Liu Hesong, Atrooz Fatin, Salvi Ankita, Salim Samina
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, TX 77204, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Aug 1;78:88-95. doi: 10.1016/j.pnpbp.2017.05.015. Epub 2017 May 17.
Children subjected to traumatic events during childhood are reported to exhibit behavioral and cognitive deficits later in life, often leading to post-traumatic stress disorder (PTSD) and major depression. Interestingly, some children continue to remain normal despite being exposed to the same risk factors. These trauma-related behavioral and cognitive profiles across different stages of life are not well understood. Animal studies can offer useful insights.
The goal of this study was to determine the impact of early life exposure to traumatic events on behavioral and cognitive profile in rats by tracking the behavior of each rat at different ages.
We utilized the single prolonged stress (SPS), a rodent model of PTSD, to study the effects of early life stress. Male Sprague-Dawley rats were exposed to SPS on post-natal day (PND) 25. Tests to assess anxiety- and depression-like behavior, as well as learning and memory function were performed at PND32, 60 and 90.
Rats exposed to SPS exhibited both anxiety- and depression-like behavior at PND32. And, short-term (STM) but not long-term memory (LTM) was impaired. Rats exposed to SPS at PND60 exhibited anxiety- but not depression-like behavior. STM but not LTM was impaired. Rats exposed to SPS at PND90 exhibited fearful (as indicated by elevated plus maze test) but not an overall anxiety-like behavior (in light and dark test). These rats also displayed significant depression-like behavior with no changes in STM or LTM. Interestingly, when data was further analyzed, two subsets of PND90 rats exposed to SPS were identified, "susceptible": with depression-like behavior and "resilient": without depression-like behavior. Importantly, while resilient group expressed early signs of anxiety- (at PND32 and PND60) and depression-like behavior (at PND32), these behavioral deficits were absent at PND90. On the other hand, susceptible PND90 rats exposed to SPS expressed later onset of anxiety-like behavior (at PND60), while depression-like phenotype was evident only later on at PND90.
Our findings suggest that early life stress caused co-occurrence of anxiety and depression-like behavior at PND32 (mimics human early-adolescent period). This co-occurrence was lost at PND60 with demonstration of anxiety- but not depression-like behavior. Later, depression but not anxiety-like behavior was observed at PND90. It seems that behavioral adaptations occur at the critical PND60 stage (mimics human late-adolescent period), where behavioral and cognitive switching occurs, thereby, expressing susceptible and resilient phenotypes.
据报道，童年时期遭受创伤性事件的儿童在日后生活中会出现行为和认知缺陷，常导致创伤后应激障碍（PTSD）和重度抑郁症。有趣的是，一些儿童尽管暴露于相同的风险因素下，仍能保持正常。人们对不同生命阶段中这些与创伤相关的行为和认知特征了解不足。动物研究可以提供有用的见解。
本研究的目的是通过追踪每只大鼠在不同年龄的行为，确定生命早期暴露于创伤性事件对大鼠行为和认知特征的影响。
我们利用单次长时间应激（SPS），一种PTSD的啮齿动物模型，来研究生命早期应激的影响。在出生后第25天（PND25）对雄性Sprague-Dawley大鼠施加SPS。在PND32、60和90进行评估焦虑样和抑郁样行为以及学习和记忆功能的测试。
在PND32时，暴露于SPS的大鼠表现出焦虑样和抑郁样行为。并且，短期记忆（STM）受损，但长期记忆（LTM）未受损。在PND60时暴露于SPS的大鼠表现出焦虑样行为，但没有抑郁样行为。STM受损，但LTM未受损。在PND90时暴露于SPS的大鼠表现出恐惧（如高架十字迷宫试验所示），但没有整体焦虑样行为（在明暗试验中）。这些大鼠还表现出明显的抑郁样行为，STM或LTM没有变化。有趣的是，当进一步分析数据时，识别出了两个在PND90时暴露于SPS的大鼠亚组，“易感组”：有抑郁样行为，以及“ resilient组”：没有抑郁样行为。重要的是，虽然resilient组在早期（PND32和PND60）表现出焦虑样和抑郁样行为的迹象，但在PND90时这些行为缺陷消失了。另一方面，在PND90时暴露于SPS的易感大鼠表现出较晚出现的焦虑样行为（在PND60时），而抑郁样表型仅在PND90时才明显。
我们的研究结果表明，生命早期应激在PND32时导致焦虑和抑郁样行为同时出现（模拟人类青少年早期）。这种同时出现的情况在PND60时消失，表现出焦虑样行为但没有抑郁样行为。后来，在PND90时观察到抑郁样行为但没有焦虑样行为。似乎在关键的PND60阶段（模拟人类青少年后期）发生了行为适应，此时发生了行为和认知转换，从而表现出易感和resilient表型。
