Section on Neuroplasticity, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Hippocampus. 2019 Sep;29(9):848-861. doi: 10.1002/hipo.23087. Epub 2019 Mar 13.
Post-traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single-prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long-lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety-like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hr produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, 1 month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety-like behavior. However, GFAP-TK rats, which lacked new neurons, continued to show elevated anxiety-like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 region of the hippocampus paralleled increases in anxiety-like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6-hr daily stress but was not apparent in any hippocampal subregion after 2-hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress-induced anxiety-like behavior.
创伤后应激障碍（PTSD）与焦虑、记忆障碍、恐惧增强和海马体积损失有关，尽管这些变化之间的关系尚不清楚。单一延长应激（SPS）是 PTSD 的一种模型，它将三种应激形式（束缚、游泳和麻醉）结合在一次单一的治疗中，导致长期的行为效应。使用大鼠海马新生神经元的药理学消融，我们研究了海马中的新生神经元在 SPS 的长期结构和行为效应中的作用。在 SPS 后两周，应激大鼠表现出焦虑样行为增加，对新位置物体的偏好降低，无论是否存在新生神经元。每天束缚 2 或 6 小时产生的慢性应激产生了类似的行为效应，也与持续的神经发生无关。在更长的恢复期，SPS 后 1 个月，具有完整神经发生的大鼠已经恢复正常，表现出类似控制水平的焦虑样行为。然而，缺乏新生神经元的 GFAP-TK 大鼠继续表现出升高的焦虑样行为和增强的对焦虑体验的血清皮质酮反应。海马腹侧 CA1 区的体积损失与焦虑样行为的增加平行，在所有早期暴露于 SPS 的大鼠中发生，仅在缺乏成年神经发生的大鼠中在较晚时间点发生。在慢性应激实验中，6 小时/天的慢性应激后，齿状回和 CA1 广泛出现体积损失，但在 2 小时/天的慢性应激后，任何海马亚区都没有明显的体积损失。SPS 对齿状回的细胞增殖没有影响，但应激后一周出生的年轻神经元的存活减少。总之，这些数据表明，新神经元对于强烈的急性应激后正常行为和海马结构的恢复是重要的，并指出 CA1 腹侧区域可能是应激诱导的焦虑样行为的潜在关键介质。
