The Neurobiology of the Stress Resistant Brain

抗压大脑的神经生物学

• 批准号: 6860148
• 负责人: MONIKA FLESHNER
• 金额: $ 32.32万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6860148
• 关键词: aerobic exercise; amygdala; behavior test; behavior therapy; behavioral /social science research tag; densitometry; dorsal raphe nucleus; electrodes; escape reaction; fear; horseradish peroxidase; immunocytochemistry; laboratory rat; learned helplessness; locus coeruleus; messenger RNA; microdialysis; neural transmission; nonhuman therapy evaluation; nontherapeutic iontophoresis; physiologic stressor; receptor expression; serotonin receptor; serotonin transporter; thalamus; video recording system

DESCRIPTION (provided by applicant): Exposure to stressful events can precipitate and/or exacerbate various types of affective disorders such as depression and anxiety. Physical activity increases stress resistance and reduces depression and anxiety. For example, voluntary freewheel running increases stress resistance and conveys antidepressant/anxiolytic effects in various animal models of affective dysregulation, including "learned helplessness" (LH). LH is an acute behavioral state produced after exposure to uncontrollable, but not controllable, stress. Evidence suggests that LH is due to activation of a neural circuit that produces intense stimulation of serotonin (5HT) neurons of the dorsal raphe nucleus (DRN). This intense 5HT drive results in sensitization of the DRN 5HT system. The neurobiological mechanisms for the protective effect of physical activity on LH remain unknown. Results from our preliminary studies suggest that physical activity (voluntary freewheel running) prevents LH by changing the DRN 5HT response to uncontrollable stress. In the DRN, rats that voluntary freewheel run compared to sedentary (standard housing) controls have an increase in 5HT/1A somatodendritic autoreceptor expression (mRNA & protein), a decrease in 5HT/1B axonal autoreceptor mRNA, and a decrease in serortonin transporter expression (SERT, mRNA & protein). Freewheel running also conveys resistance to stress-induced decreases in DRN 5HT/1A protein expression and results in an attenuation of DRN 5HT neural responses (cFos expression) to uncontrollable stress. The reduction in stress-induced cFos expression is mirrored in a subset of areas that interact with the DRN and are involved with LH, namely the bed nucleus of the stria terminalis (BNST), the locus coeruleus (LC)-A5, and the amygdala (AMG). The changes in neural responses to stress are more robust after 6wks than after 3wks of freewheel running, and 6wks of freewheel running prevents LH behaviors (escape deficit & exaggerated freezing) after uncontrollable stress. The current proposal will test the hypothesis that the protective effect of physical activity on the development of learned helplessness is due to modulation of the DRN 5HT response. Both intra-DRN alterations and modulation of stress-induced interactions of the DRN with the AMG, BNST and LC-A5 could contribute to this effect. Together, these changes may prevent the intense DRN 5HT activation during uncontrollable stress, and/or the subsequent development & expression of LH.

描述(由申请人提供)：暴露在应激性事件中会引发和/或加剧各种类型的情感障碍，如抑郁和焦虑。体力活动增加了抗压性，减少了抑郁和焦虑。例如，在包括“习得性无助”在内的各种情感失调的动物模型中，自愿的自由飞轮运动增加了对压力的抵抗，并传递了抗抑郁/缓解焦虑的效果。黄体生成素是在无法控制的压力下产生的一种急性行为状态。有证据表明，黄体生成素是由于中缝背核(DRN)产生强烈刺激5-羟色胺(5-HT)神经元的神经回路激活所致。这种高强度的5羟色胺驱动导致DRN 5羟色胺系统的敏化。体力活动对黄体生成素的保护作用的神经生物学机制尚不清楚。我们的初步研究结果表明，体力活动(自愿的自由飞轮运动)通过改变DRN 5HT对不可控压力的反应来预防黄体生成素。在DRN中，与安静(标准住房)对照组相比，自由奔跑的大鼠5HT/1A型躯体树突状细胞自身受体的表达(mRNA和蛋白)增加，5HT/1B轴突自身受体的mRNA表达降低，血清素转运体的表达(SERT，mRNA和蛋白)降低。飞轮运动还传递了对压力诱导的DRN 5HT/1A蛋白表达减少的抵抗，并导致DRN 5HT神经反应(CFO表达)对不可控压力的减弱。应激诱导的CFos表达的减少反映在与DRN相互作用并与黄体生成素相关的一部分区域，即终纹床核(BNST)、蓝斑(LC)-A5和杏仁核(AMG)。自由飞轮运动6周后神经反应的变化比自由飞轮运动3周后更强烈，并且6周自由飞轮运动可以阻止失控应激后的黄体生成素行为(逃逸缺陷和过度冻结)。目前的建议将检验这样一个假设，即体育活动对习得性无助发展的保护作用是由于DRN 5HT反应的调节。DRN内的改变和DRN与AMG、BNST和LC-A5应激诱导的相互作用的调制都可能有助于这种效应。综上所述，这些变化可能会阻止在不可控的应激中DRN-5HT的强烈激活，和/或随后的黄体生成素的发展和表达。