Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.

中文翻译：

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对前脑缺血的microRNA反应中的海马亚区域差异。

短暂性前脑缺血（如发生心脏骤停和复苏）会导致继发于海马角膜ammonis-1（CA1）的神经元细胞死亡延迟继发的认知功能受损。比较而言，相邻齿状回（DG）中的海马神经元存活，这表明阐明支持缺血性耐受的海马亚区域差异的分子机制可能是开发新的干预措施以改善前脑缺血幸存者预后的关键。MicroRNA（miRNA）是非编码RNA，可调节靶基因的翻译，并已被确立为其他损伤模型的有效治疗靶标。本研究的目的是使用前脑缺血的大鼠模型评估和比较CA1和DG之间的损伤后miRNA图谱。在三个时间点（3小时，24小时和72小时）和基线前脑缺血10分钟后，从大鼠海马切开CA1和DG子区域。对于几种选择的miRNA，包括已知的脑缺血损伤调节剂miR-181a-5p，观察到CA1和DG之间存在明显差异。我们将荧光原位杂交与免疫组织化学进行了复合，以观察响应于损伤的CA1和DG之间mir-181a-5p表达的细胞类型特异性和时间差异。使用已建立的miRNA-mRNA预测算法，我们扩展了对CA1 miRNA失调的观察，以识别关键功能途径作为CA1缺血性脆弱性的潜在调节剂。总之，