Exercise Prevents Stress-Induced Memory Impairments

描述（由申请人提供）：压力源暴露是精神疾病（如抑郁症、焦虑症和创伤后应激障碍（PTSD））发展的主要原因。与压力相关的精神障碍伴随着学习和记忆障碍。例如，患有PTSD的人可以表现出对创伤事件的扭曲记忆，包括碎片记忆，健忘症和闪回。此外，PTSD患者表现出恐惧的泛化和/或对轻度压力源的敏感。虽然压力暴露可以改变学习和记忆过程，但压力诱导的健忘症，泛化和敏化的机制仍然难以捉摸。此外，能够提供抵抗压力相关精神疾病（包括PTSD）发展的弹性的因素仍然未知。身体活动是一种行为操纵，可以降低焦虑症的发病率和严重程度，包括创伤后应激障碍。大鼠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，运动和压力对学习和记忆的相互作用还有待研究。 暴露于急性不可预测的应激源的大鼠显示1）应激源背景的遗忘，2）恐惧泛化，以及3）对新的应激源敏感。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。海马功能障碍可能会导致应激诱导的学习和记忆障碍，使其难以区分安全的环境与危险的环境[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于海马体中通常发生的压力源背景的记忆巩固中断而引起的。此外，较弱的背景记忆可能导致恐惧的更大泛化。六周的转轮跑步可以防止压力诱发的健忘症，这可能是通过提高巩固压力源背景下依赖于记忆的能力。去甲肾上腺素（NE）和脑源性神经营养因子（BDNF）是两种有助于改善运动后大脑依赖性学习和记忆的因素。转轮跑步增加了海马中NE和BDNF的含量，运动诱导的BDNF增加通过NE和2-肾上腺素能受体依赖性机制发生。基于这些数据，我们假设：1）压力诱导的恐惧泛化和敏感化依赖于对压力源背景的大脑皮层依赖性巩固的破坏; 2）压力源暴露前的运动通过2-肾上腺素能受体依赖性机制防止压力诱导的健忘症、泛化和敏感化。 公共卫生相关性：目前的建议的目标是调查身体活动对应激诱导的学习和记忆障碍的保护作用，特别关注2肾上腺素能受体，脑源性神经营养因子和海马之间的相互作用。这项工作的结果将提高我们对压力暴露对学习和记忆过程的影响以及压力相关精神疾病的神经生物学的基本理解，并可能导致新的治疗策略，以预防或逆转压力暴露对心理健康的有害后果。

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.