emitting diode flashes, while they do not respond to the rewarding stimulus of water drops. Three groups of functional experiments were carried out to decipher the roles of MRR vGluT2-neurons in negative experience. First, acute in vivo optogenetic somatic activation of these neurons caused significant real-time place aversion and conditioned place aversion, and a decrease in nose-pokes for food pallet rewards in hungry mice after pairing. Second, in vivo chemogenetic activation of the soma of the neurons led to highly aggressive behavior in a social interaction test and the resident-intruder test. Moreover, chronic chemogenetic activation of somata for 3 weeks induced anhedonia in the sucrose preference test. Third, the optogenetic activation of the MRR vGluT2-neurons triggered movement of the mice as well as hippocampal theta oscillations. In a loss-of-function study using a delay-cued fear conditioning paradigm, optogenetic inhibition of these neurons during the presentation of adverse stimuli decreased contextual freezing behavior and generalized conditioned fear, showing their essential role in storing the memory of a negative experience. Szonyi et al. reached the conclusion that ‘‘MRR controls acquisition of negative experience in the mouse’’based not only on the above functional data but also their solid and detailed tracing of the inputs and outputs of MRR vGluT2-neurons. It is worth pointing out that the use of block-face scanning immunoelectron microscopy to demonstrate the details of the synapses formed by MRR vGluT2-neurons with their downstream targets is a highlight. As shown in Figure 1 (green lines), MRR vGluT2-neurons receive