Exercise Prevents Stress-Induced Memory Impairments

描述（由申请人提供）：压力源暴露是精神疾病如抑郁、焦虑和创伤后应激障碍（PTSD）发展的主要原因。与压力相关的精神疾病伴随着学习和记忆障碍。例如，患有创伤后应激障碍的人可能会对创伤事件表现出扭曲的记忆，包括碎片化记忆、健忘症和闪回。此外，创伤后应激障碍患者表现出对轻度压力源的恐惧和/或敏感。虽然应激源暴露可以改变学习和记忆过程是明确的，但应激诱导的健忘症、泛化和敏化的机制仍然是难以捉摸的。此外，能够提供抗压力相关精神疾病（包括创伤后应激障碍）发展的复原力的因素仍然未知。体育活动是一种行为操纵，可以减少包括创伤后应激障碍在内的焦虑症的发病率和严重程度。大鼠的自愿运动还可以抵抗应激源暴露的行为影响，并可以改善海马依赖的学习和记忆过程。然而，运动与学习和记忆压力之间的相互作用还有待研究。大鼠暴露于急性的、不可预测的压力源，表现出1)对压力源背景的健忘症，2)恐惧泛化，3)对新压力源的敏感性。压力源暴露的这些特殊后果取决于压力源的不可预测性，持续数周，类似于人类创伤后应激障碍的长期症状。海马功能障碍可能导致压力诱导的学习和记忆障碍，使其难以区分安全环境和危险环境[1,2]。事实上，我们的初步数据表明，压力诱发的健忘症可能是由通常发生在海马体中的压力源背景的记忆巩固中断引起的。此外，较弱的情境记忆会导致更大的恐惧泛化。六个星期的滚轮运动可以预防压力引起的健忘症，这可能是通过加强海马体对压力源背景的依赖记忆的能力来实现的。去甲肾上腺素（NE）和脑源性神经营养因子（BDNF）是运动后海马依赖性学习和记忆改善的两个因素。轮跑增加海马NE和BDNF的含量，运动诱导的BDNF的增加是通过NE和2-肾上腺素能受体依赖的机制发生的。基于这些数据，我们假设1)应激诱导的恐惧泛化和敏化依赖于海马依赖性的应激源背景巩固的破坏；2)应激源暴露前的锻炼通过2-肾上腺素能受体依赖机制防止应激诱导的健忘症、泛化和敏化。

DESCRIPTION (provided by applicant): Stressor exposure is a primary causal factor in the development of psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Stress-related psychiatric disorders are accompanied by disturbances in learning & memory. Individuals with PTSD, for example, can display distorted memory of the traumatic event, including fragmented memory, amnesia, & flashbacks. In addition, PTSD sufferers display generalization of fear &/or sensitization to mild stressors. Although it is clear that stressor exposure can alter learning & memory processes, the mechanisms underlying stress-induced amnesia, generalization, & sensitization remain elusive. Additionally, factors that can provide resilience against the development of stress-related psychiatric disorders including PTSD remain unknown. Physical activity is one behavioral manipulation that can reduce the incidence & severity of anxiety disorders, including PTSD. Voluntary exercise in rats also provides resistance against behavioral effects of stressor exposure & can improve hippocampal- dependent learning & memory processes. The interactions between exercise & stress on learning & memory have, however, yet to be investigated. Rats exposed to an acute, unpredictable stressor, display 1) amnesia of the stressor context, 2) fear generalization, & 3) sensitization to novel stressors. These particular consequences of stressor exposure are dependent on the unpredictability of the stressor, persist for weeks, & resemble long- lasting symptoms of human PTSD. Hippocampal dysfunction could contribute to stress-induced learning & memory impairments by making it difficult to distinguish safe contexts from dangerous ones [1, 2]. Indeed, our preliminary data indicate that stress-induced amnesia can be caused by a disruption in consolidation of the memory of the stressor context that typically occurs in the hippocampus. Additionally, weaker context memories can lead to greater generalization of fear. Six wk of wheel running prevents stress-induced amnesia, perhaps by improving the ability to consolidate the hippocampal-dependent memory of the stressor context. Norepinephrine (NE) & brain-derived neurotrophic factor (BDNF) are 2 factors that could contribute to improved hippocampal-dependent learning & memory following exercise. Wheel running increases NE & BDNF content in the hippocampus & the exercise-induced increase in BDNF occurs via a NE & 2-adrenergic receptor- dependent mechanism. Based on these data, we hypothesize that 1) stress-induced fear generalization & sensitization are dependent on disruption of hippocampal-dependent consolidation of the stressor context & 2) exercise prior to stressor exposure prevents stress-induced amnesia, generalization, & sensitization through a 2-adrenergic receptor-dependent mechanism. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to investigate the protective effects of physical activity against stress-induced learning and memory impairments, focusing specifically on interactions between the 2 adrenergic receptor, brain-derived neurotrophic factor, and the hippocampus. The results of this work will improve our basic understanding of the effects of stressor exposure on learning and memory processes and the neurobiology of stress-related psychiatric disorders, and could lead to novel therapeutic strategies to prevent or reverse the detrimental consequences of stressor exposure on mental health.