Buller-Peralta Ingrid, Diaz Javier, Gonzalez Valeria, Bassi Alejandro, Ocampo-Garcés Adrian, Valdés José L
Laboratorio de Sueño y Cronobiología, Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.
Departamento de Neurociencia, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Eur J Neurosci. 2025 Jul;62(1):e70189. doi: 10.1111/ejn.70189.
Posttraumatic stress disorder (PTSD) is a pathological condition mainly characterized by the inability to extinct fear responses associated with a traumatic event and profound alteration in REM sleep. A decrease in the activity of dopaminergic neurons of the ventral tegmental area (VTA) after trauma has emerged as a potential neurophysiological substrate for PTSD development through reciprocal interactions between fear extinction and REM sleep. We disinhibited the neuronal activity of the VTA by blocking GABA transmission immediately after a foot shock trauma. Rats were treated during a six-hour sleep recording with bilateral microinjections of picrotoxin or vehicle. A group of picrotoxin and REM sleep deprivation was included to test the role of REM sleep. Conditioned fear was tested 24 h following a 5-day fear extinction protocol, after which extinction learning was evaluated before another 6 h of sleep recording. Animals treated with picrotoxin could extinguish fear and did not show REM sleep disturbances compared to vehicle-treated animals. This improvement was REM sleep-dependent, as deprived rats evidenced similar REM sleep decrease and memory fear extinction impairments compared to the vehicle group. The effect on REM sleep was achieved by preserving the number of bouts but not increasing their duration, suggesting a protective effect over the ability to transition towards REM. Our results suggest that the disinhibition of dopaminergic neurons during a critical window after trauma could reduce the REM sleep and memory fear extinction disturbances induced by trauma, opening new avenues for therapeutic interventions.
创伤后应激障碍（PTSD）是一种病理状态，主要特征为无法消除与创伤事件相关的恐惧反应以及快速眼动睡眠（REM睡眠）的深刻改变。创伤后腹侧被盖区（VTA）多巴胺能神经元活动的降低，已成为PTSD发展的潜在神经生理基础，这是通过恐惧消退与REM睡眠之间的相互作用实现的。我们在足部电击创伤后立即通过阻断γ-氨基丁酸（GABA）传递来解除VTA的神经元活动抑制。在六小时的睡眠记录期间，对大鼠进行双侧微量注射印防己毒素或赋形剂治疗。纳入一组接受印防己毒素和REM睡眠剥夺处理的大鼠，以测试REM睡眠的作用。在进行为期5天的恐惧消退实验方案后24小时测试条件性恐惧，之后在另外6小时的睡眠记录之前评估消退学习情况。与接受赋形剂治疗的动物相比，接受印防己毒素治疗的动物能够消除恐惧，并且未表现出REM睡眠障碍。这种改善依赖于REM睡眠，因为与赋形剂组相比，剥夺REM睡眠的大鼠表现出类似的REM睡眠减少和记忆恐惧消退受损。对REM睡眠的影响是通过保持发作次数而非增加其持续时间实现的，这表明对向REM睡眠转换能力具有保护作用。我们的结果表明，创伤后关键期内多巴胺能神经元的去抑制作用可减少创伤诱导的REM睡眠和记忆恐惧消退障碍，为治疗干预开辟了新途径。
