The Neurobiology of the Stress Resistant Brain

描述（由申请人提供）：暴露于压力事件会引发和/或加剧各种类型的情感障碍，如抑郁和焦虑。体育锻炼可以增强抗压能力，减少抑郁和焦虑。例如，在包括“习得性无助”（LH）在内的各种情感失调动物模型中，自愿自由跑动增加了应激抵抗能力，并传达了抗抑郁/抗焦虑作用。LH是暴露于不可控但不可控的压力后产生的一种急性行为状态。有证据表明，LH是由于神经回路的激活，该神经回路产生强烈刺激中隔核（DRN）的5 -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尚不清楚。我们的初步研究结果表明，体育活动（自愿自由跑动）通过改变DRN - 5HT对不可控压力的反应来预防LH。在DRN中，与久坐不动（标准居住环境）的对照组相比，自愿自由跑的大鼠5HT/1A体树突自受体表达（mRNA和蛋白质）增加，5HT/1B轴突自受体mRNA减少，5 -羟色胺转运蛋白表达（SERT， mRNA和蛋白质）减少。飞轮跑也传递了对压力诱导的DRN 5HT/1A蛋白表达降低的抵抗力，并导致DRN 5HT神经反应（cFos表达）对不可控压力的衰减。应激诱导的cFos表达减少反映在与DRN相互作用并与LH有关的区域，即终纹床核（BNST）、蓝斑核(LC)-A5和杏仁核（AMG）。6周后神经对压力反应的变化比3周后更为强劲，6周的自由跑可以防止失控压力后的LH行为（逃逸缺陷和夸张冻结）。本研究将验证身体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内部的改变和DRN与AMG、BNST和LC-A5的应力诱导相互作用的调节都可能导致这种效应。总之，这些变化可能会阻止DRN 5HT在不可控应激期间的强烈激活，和/或随后的LH的发展和表达。

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.