Pathophysiological evidence from temporal lobe epilepsy models highlights the hippocampus as the most affected structure due to its high degree of neuroplasticity and control of the dynamics of limbic structures, which are necessary to encode information, conferring to it an intrinsic epileptogenicity. A loss in this control results in observable oscillatory perturbations called fast ripples, in epileptic rats those events are found in CA1, CA3, and the dentate gyrus (DG), which are the principal regions of the trisynaptic circuit of the hippocampus. The present work used Granger causality to address which relationships among these three regions of the trisynaptic circuit are needed to cause fast ripples in CA1 in an in vivo model. For these purposes, male Wistar rats (210–300 g) were injected with a single dose of pilocarpine hydrochloride (2.4 mg/2 µl) into the right lateral ventricle and video-monitored 24 h/day to detect spontaneous and recurrent seizures. Once detected, rats were implanted with microelectrodes in these regions (fixed-recording tungsten wire electrodes, 60-μm outer diameter) ipsilateral to the pilocarpine injection. A total of 336 fast ripples were recorded and probabilistically characterized, from those fast ripples we made a subset of all the fast ripple events associated with sharp-waves in CA1 region (n = 40) to analyze them with Granger Causality. Our results support existing evidence in vitro in which fast ripple events in CA1 are initiated by CA3 multiunit activity and describe a general synchronization in the theta band across the three regions analyzed DG, CA3, and CA1, just before the fast ripple event in CA1 have begun. This in vivo study highlights the causal participation of the CA3 back-projection to the DG, a connection commonly overlooked in the trisynaptic circuit, as a facilitator of a closed-loop among these regions that prolongs the excitatory activity of CA3. We speculate that the loss of inhibitory drive of DG and the mechanisms of ripple-related memory consolidation in which also the CA3 back-projection to DG has a fundamental role might be underlying processes of the fast ripples generation in CA1.

中文翻译：

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CA3 反投影到齿状回的因果关系及其在 CA1 快速纹波生成中的作用

来自颞叶癫痫模型的病理生理学证据强调，海马体是受影响最严重的结构，因为它具有高度的神经可塑性和对边缘结构动力学的控制，而边缘结构是编码信息所必需的，赋予其内在的致癫痫性。这种控制的丧失会导致可观察到的称为快速波动的振荡扰动，在癫痫大鼠中，这些事件出现在 CA1、CA3 和齿状回 (DG) 中，这些区域是海马三突触回路的主要区域。目前的工作使用格兰杰因果关系来解决体内模型中需要三突触回路的这三个区域之间的哪些关系来引起 CA1 中的快速波动。为此，将雄性 Wistar 大鼠（210-300 g）的右侧侧脑室注射单剂量盐酸毛果芸香碱（2.4 mg/2 µl），并每天 24 小时进行视频监测，以检测自发性和复发性癫痫发作。一旦检测到，就在毛果芸香碱注射同侧的这些区域（固定记录钨丝电极，外径 60 μm）植入微电极。总共记录了 336 个快速波纹并进行了概率表征，从这些快速波纹中，我们制作了与 CA1 区域 (n = 40) 中的尖波相关的所有快速波纹事件的子集，以使用格兰杰因果关系对其进行分析。我们的结果支持现有的体外证据，其中 CA1 中的快速脉动事件是由 CA3 多单元活动引发的，并描述了在 CA1 中的快速脉动事件发生之前，DG、CA3 和 CA1 三个分析区域的 θ 带的一般同步。开始了。这项体内研究强调了 CA3 反向投射到 DG 的因果参与，这是三突触回路中经常被忽视的连接，它是这些区域之间闭环的促进者，延长了 CA3 的兴奋活性。我们推测 DG 抑制驱动力的丧失以及与纹波相关的记忆巩固机制（其中 CA3 对 DG 的反投影也发挥着根本作用）可能是 CA1 中快速纹波生成的潜在过程。