Early Stroke Induces Long-Term Impairment of Adult Neurogenesis Accompanied by Hippocampal-Mediated Cognitive Decline
Early Stroke Induces Long-Term Impairment of Adult Neurogenesis Accompanied by Hippocampal-Mediated Cognitive Decline
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DOI：
10.3390/cells8121654
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发表时间：
2019-12-01
期刊：
影响因子：
6
通讯作者：
Keiner, Silke
中科院分区：
文献类型：
--
作者：
Kathner-Schaffert, Carolin;Karapetow, Lina;Keiner, Silke
中风在短期内增加成人齿状回的神经发生，然而，在细胞和功能水平上的长期影响尚不清楚。在这里，我们评估了早期中风损害对衰老大脑的神经发生和认知功能的影响。我们假设中风在衰老过程中扰乱齿状神经发生与灵活学习受损相关。为了解决这个问题，我们在3个月大的C57B1/6小鼠中通过大脑中动脉闭塞（MCAO）诱导中风。为了验证成人神经发生的长期变化，在衰老的不同时间点给予胸腺嘧啶类似物BrdU（5-溴-2'-脱氧尿苷）。注射BrdU一个半月后，使用改良版Morris水迷宫（MWM）评估学习和记忆表现，其中包括再学习范式，以及海马体依赖和独立搜索策略。MWM表现后小鼠经心灌注。为了进一步详细评估中风介导的干细胞和祖细胞以及内源性增殖的变化，我们使用巢蛋白绿色荧光蛋白（GFP）小鼠。成年巢蛋白gfp小鼠海马接受逆转录病毒载体注射，以评估神经元形态的变化。在20月龄时，巢用gfp小鼠在MWM表现后经心脏灌注，并在1.5个月后应用BrdU。早期中风损伤显著降低7.5月龄和9月龄大鼠的神经发生，并降低后者的内源性增殖。此外，损伤后20月龄巢用gfp小鼠的未成熟双皮质素（DCX）阳性神经元减少。所有MCAO组在MWM中表现出受损的表现，并且主要依赖于海马体独立的搜索策略。这些发现表明，早期缺血性损伤导致衰老过程中神经发生的急剧下降，这与海马依赖性缺陷的过早发展有关。我们的研究支持这样一种观点，即早期中风可能导致长期认知缺陷，正如在人类患者损伤后观察到的那样。
Stroke increases neurogenesis in the adult dentate gyrus in the short term, however, long-term effects at the cellular and functional level are poorly understood. Here we evaluated the impact of an early stroke lesion on neurogenesis and cognitive function of the aging brain. We hypothesized that a stroke disturbs dentate neurogenesis during aging correlate with impaired flexible learning. To address this issue a stroke was induced in 3-month-old C57B1/6 mice by a middle cerebral artery occlusion (MCAO). To verify long-term changes of adult neurogenesis the thymidine analogue BrdU (5-Bromo-2'-deoxyuridine) was administrated at different time points during aging. One and half months after BrdU injections learning and memory performance were assessed with a modified version of the Morris water maze (MWM) that includes the re-learning paradigm, as well as hippocampus-dependent and -independent search strategies. After MWM performance mice were transcardially perfused. To further evaluate in detail the stroke-mediated changes on stem- and progenitor cells as well as endogenous proliferation nestin-green-fluorescent protein (GFP) mice were used. Adult nestin-GFP mice received a retroviral vector injection in the hippocampus to evaluate changes in the neuronal morphology. At an age of 20 month the nestin-GFP mice were transcardially perfused after MWM performance and BrdU application 1.5 months later. The early stroke lesion significantly decreased neurogenesis in 7.5- and 9-month-old animals and also endogenous proliferation in the latter group. Furthermore, immature doublecortin (DCX)-positive neurons were reduced in 20-month-old nestin-GFP mice after lesion. All MCAO groups showed an impaired performance in the MWM and mostly relied on hippocampal-independent search strategies. These findings indicate that an early ischemic insult leads to a dramatical decline of neurogenesis during aging that correlates with a premature development of hippocampal-dependent deficits. Our study supports the notion that an early stroke might lead to long-term cognitive deficits as observed in human patients after lesion.