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）：暴露于压力事件会导致和/或加剧各种类型的情感障碍，例如抑郁和焦虑。体育锻炼会增加压力抗性，并减少抑郁症和焦虑。例如，在各种情感失调的动物模型中，包括“学习的无助性”（LH），自愿自愿施加会增加压力抗性，并传达抗抑郁药/抗焦虑作用。 LH是暴露于无法控制但无法控制的压力后产生的急性行为状态。有证据表明，LH是由于神经回路的激活，该神经回路会产生强烈的刺激背侧raphe核（DRN）的羟色胺（5HT）神经元。这种强烈的5HT驱动导致DRN 5HT系统的敏化。体育活动对LH的保护作用的神经生物学机制仍然未知。我们初步研究的结果表明，通过改变对无法控制的应力的DRN 5HT响应，体育锻炼（自愿自由运动）可以防止LH。在DRN中，与久坐的（标准住房）对照组相比，自愿自愿运行的大鼠增加了5HT/1A体育体自身受体表达（mRNA＆蛋白），5HT/1B轴突自身受体mRNA的降低，而降低了血清转运蛋白转运蛋白（sertporter surment＆Protine），mRNA＆Protin＆Protin＆Protin＆Protin＆Protin＆Protin＆Protin＆Protin＆protin＆Protin＆Protin＆Protine＆Protine）。 freewheel运行还表达了DRN 5HT/1A蛋白表达中应力诱导的降低的抵抗力，并导致DRN 5HT神经反应（CFOS表达）的衰减对无法控制的应激。应力诱导的CFOS表达的降低在与DRN相互作用并与LH相互作用的区域的子集中反映，即Stria derminalis（BNST）的床核（BNST），基因座（LC）-A5和Amygdala（AMG）。在6wks之后的神经反应变化比3WKS自由式训练之后更强大，而6wks的自由式轮往后可以防止LH行为（逃避赤字和夸大的冻结）在无法控制的压力之后。当前的建议将检验以下假设：体育活动对学习无助的发展的保护作用是由于调节了DRN 5HT响应。 DRN的内部变化以及DRN与AMG，BNST和LC-A5的应力诱导相互作用的调节都可能有助于这种效果。这些变化总之可以防止在无法控制的应力期间强烈的DRN 5HT激活和/或随后的LH发育和表达。