Center for Brain Science, Department of Anesthesiology and Pediatric Clinical Pharmacology Laboratory, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Commun Biol. 2024 Jun 14;7(1):728. doi: 10.1038/s42003-024-06417-w.
Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.
苯二氮䓬类药物，通常用于抗焦虑，会阻碍条件性恐惧的消退，但其潜在的回路机制尚不清楚。利用超短效苯二氮䓬类药物 remimazolam，我们在此揭示了它在恐惧消退期间对丘脑核 reuniens (RE) 和相互连接的海马隔核回路的影响。系统或 RE 特异性给予 remimazolam 通过减少通过 A 型 GABA 受体的 RE 激活来阻碍恐惧消退。Remimazolam 增强了来自外侧隔核 (LS) 到 RE 的长程 GABA 抑制，从而导致恐惧消退受损。RE 投射到腹侧海马 (vHPC)，反过来又向 LS 的 GABA 能神经元发送具有前馈抑制特征的投射。这与来自 LS 到 RE 的长程 GABA 投射相结合，共同构成了促进恐惧消退的整体正反馈回路结构。RE 特异性 remimazolam 通过破坏该回路否定了对恐惧消退的促进作用。因此，RE 中的 remimazolam 破坏了由海马隔核中介引起的恐惧消退，为结合抗焦虑药和基于消退的暴露疗法的困境提供了机制见解。
