Dissecting a neural substrate for stress-induced analgesia

摘要 疼痛的情感调节是在不同的情况下选择适当行为的重要机制。 contexts.作为一种适应机制，它可以帮助动物在危及生命的情况下生存。应力诱发 镇痛（SIA）是这样一种现象，其中由诸如以下刺激引起的高应激的情感状态， 捕食者气味，对有害刺激产生镇痛作用。以前的SIA研究表明，压力刺激 增加冻结行为和减少伤害性反应，镇痛的读数。此外， 显示严重依赖于中央杏仁核（CeA）。众所周知，CeA在以下方面发挥着多种作用： 处理对疼痛和恐惧的情绪反应问题是CeA是否参与了生产真正的 镇痛或其引起冷冻的作用使动物对疼痛表现出较少的运动反应。最近 我们的实验室已经发现了两个不同的CeA神经元群体来控制冻结 与镇痛相比。特别是，CeA内的生长抑素阳性细胞（CeASST）已经被发现。 许多研究小组都表明，它可以介导冻结行为，而我们的实验室已经发现了一群细胞， 由全身麻醉剂（CeAGA）激活，其在光遗传学刺激时产生强镇痛。 使用捕食者气味作为SIA的模型，我将评估CeASST冷冻神经元与CeAGA 神经元在这个模型中此外，初步研究表明，CeAGA细胞接受强烈的投射， 杏仁核-梨状核过渡区（AmPir），该区域被称为激活 捕食者的气味因此，我将进一步测试AmPir到CeA电路传递捕食者气味的假设 信息到CeA制作SIA。我将通过使用转基因小鼠品系来实现这些目标， 靶向行为特异性神经群体的病毒策略， 捕食者气味SIA。这一建议将提供新的见解神经回路介导的相互作用 压力和疼痛之间的联系，并推进我们对情绪如何调节疼痛的理解。

ABSTRACT Affective modulation of pain is an important mechanism for selecting appropriate behavior given different contexts. As an adaptive mechanism, it can aid an animal in surviving a life-threatening situation. Stress-induced analgesia (SIA) is such a phenomenon in which an affective state of high stress, induced by such stimuli as predator odor, produces analgesia to noxious stimuli. Previous studies of SIA have shown that stressful stimuli increase freezing behavior and decrease nociceptive responses, a readout of analgesia. Furthermore, SIA was shown to critically depend on the central amygdala (CeA). CeA is known to have a multitude of roles in processing emotional responses to pain and fear. The question is whether CeA is involved in producing true analgesia, or its role on eliciting freezing renders animals to show less motor responses to pain. Recent advances from others and our lab have discovered two distinct CeA neuronal populations for controlling freezing versus analgesia, respectively. Specifically, somatostatin-positive cells within the CeA (CeASST) have been shown by numerous groups to mediate freezing behavior, while our lab has discovered a population of cells activated by general anesthetics (CeAGA) which produces robust analgesia when optogenetically stimulated. Using predator odor as a model of SIA, I will assess the contribution of CeASST-freezing neurons versus CeAGA neurons in this model. Furthermore, preliminary studies revealed that CeAGA cells receive strong projections from a region called the amygdala-piriform transition zone (AmPir), and this region is known to be activated by predator odor. I will therefore further test the hypothesis that the AmPir-to-CeA circuit relays predator odor information to CeA to produce SIA. I will accomplish these aims through the use of transgenic mouse lines and viral strategies to target behaviorally-specific neural populations and optogenetically manipulate them during predator odor SIA. This proposal will provide novel insights into the neural circuits mediating the interplay between stress and pain, and advance our understandings of how emotions modulate pain.