The Neurobiology of the Stress Resistant Brain

描述（由申请人提供）：暴露于压力事件可能会诱发和/或加剧各种类型的情感障碍，例如抑郁和焦虑。体育锻炼可以增强抗压能力，减少抑郁和焦虑。例如，自愿的自由轮跑步增加了抗压力能力，并在各种情感失调的动物模型中传达了抗抑郁/抗焦虑作用，包括“习得性无助”（LH）。LH是一种急性行为状态，在暴露于无法控制的压力后产生。有证据表明，LH是由于神经回路的激活，该神经回路产生中缝背核（DRN）的5-羟色胺（5-HT）神经元的强烈刺激。这种强烈的5 HT驱动导致DRN 5 HT系统的敏化。体力活动对LH的保护作用的神经生物学机制仍不清楚。我们的初步研究结果表明，体力活动（自愿自由轮跑）通过改变DRN 5 HT对不可控制的压力的反应来预防LH。在DRN中，与久坐（标准住房）对照组相比，自愿自由轮跑的大鼠具有5 HT/1A体树突自身受体表达（mRNA和蛋白质）的增加，5 HT/1B轴突自身受体mRNA的减少，以及血清素转运蛋白表达（SERT，mRNA和蛋白质）的减少。自由轮跑还传递了对应激诱导的DRN 5 HT/1A蛋白表达降低的抵抗，并导致对不可控制的应激的DRN 5 HT神经反应（cFos表达）减弱。应激诱导的cFos表达的减少反映在与DRN相互作用并与LH相关的区域的子集中，即终纹床核（BNST）、蓝斑（LC）-A5和杏仁核（AMG）。6周后神经对应激反应的变化比3周后的自由轮跑更稳健，并且6周的自由轮跑防止了不可控制的应激后的LH行为（逃避缺陷和过度冻结）。目前的建议将测试这一假设，即身体活动的发展习得性无助的保护作用是由于调制的DRN 5 HT反应。DRN内的改变和DRN与AMG、BNST和LC-A5的应激诱导的相互作用的调节都可能有助于这种效应。总之，这些变化可能会阻止在不可控制的压力期间强烈的DRN 5 HT激活，和/或随后的LH的发育和表达。

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.