The Neurobiology of the Stress Resistant Brain

抗压大脑的神经生物学

• 批准号: 8242052
• 负责人: MONIKA FLESHNER
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242052
• 关键词: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Autoreceptors; Behavior; Behavior Control; Behavioral; Brain; Clinical; Data; Development; Exercise; Genes; Goals; Housing; Human; Lead; Learned Helplessness; Medial; Mental Depression; Mental disorders; Neurobiology; Neurons; Perception; Physical activity; Prefrontal Cortex; Prevention; Proteins; Rat Strains; Rattus; Recruitment Activity; Resistance; Role; Running; Serotonin; Stress; System; Testing; Work; behavior test; biological adaptation to stress; density; desensitization; design; dorsal raphe nucleus; experience; fitness; improved; innovation; locus ceruleus structure; mRNA Expression; noradrenergic; novel strategies; prevent; protective effect; psychologic; public health relevance; relating to nervous system; resilience; stress related disorder; stress resilience; stressor

DESCRIPTION (provided by applicant): Identification of means to prevent stress-related psychiatric disorders such as depression & anxiety is of primary importance. One manipulation with established stress resilient effects is exercise. We have observed that rats allowed access to running wheels are protected against the depression- & anxiety-like consequences of uncontrollable stress, or learned helplessness (LH). Growing evidence indicates that LH behaviors are produced by hyperactivation & sensitization of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Hyperactivation of DRN 5-HT neurons during stress could lead to later sensitization of these neurons by desensitizing 5-HT1A inhibitory autoreceptors in the DRN. Results from our prior work & preliminary studies suggest that wheel running prevents LH by constraining the activity of DRN 5-HT neurons during stressor exposure & preventing the desensitization of 5-HT1A autoreceptors. Constraint over 5-HT neural activity could be an adaptive feature of the stress response that is dysregulated in stress-related psychiatric disorders but facilitated by prior voluntary exercise. Understanding how the experience of exercise is communicated to the DRN to result in stress resilience is a primary goal of this project that has clear clinical implications for the prevention of stress-related disorders. Exercise is a unique behavioral manipulation that will likely recruit neurocircuits that together result in unique adaptations in the brain. To facilitate identification of these neurocircuits, we propose an innovative approach of controllable / yoked uncontrollable wheel running. Although voluntary wheel running is associated with stress resilience, forced exercise often fails to produce stress protective effects despite considerable fitness benefits. These data suggest that activity or fitness per se is not sufficient to produce stress resilience. Instead, exercise plus the psychological variable of "perceived control" may be critical. This is an important distinction because it implies involvement of distinct neural substrates involved in the perception of control (such as the medial prefrontal cortex; mPFC), vs. those simply recruited by physical activity per se (such as the noradrenergic system), in the stress resilience produced by exercise. Indeed, we have observed that voluntary exercise recruits both of these systems; repeated activation of which could contribute to the increase in DRN 5- HT1A autoreceptors by inhibiting the activity of the 5-HT1A gene repressor Freud-1. The current project tests the hypotheses that 1) wheel running prevents LH by preventing DRN 5-HT1A autoreceptor desensitization &/or increasing mPFC-inhibition of the DRN during stress, 2) the effects of wheel running on behavior & 5-HT1A autoreceptors are dependent on exercise controllability, & 3) repeated activation of the mPFC &/or DRN 11- ADRs contribute to the increase in 5-HT1A autoreceptors & the protective effect of wheel running against LH. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders.

描述(由申请人提供)：确定预防抑郁症和焦虑症等与压力相关的精神障碍的方法是首要的。一种已被证实具有抗压力效果的手法是锻炼。我们观察到，被允许接触转轮的大鼠受到保护，免受无法控制的压力或习得性无助(LH)造成的类似抑郁和焦虑的后果。越来越多的证据表明，黄体生成素行为是由中缝背核(DRN)中5-羟色胺(5-HT)神经元的过度激活和敏化所产生的。DRN 5-HT神经元在应激过程中的过度激活可能通过脱敏DRN中的5-HT1A抑制性自身受体而导致这些神经元的后期敏化。我们前期工作的结果和初步研究表明，车轮运动通过抑制应激源暴露时DRN 5-HT神经元的活动和防止5-HT1A自身受体的脱敏来防止黄体生成素的生成。对5-羟色胺神经活动的限制可能是应激反应的一种适应性特征，这种应激反应在应激相关的精神障碍中调节失调，但之前的自愿锻炼促进了这种反应。了解锻炼的经验如何传达给DRN以产生应激恢复能力是该项目的主要目标，该项目对预防应激相关疾病具有明确的临床意义。运动是一种独特的行为操作，它可能会招募神经回路，共同导致大脑中独特的适应。为了便于识别这些神经回路，我们提出了一种创新的方法，即可控/带轭不可控车轮运行。尽管自愿跑步与压力恢复能力有关，但强迫运动往往不能产生压力保护效果，尽管它对健康有相当大的好处。这些数据表明，运动或健身本身不足以产生抗压能力。相反，锻炼加上“感知控制”这一心理变量可能是至关重要的。这是一个重要的区别，因为它意味着参与控制感知的不同神经底物(如内侧前额叶皮质；mPFC)，而不是那些仅由身体活动本身招募的神经底物(如去甲肾上腺素系统)，参与运动产生的压力弹性。事实上，我们已经观察到，自愿运动招募了这两个系统；重复激活这两个系统可能通过抑制5-HT1A基因抑制物弗洛伊德-1的活性而导致DRN 5-HT1A自身受体的增加。目前的项目测试的假设是：1)车轮跑通过防止DRN 5-HT1A自身受体脱敏和/或增加应激期间DRN的mPFC抑制来预防黄体生成素，2)车轮运动对行为的影响和5-HT1A自体受体依赖于运动的可控性，3)重复激活mPFC和/或DRN 11-ADR有助于5-HT1A自体受体的增加和车轮跑步对黄体生成素的保护作用。 与公共健康相关：当前提案的目标是确定运动经验如何传递到中枢5-羟色胺能系统，以产生对应激诱导的焦虑的弹性，特别关注汇聚在5-HT1A自身受体上的中央回路。这项工作的结果将提高我们对应激源暴露和运动对5-羟色胺系统影响的基本理解，并可能导致预防或治疗应激相关精神障碍的新方法。