Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Baton Rouge, Louisiana, USA.
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Genes Brain Behav. 2023 Apr;22(2):e12840. doi: 10.1111/gbb.12840. Epub 2023 Feb 17.
Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Non-Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation-associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non-Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non-Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress-paired context.
压力与情境记忆缺陷有关，而后者可能是创伤后应激障碍患者回避创伤相关情境的原因。这些缺陷可能源于模式分离受损，即背侧海马齿状回-CA3 区（DG-CA3）回路对相似经历的独立表示，这使得个体能够对特定环境刺激做出适当的行为反应。DG 中的神经发生受线粒体活性氧（ROS）产生的控制，并且可能有助于模式分离。在实验 1 中，我们对经历应激后 16 天的大鼠的背侧海马进行了 RNA 测序，这些大鼠分为对捕食者尿液相关情境形成条件性回避（回避者）和不形成回避（非回避者）的两类。加权基因组关联网络分析显示，氧化磷酸化相关基因转录物的表达增加和轴突导向及胰岛素信号相关基因转录物的表达减少与回避行为有关。基于这些数据，在实验 2 中，我们假设回避者与非回避者相比，会表现出更高的海马（HPC）ROS 产生和受损的物体模式分离（OPS）。与非应激对照相比，应激会损害非回避者和回避者的模式分离表现，但令人惊讶的是，与非回避者相比，回避者表现出部分保留的模式分离表现和显著降低的 ROS 产生。在应激大鼠中，较低的 ROS 产生与更好的 OPS 表现相关，但在对照组中，ROS 产生与 OPS 表现无关。这些结果表明，应激后 HPC ROS 产生与模式分离之间存在强烈的负相关，而应激对这些结果变量的影响可能与回避应激相关情境有关。
