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）：确定预防压力相关精神疾病（如抑郁症和焦虑症）的方法至关重要。一种具有确定的压力恢复效果的操纵是锻炼。我们已经观察到，被允许接近跑步轮的大鼠被保护免受不可控制的压力或习得性无助（LH）的抑郁和焦虑样后果。越来越多的证据表明，LH行为是由中缝背核（DRN）5-羟色胺（5-HT）神经元的过度激活和敏化产生的。在应激过程中，DRN 5-HT神经元的过度激活可能导致这些神经元通过DRN中的5-HT 1A抑制性自身受体脱敏而致敏。我们之前的工作和初步研究结果表明，车轮运行通过抑制DRN 5-HT神经元在应激暴露期间的活动和防止5-HT 1A自身受体的脱敏来防止LH。对5-HT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疾病中失调，但通过先前的自愿运动促进。 了解运动的经验是如何传达到DRN，导致压力恢复是本项目的主要目标，对预防压力相关疾病有明确的临床意义。运动是一种独特的行为操纵，可能会招募神经回路，共同导致大脑的独特适应。为了便于识别这些神经回路，我们提出了一种创新的方法，可控/轭不可控轮运行。虽然自愿轮运行与压力恢复有关，强迫运动往往无法产生压力保护作用，尽管相当大的健身效益。这些数据表明，活动或健身本身不足以产生压力恢复力。相反，运动加上“感知控制”的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基质（如内侧前额叶皮层; mPFC），与那些简单地由身体活动本身招募的神经基质（如去甲肾上腺素能系统），在运动产生的压力恢复中。事实上，我们已经观察到，自愿运动招募这两个系统;重复激活这可能有助于增加DRN 5-HT 1A自身受体通过抑制5-HT 1A基因阻遏物弗洛伊德-1的活性。目前的项目测试了以下假设：1）轮跑通过防止DRN 5-HT 1A自身受体脱敏和/或增加应激期间DRN的mPFC抑制来防止LH，2）轮跑对行为和5-HT 1A自身受体的影响取决于运动可控性，和3）mPFC和/或DRN 11-ADR的重复激活有助于5-HT 1A自身受体的增加和车轮运行对LH的保护作用。 公共卫生关系：当前提案的目标是确定运动体验如何传达到中枢神经系统，以产生对抗压力诱导的焦虑的弹性，特别关注集中在5-HT 1A自身受体上的中枢回路。这项工作的结果将提高我们对压力源暴露和运动对5-羟色胺系统影响的基本理解，并可能导致预防或治疗与压力相关的精神疾病的新方法。