Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tobetsu, 061-0293, Japan.
Neuroscience. 2010 Sep 15;169(4):1705-14. doi: 10.1016/j.neuroscience.2010.06.035. Epub 2010 Jun 25.
Traumatic events during early life may affect the neural systems associated with memory function, including extinction, and lead to altered sensitivity to stress later in life. We recently reported that changes in prefrontal synaptic efficacy in response to extinction trials did not occur in adult rats exposed to early postnatal stress (i.e. footshock [FS] stress during postnatal day 21-25 [3W-FS group]). However, identifying neurocircuitry and neural mechanisms responsible for extinction retrieval after extinction training have not been precisely determined. The present study explored whether synaptic transmission in the hippocampal-medial prefrontal cortex (mPFC) neural pathway is altered by extinction retrieval on the day after extinction trials using electrophysiological approaches combined with behavioral analysis. We also elucidated the effects of early postnatal stress on the synaptic response in this neural circuit underlying extinction retrieval. Evoked potential in the mPFC was enhanced following extinction retrieval, accompanied by reduced freezing behavior. This synaptic facilitation (i.e. a long-term potentiation [LTP]-like response) did not occur; rather synaptic inhibition was observed in the 3W-FS group, accompanied by sustained freezing. The behavioral deficit and synaptic inhibition observed in the 3W-FS group were time-dependently ameliorated by the partial N-methyl-D-aspartate (NMDA) receptor agonist D-cycloserine (15 mg/kg, i.p.). These findings suggest that the LTP-like response in the hippocampal-mPFC pathway is associated with extinction retrieval of context-dependent fear memory. Early postnatal stress appears to induce neurodevelopmental dysfunction of this neural circuit and lead to impaired fear extinction later in life. The present data indicate that psychotherapy accompanied by pharmacological interventions that accelerate and strengthen extinction, such as d-cycloserine treatment, may have therapeutic potential for the treatment of anxiety disorders, including posttraumatic stress disorder.
创伤性事件发生在生命早期可能会影响与记忆功能相关的神经系统，包括遗忘，导致成年后对压力的敏感性发生变化。我们最近报道，在经历早期产后应激（即产后第 21-25 天[3W-FS 组]的足底电击应激）的成年大鼠中，对消退试验的前额叶突触效能的变化并没有发生。然而，负责消退后提取的神经回路和神经机制尚未被精确确定。本研究使用电生理方法结合行为分析，探讨了在消退试验后的第二天进行消退提取是否会改变海马-内侧前额叶皮质（mPFC）神经通路中的突触传递。我们还阐明了早期产后应激对该神经回路中与消退提取相关的突触反应的影响。在消退提取后，mPFC 中的诱发电位增强，同时冻结行为减少。这种突触易化（即长时程增强[LTP]样反应）没有发生；相反，在 3W-FS 组中观察到突触抑制，同时持续冻结。3W-FS 组中观察到的行为缺陷和突触抑制随着时间的推移被部分 N-甲基-D-天冬氨酸（NMDA）受体激动剂 D-环丝氨酸（15mg/kg，腹腔注射）的治疗而逐渐改善。这些发现表明，海马-mPFC 通路中的 LTP 样反应与上下文相关恐惧记忆的消退提取有关。早期产后应激似乎导致该神经回路的神经发育功能障碍，并导致成年后恐惧消退受损。目前的数据表明，伴随药理学干预的心理治疗，如 D-环丝氨酸治疗，可以加速和增强消退，从而具有治疗创伤后应激障碍等焦虑障碍的治疗潜力。
