中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (1): 129-136.doi: 10.4103/1673-5374.286970

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

神经元蛋白酪氨酸磷酸酶1B阻碍局灶性脑缺血后感觉运动功能恢复并引起情感障碍

  

  • 出版日期:2021-01-15 发布日期:2020-11-23
  • 基金资助:
    加拿大心脏和中风基金会（G-13-0002596，G-18-0022157，G-16-00014085），自然科学和工程研究；加拿大理事会（RGPIN / 06212-2014，RGPIN / 2016-04985）和加拿大卫生研究院（201610PJT）;安大略省心脏和中风基金会的职业研究人员奖（第7506号）

Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

Shelly A. Cruz1, 2, Zhaohong Qin1, 2, Konrad M. Ricke2, 3, 7, Alexandre F.R. Stewart3, 6, 7, *, Hsiao-Huei Chen1, 2, 4, 5, 6, *   

  1. 1 Ottawa Hospital Research Institute, Neuroscience Program, University of Ottawa, Ottawa, ON, Canada;  2 Brain and Mind Institute, University of Ottawa, Ottawa, ON, Canada;   3 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada;    4 Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada;  5 Department of Medicine, University of Ottawa, Ottawa, ON, Canada;    6 Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada;  7 University of Ottawa Heart Institute, Ottawa, ON, Canada
  • Online:2021-01-15 Published:2020-11-23
  • Contact: Hsiao-Huei Chen, PhD, hchen@uottawa.ca; Alexandre F.R. Stewart, PhD, astewart@ottawaheart.ca.
  • Supported by:
    This work was supported by grants from the Heart and Stroke Foundation of Canada (Nos. G-13-0002596 & G-18-0022157, to HHC; No. G-16-00014085, to AFRS), the Natural Science and Engineering Research Council of Canada (No. RGPIN/06212-2014, to HHC; No. RGPIN/2016-04985, to AFRS) and the Canadian Institutes of Health Research (No. 201610PJT, to HHC). HHC is also supported by a Mid-Career Investigator Award (No. 7506) from the Heart and Stroke Foundation of Ontario. 

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摘要：

缺血性脑卒中可导致神经元死亡和炎症，炎症可激活蛋白酪氨酸磷酸酶1B，但蛋白酪氨酸磷酸酶1B对脑卒中临床结局的影响尚不明确。实验探讨了两种脑缺血模型中谷氨酸能投射神经元中蛋白酪氨酸磷酸酶1B激活对功能恢复的意义。实验应用光化学栓塞法建立感觉运动皮质或前额周围皮质局灶性脑缺血小鼠模型。在卒中后第4天和6周时检测到蛋白酪氨酸磷酸酶1B表达升高。神经元PTP1B敲除对小鼠脑梗死体积没有影响，但对功能恢复的影响明显不同。感觉运动皮质缺血第4天时神经元PTP1B敲除和野生型小鼠均产生明显的感觉和运动功能障碍（移除黏附物能力测试），神经元PTP1B敲除小鼠在第8天显示出明显的感觉和运动功能恢复。野生型小鼠在前额周围皮质缺血后9和28天出现焦虑样行为（高架十字迷宫实验和旷野实验）和抑郁样行为（强迫游泳和悬尾实验），而感觉和运动功能几乎无变化。与假手术组小鼠相比，前额周围皮质缺血诱发的情感障碍与前额叶皮质和伏隔核中FosB +神经元较少，而杏仁基底外侧核中的FosB +神经元较多有关。神经元蛋白酪氨酸磷酸酶1B敲除使前额周围皮质缺血小鼠未发生焦虑样和抑郁样行为，且FosB +神经元没有变化。说明神经元蛋白酪氨酸磷酸酶1B表达不仅阻碍感觉和运动功能的恢复，并且促进了于脑缺血后焦虑样和抑郁样行为的发展。因此，蛋白酪氨酸磷酸酶1B可视为一种新型的治疗靶点，以促进缺血性脑卒中的恢复。

https://orcid.org/0000-0003-2914-6057 (Hsiao-Huei Chen); 

0000-0003-2673-9164 (Alexandre F.R. Stewart)

关键词: 缺血性脑卒中, 蛋白酪氨酸磷酸酶1B, Iba1, 小胶质细胞, 肿瘤坏死因子, 运动, 感觉, 焦虑, 抑郁

Abstract: Ischemic brain injury causes neuronal death and inflammation. Inflammation activates protein-tyrosine phosphatase 1B (PTP1B). Here, we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke: by photothrombosis, focal ischemic lesions were induced in the sensorimotor cortex (SM stroke) or in the peri-prefrontal cortex (peri-PFC stroke). Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke. While ablation of PTP1B in neurons of neuronal knockout (NKO) mice had no effect on the volume or resorption of ischemic lesions, markedly different effects on functional recovery were observed. SM stroke caused severe sensory and motor deficits (adhesive removal test) in wild type and NKO mice at 4 days, but NKO mice showed drastically improved sensory and motor functional recovery at 8 days. In addition, peri-PFC stroke caused anxiety-like behaviors (elevated plus maze and open field tests), and depression-like behaviors (forced swimming and tail suspension tests) in wild type mice 9 and 28 days after stroke, respectively, with minimal effect on sensory and motor function. Peri-PFC stroke-induced affective disorders were associated with fewer active (FosB+) neurons in the PFC and nucleus accumbens but more FosB+ neurons in the basolateral amygdala, compared to sham-operated mice. In contrast, mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+ neurons after peri-PFC stroke. Taken together, our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke. Thus, PTP1B may represent a novel therapeutic target to improve stroke recovery. All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service (protocol 1806) on July 27, 2018.

Key words: adhesive removal test, anxiety, depression, elevated plus maze, forced swimming test, Iba1, interleukin-1β, microglia, open field test, tail suspension test, tumor necrosis factor-α