PDF(Pubmed)
Abstract：
BACKGROUND: Chronic adolescent stress profoundly affects prefrontal cortical networks regulating top-down behavior control. However, the neurobiological pathways contributing to stress-induced alterations in the brain and behavior remain largely unknown. Chronic stress influences brain growth factors and immune responses, which may, in turn, disrupt the maturation and function of prefrontal cortical networks. The tumor necrosis factor alpha-converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17) is a sheddase with essential functions in brain maturation, behavior, and inflammatory responses. This study aimed to determine the impact of stress on the prefrontal cortex and whether TACE/ADAM17 plays a role in these responses.
METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma.
RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle).
CONCLUSIONS: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.
METHODS: We used a Lewis rat model that incorporates critical elements of chronic psychosocial stress, such as uncontrollability, unpredictability, lack of social support, and re-experiencing of trauma.
RESULTS: Chronic stress during adolescence reduced the acoustic startle reflex and social interactions while increasing extracellular free water content and TACE/ADAM17 mRNA levels in the medial prefrontal cortex. Chronic stress altered various ethological behavioral domains in the observation home cages (decreased ingestive behaviors and increased walking, grooming, and rearing behaviors). A group of rats was injected intracerebrally either with a novel Accell™ SMARTpool TACE/ADAM17 siRNA or a corresponding siRNA vehicle (control). The RNAscope Multiplex Fluorescent v2 Assay was used to visualize mRNA expression. Automated puncta quantification and analyses demonstrated that TACE/ADAM17 siRNA administration reduced TACE/ADAM17 mRNA levels in the medial prefrontal cortex (59% reduction relative to control). We found that the rats that received prefrontal cortical TACE/ADAM17 siRNA administration exhibited altered eating patterns (e.g., increased food intake and time in the feeding zone during the light cycle).
CONCLUSIONS: This study supports that the prefrontal cortex is sensitive to adolescent chronic stress and suggests that TACE/ADAM17 may be involved in the brain responses to stress.
摘要：
背景：慢性青少年压力深刻影响调节自上而下行为控制的前额叶皮质网络。然而,导致应激诱导的大脑和行为改变的神经生物学途径在很大程度上仍然未知。慢性应激影响大脑生长因子和免疫反应，可能，反过来,破坏前额叶皮质网络的成熟和功能。肿瘤坏死因子α转化酶/解整合素和金属蛋白酶17（TACE/ADAM17）是一种在脑成熟中具有重要功能的脱落酶，行为，和炎症反应。这项研究旨在确定压力对前额叶皮层的影响以及TACE/ADAM17是否在这些反应中起作用。
方法：我们使用了Lewis大鼠模型，该模型包含了慢性社会心理压力的关键要素，比如不可控性，不可预测性,缺乏社会支持,重新体验创伤。
结果：青春期的慢性应激降低了听觉惊吓反射和社会相互作用，同时增加了内侧前额叶皮层的细胞外游离水含量和TACE/ADAM17mRNA水平。慢性压力改变了观察家庭笼子中的各种行为学行为域（减少的摄食行为和增加的行走，梳理,和饲养行为)。一组大鼠脑内注射新型Accell™SMARTpuneTACE/ADAM17siRNA或相应的siRNA载体(对照)。RNAscope多重荧光v2测定用于可视化mRNA表达。自动点定量和分析表明,TACE/ADAM17siRNA施用降低内侧前额叶皮质中的TACE/ADAM17mRNA水平(相对于对照降低59%)。我们发现接受前额叶皮质TACE/ADAM17siRNA给药的大鼠表现出改变的进食模式（例如，在光照周期内增加食物摄入量和喂养区的时间)。
结论：这项研究支持前额叶皮质对青少年慢性应激敏感，并提示TACE/ADAM17可能参与大脑对应激的反应。
方法：我们使用了Lewis大鼠模型，该模型包含了慢性社会心理压力的关键要素，比如不可控性，不可预测性,缺乏社会支持,重新体验创伤。
结果：青春期的慢性应激降低了听觉惊吓反射和社会相互作用，同时增加了内侧前额叶皮层的细胞外游离水含量和TACE/ADAM17mRNA水平。慢性压力改变了观察家庭笼子中的各种行为学行为域（减少的摄食行为和增加的行走，梳理,和饲养行为)。一组大鼠脑内注射新型Accell™SMARTpuneTACE/ADAM17siRNA或相应的siRNA载体(对照)。RNAscope多重荧光v2测定用于可视化mRNA表达。自动点定量和分析表明,TACE/ADAM17siRNA施用降低内侧前额叶皮质中的TACE/ADAM17mRNA水平(相对于对照降低59%)。我们发现接受前额叶皮质TACE/ADAM17siRNA给药的大鼠表现出改变的进食模式（例如，在光照周期内增加食物摄入量和喂养区的时间)。
结论：这项研究支持前额叶皮质对青少年慢性应激敏感，并提示TACE/ADAM17可能参与大脑对应激的反应。
