BACKGROUND Up to 80% of mesial temporal lobe epilepsy patients with hippocampal sclerosis (mTLE-HS) are resistant to pharmacological treatment, often necessitating surgical resection. Deep brain stimulation (DBS) has emerged as an alternative treatment for patients who do not qualify for resective brain surgery. Brain stimulation may also exert disease-modifying effects, and noncoding microRNAs have recently been proposed to shape the gene expression landscape in epilepsy. OBJECTIVE We compared the effect of DBS of 4 different hippocampal target regions on epileptogenesis and manifest epilepsy in a rat model of mTLE-HS. To explore mechanisms, we profiled the effect of the most effective DBS paradigm on hippocampal microRNA levels. METHODS MTLE-HS was induced by electrical stimulation of the perforant pathway (PP) in rats. This paradigm leads to spontaneous seizures within 4 weeks. We investigated DBS of 4 targets: PP, fimbria fornix (FF) formation, dentate gyrus (DG) and ventral hippocampal commissure (VHC). We applied both high- (130 Hz) and low-frequency (5 Hz or 1 Hz) stimulation. Functional microRNAs were identified in the hippocampus immediately after VHC-DBS and after a 97-day recording period by sequencing small RNAs bound to Argonaute-2, a component of the miRNA silencing complex. RESULTS Low frequency DBS of the VHC significantly delayed the occurrence of the first spontaneous recurrent seizure in the PPS model by ∼300%, from 19 to 56 days. No other stimulation regime altered the latency phase. Upregulation of 5 microRNAs during epileptogenesis was suppressed by VHC-stimulation. CONCLUSION We conclude that DBS of the VHC delays epilepsy in the PPS model in rats and is associated with differential regulation of several miRNAs. Additional studies are required to determine whether VHC-regulated miRNAs serve causal roles in the anti-epileptogenic effects of this DBS model.

中文翻译：

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腹侧海马连合处的电刺激延迟了实验性癫痫，并与改变的 microRNA 表达有关

背景 高达 80% 的颞叶内侧癫痫患者海马硬化 (mTLE-HS) 对药物治疗有抵抗力，通常需要手术切除。深部脑刺激 (DBS) 已成为不符合切除性脑部手术资格的患者的替代治疗方法。脑刺激也可能发挥改善疾病的作用，最近有人提出非编码 microRNA 可塑造癫痫中的基因表达格局。目的我们在 mTLE-HS 大鼠模型中比较了 4 个不同海马靶区的 DBS 对癫痫发生和明显癫痫的影响。为了探索机制，我们分析了最有效的 DBS 范式对海马 microRNA 水平的影响。方法 MTLE-HS 是通过电刺激大鼠穿孔通路 (PP) 来诱导的。这种范式会在 4 周内导致自发性癫痫发作。我们研究了 4 个目标的 DBS：PP、穹窿 (FF) 形成、齿状回 (DG) 和腹侧海马连合 (VHC)。我们同时应用了高频（130 Hz）和低频（5 Hz 或 1 Hz）刺激。在 VHC-DBS 之后和 97 天的记录期后，通过对与 Argonaute-2（miRNA 沉默复合物的一个组成部分）结合的小 RNA 进行测序，在海马中发现了功能性 microRNA。结果 VHC 的低频 DBS 将 PPS 模型中第一次自发性复发性癫痫的发生从 19 天到 56 天显着延迟了约 300%。没有其他刺激方案改变了潜伏期。VHC 刺激抑制了癫痫发生过程中 5 个 microRNA 的上调。结论 我们得出结论，VHC 的 DBS 延迟了大鼠 PPS 模型中的癫痫，并且与几种 miRNA 的差异调节有关。需要额外的研究来确定 VHC 调节的 miRNA 是否在该 DBS 模型的抗癫痫作用中起因果作用。