Exercise Prevents Stress-Induced Memory Impairments

描述(由申请人提供)：应激源暴露是精神障碍发展的主要原因，如抑郁、焦虑和创伤后应激障碍(PTSD)。与压力相关的精神障碍伴随着学习和记忆的障碍。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，包括记忆碎片、健忘症和闪回。此外，创伤后应激障碍患者表现出对轻微应激源的一般性恐惧和/或敏感化。虽然很明显，应激源暴露可以改变学习和记忆过程，但应激诱导的健忘症、概括化和敏感化的潜在机制仍然不清楚。此外，对包括创伤后应激障碍在内的应激相关精神障碍的发展提供韧性的因素仍不清楚。体力活动是一种行为操作，可以降低焦虑症的发生率和严重程度，包括创伤后应激障碍。大鼠的自愿运动还能抵抗应激源暴露的行为影响，并能改善海马区依赖的学习和记忆过程。然而，运动和压力对学习和记忆的影响之间的相互作用还有待研究。暴露在急性、不可预测的应激源下的大鼠表现出1)对应激源环境的遗忘，2)恐惧泛化，3)对新应激源的敏感化。这些特定的压力源暴露的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。海马体功能障碍可能会导致压力诱导的学习和记忆损伤，因为它使得区分安全和危险的环境变得困难[1，2]。事实上，我们的初步数据表明，应激诱导的健忘症可能是由于对通常发生在海马体中的应激源背景的记忆巩固的破坏而引起的。此外，较弱的情景记忆可能会导致对恐惧的更大概括。六周的轮子跑可以防止压力诱发的健忘症，这可能是通过提高巩固海马区对应激源环境的记忆的能力。去甲肾上腺素(NE)和脑源性神经营养因子(BDNF)是运动后改善海马区依赖学习记忆的两个因素。跑轮增加了海马区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实现的。基于这些数据，我们假设1)应激诱导的恐惧概化和敏化依赖于海马依赖的应激源环境的巩固的中断；2)应激源暴露前的锻炼通过2-肾上腺素能受体依赖的机制防止应激诱导的健忘、概化和敏化。 公共卫生相关性：本提案的目标是研究体育运动对应激诱导的学习和记忆损伤的保护作用，特别是关注2肾上腺素能受体、脑源性神经营养因子和海马体之间的相互作用。这项工作的结果将提高我们对应激源暴露对学习和记忆过程的影响以及应激相关精神障碍的神经生物学的基本理解，并可能导致预防或逆转应激源暴露对心理健康的有害后果的新的治疗策略。

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.