Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function
Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function
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DOI：
10.1016/j.neuropharm.2014.05.039
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发表时间：
2014-10-01
影响因子：
4.7
通讯作者：
Pryce, Christopher R.
中科院分区：
文献类型：
--
作者：
Azzinnari, Damiano;Sigrist, Hannes;Pryce, Christopher R.
在神经精神病学中，动物研究证明了与人类病因学相关的环境操纵对与人类精神病理学相关的行为的因果影响是有价值的。这些有效的模型可以提高病因病理生理学的理解和临床前发现和新的治疗方法的开发。在抑郁症中，特定的无法控制的压力性生活事件是主要的病因因素，随后恐惧、无助和疲劳的普遍增加是核心症状或特征。在这里，我们将成年雄性C57 BL/6小鼠暴露于15天的社会心理压力，失去社会控制，但身体创伤最小。一个队列在第16-18天在运动活动、恐惧条件反射和双向回避-逃避行为的3天测试范例中进行评估，第二个队列在第19和29天在跑步机疲劳范例中进行评估，然后在第30-32天进行3天范例。所有的测试都使用了物理厌恶刺激，即温和的，短暂的电击。社会应激小鼠表现出运动活动减少，恐惧获得增加，双向回避-逃避反应减少（无助感增加）和疲劳增加。他们还显示血浆TNF和脾脏肥大增加，肾上腺肥大，无高皮质激素。在第三个队列中，使用下一代测序评估了心理社会压力对大脑基因表达的影响。前额叶皮层和杏仁核中炎症途径和G蛋白偶联受体的基因表达发生了改变;在后者中，多巴胺功能中重要基因的表达被解除调节，包括下调的Drd 2、Adora 2a和Darpp-32。该模型可用于识别治疗精神病理学（如无助或疲劳）的靶点，并筛选开发用于这些靶点的化合物/生物制剂。(C)2014爱思唯尔有限公司版权所有。
In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. (C) 2014 Elsevier Ltd. All rights reserved.