Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress.
Interleukin-1 receptor on hippocampal neurons drives social withdrawal and cognitive deficits after chronic social stress.
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海马神经元上的白细胞介素-1受体驱动慢性社会应激后的社会退缩和认知缺陷。
DOI：
10.1038/s41380-020-0788-3
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发表时间：
2021-09
影响因子：
11
通讯作者：
Quan N
中科院分区：
文献类型：
--
作者：
DiSabato DJ;Nemeth DP;Liu X;Witcher KG;O'Neil SM;Oliver B;Bray CE;Sheridan JF;Godbout JP;Quan N
慢性压力会导致精神疾病，包括焦虑和抑郁。应激的几种炎症相关效应与中枢神经系统内增加的白细胞介素-1（IL-1）信号传导相关，并且由几种不同细胞类型上的IL-1受体1（IL-1 R1）介导。神经元IL-1 R1在齿状回的神经元上显著表达，但其在介导对应激的行为反应中的作用尚不清楚。我们假设IL-1作用于海马神经元的这一亚群，从而影响应激时的认知和情绪改变。在这里，受到心理社会压力的小鼠表现出减少的社会互动和受损的工作记忆，而这些缺陷可以通过整体IL-1 R1敲除来预防。应激诱导的单核细胞向脑的运输也被IL-1 R1敲除阻断。选择性地删除海马神经元中的IL-1 R1（nIL-1 R1 −/−）消除了社会交往和工作记忆中的应激诱导缺陷。此外，病毒介导的海马神经元中的选择性IL-1 R1缺失证实了海马中的IL-1受体对应激诱导的行为缺陷至关重要。此外，选择性恢复IL-1 R1对多巴胺能神经元的作用足以重建应激后社会交往和工作记忆的损伤。海马的RNA测序显示，应激增加了与炎症相关的几种典型途径（TREM 1、NF-κB、补体、IL-6信号传导）和上游调节因子（INFγ、IL-1β、NF-κB、MYD 88）。TREM 1信号传导，补体和白细胞外渗的诱导与应激被逆转nIL-1 R1 −/−。总的来说，海马神经元中的应激依赖性IL-1 R1信号转导代表了一种新的机制，通过这种机制，炎症得以持续，社会互动和工作记忆得以调节。
Chronic stress contributes to the development of psychiatric disorders including anxiety and depression. Several inflammatory-related effects of stress are associated with increased interleukin-1 (IL-1) signaling within the central nervous system and are mediated by IL-1 receptor 1 (IL-1R1) on several distinct cell types. Neuronal IL-1R1 is prominently expressed on the neurons of the dentate gyrus, but its role in mediating behavioral responses to stress is unknown. We hypothesize that IL-1 acts on this subset of hippocampal neurons to influence cognitive and mood alterations with stress. Here, mice subjected to psychosocial stress showed reduced social interaction and impaired working memory, and these deficits were prevented by global IL-1R1 knockout. Stress-induced monocyte trafficking to the brain was also blocked by IL-1R1 knockout. Selective deletion of IL-1R1 in glutamatergic neurons (nIL-1R1−/−) abrogated the stress-induced deficits in social interaction and working memory. In addition, viral-mediated selective IL-1R1 deletion in hippocampal neurons confirmed that IL-1 receptor in the hippocampus was critical for stress-induced behavioral deficits. Furthermore, selective restoration of IL-1R1 on glutamatergic neurons was sufficient to reestablish the impairments of social interaction and working memory after stress. RNA-sequencing of the hippocampus revealed that stress increased several canonical pathways (TREM1, NF-κB, complement, IL-6 signaling) and upstream regulators (INFγ, IL-1β, NF-κB, MYD88) associated with inflammation. The inductions of TREM1 signaling, complement, and leukocyte extravasation with stress were reversed by nIL-1R1−/−. Collectively, stress-dependent IL-1R1 signaling in hippocampal neurons represents a novel mechanism by which inflammation is perpetuated and social interactivity and working memory are modulated.
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影响因子：
16.2
作者：
Fanselow, Michael S.;Dong, Hong-Wei
通讯作者：
Dong, Hong-Wei
影响因子：
11
作者：
Francis TC;Chandra R;Gaynor A;Konkalmatt P;Metzbower SR;Evans B;Engeln M;Blanpied TA;Lobo MK
通讯作者：
Lobo MK
影响因子：
--
作者：
Kendler, KS;Hettema, JM;Prescott, CA
通讯作者：
Prescott, CA
影响因子：
4.3
作者：
Jakobsson, Joel;Bjerke, Maria;Landen, Mikael
通讯作者：
Landen, Mikael
影响因子：
3.7
作者：
Hammond SL;Leek AN;Richman EH;Tjalkens RB
通讯作者：
Tjalkens RB