在创伤后应激障碍模型中,刺激内侧-海马消减回路可促进恐惧消减。

Ze-Jie Lin,Xue Gu,Wan-Kun Gong,Mo Wang,Yan-Jiao Wu,Qi Wang,Xin-Rong Wu,Xin-Yu Zhao,Michael X Zhu,Lu-Yang Wang,Quanying Liu,Ti-Fei Yuan,Wei-Guang Li,Tian-Le Xu
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摘要

创伤后应激障碍(PTSD)的有效心理治疗仍然具有挑战性,因为恐惧消退的过程非常脆弱,而腹侧海马 CA1(vCA1)区被认为是恐惧消退的中心枢纽。然而,实施恐惧消退的核心途径和细胞机制均不为人所知。在这里,我们揭示了一条直接通路,即外侧内侧皮层(LEC)的2a层扇形细胞以vCA1区的副发光素表达中间神经元(PV-INs)为目标,在绝迹学习过程中推动LEC-vCA1活动的低伽马波段同步。对海马PV-INs或LEC扇形细胞的双向操作都足以使恐惧消退。通过脑深部刺激(DBS)或无创经颅交变电流刺激(tACS)对LEC进行伽马夹带vCA1,可持续增强vCA1中的PV-IN活动,从而促进恐惧的消退。这些结果表明,LEC-vCA1通路形成了一种自上而下的模式,赋予低γ波段振荡以力量,从而促进恐惧的消退。最后,应用低伽马DBS和tACS对持续性创伤后应激障碍小鼠模型进行治疗显示出了强大的疗效,这表明专用的LEC-vCA1通路可用于刺激治疗,以消除创伤记忆痕迹。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Stimulation of an entorhinal-hippocampal extinction circuit facilitates fear extinction in a post-traumatic stress disorder model.
Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhanced the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD showed potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be stimulated for therapy to remove traumatic memory trace.
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