University of Ottawa, Ottawa, ON K1N6N5, Canada.
Horm Behav. 2011 Apr;59(4):594-604. doi: 10.1016/j.yhbeh.2011.02.017. Epub 2011 Mar 3.
This study investigates the association of ischemia-induced spatial memory impairment to alterations of the HPA axis and noradrenergic activation post insult. Experiment 1 characterized the effects of 10 min forebrain ischemia on corticosterone (CORT) secretion following ischemia and in response to spatial memory assessment in the Barnes maze, as well as the impact of pre-ischemia treatment with the glucocorticoid inhibitor metyrapone (175 mg/kg; s.c.). The results showed that cerebral ischemia represents a significant physiological stressor that upregulated CORT secretion 1, 24 and 72 h post-ischemia but not at 7 days. In response to testing in the Barnes maze ischemic animals showed elevated CORT secretion simultaneously with spatial memory deficits. The single dose of metyrapone attenuated the ischemia-induced adrenocortical hyper-responsiveness and subsequent memory deficits despite not providing neuroprotection in the hippocampal CA1 pyramidal cells. To complement these findings, we examined whether norepinephrine which provides positive feedback to the HPA axis and is upregulated following brain ischemia could influence memory performance at delayed intervals after ischemia. Experiment 2 demonstrated that pre-testing administration of the alpha2-adrenoceptor agonist clonidine (.04 mg/kg, s.c.) attenuated ischemia-induced working memory impairments in a radial maze while opposite effects were obtained with the antagonist yohimbine (.3 mg/kg, s.c.). Post-testing administration of clonidine produced spatial reference memory impairments in ischemic rats. The findings from the current study demonstrate increased sensitization and responsiveness of systems regulating stress hormones at long intervals post ischemia. Importantly, we demonstrate that these effects contribute to post ischemic cognitive impairments which can be attenuated pharmacologically even in the presence of hippocampal degeneration at time of testing.
本研究旨在探讨缺血诱导的空间记忆损伤与 HPA 轴改变和损伤后去甲肾上腺素能激活之间的关系。实验 1 描述了 10 分钟前脑缺血对缺血后皮质酮（CORT）分泌的影响，以及在巴恩斯迷宫中进行空间记忆评估时的影响，以及在缺血前用糖皮质激素抑制剂甲吡酮（175mg/kg；sc）治疗的影响。结果表明，脑缺血是一种显著的生理应激源，可在上缺血后 1、24 和 72 小时上调 CORT 分泌，但在 7 天内不会。在巴恩斯迷宫中进行测试时，缺血动物表现出 CORT 分泌升高，同时伴有空间记忆缺陷。单次给予甲吡酮可减轻缺血诱导的肾上腺皮质高反应性和随后的记忆缺陷，尽管不能提供海马 CA1 锥体神经元的神经保护作用。为了补充这些发现，我们研究了去甲肾上腺素是否会在缺血后延迟时间影响记忆表现，因为去甲肾上腺素为 HPA 轴提供正反馈，并且在脑缺血后会上调。实验 2 表明，在测试前给予α2-肾上腺素能受体激动剂可乐定（0.04mg/kg，sc）可减轻在放射迷宫中的缺血诱导的工作记忆损伤，而拮抗剂育亨宾（0.3mg/kg，sc）则产生相反的效果。在缺血大鼠中，可乐定在测试后给药会产生空间参考记忆损伤。本研究的结果表明，在缺血后长时间内，调节应激激素的系统会增加敏感性和反应性。重要的是，我们证明这些效应有助于缺血后认知障碍，即使在测试时存在海马退化，也可以通过药理学减轻这些效应。
