The contribution of the hippocampus to learned opiate tolerance

项目摘要 阿片类药物治疗疼痛的效用受到耐受性发展的限制，这种现象可能导致剂量- 升级和危险的副作用，如依赖和过量的责任增加。有趣的是， 环境因素与阿片类药物一起使用会极大地影响耐受性。具体来说，动物接受 吗啡在特定情况下表现出镇痛耐受性， 新环境这种关联形式的耐受性背后的细胞和电路机制一直不太清楚 表征了然而，它们在临床上是高度相关的，因为当成瘾者服用大量的 鸦片在新的地方在这个应用中，我们建议解剖相关吗啡耐受的电路 使用现代行为神经科学工具。具体来说，我们将联合收割机与转基因技术相结合， 报告小鼠，以确定特定的神经回路和细胞介导的联想耐受。我们的核心假设 海马体中的特定环境表征与阿片类药物的使用有关， 杏仁核中阻止疼痛抑制的补偿反应。为了验证这个想法，我们将表达光 在特定神经元中的敏感视蛋白，其在联合吗啡耐受的表达期间是活跃的。我们 预测沉默这些细胞将阻止吗啡配对环境中的耐受性。相反，刺激这些细胞， 应该在一个从未与吗啡配对的新环境中诱导耐受性。类似的战略已经 用于识别和操纵杏仁核中编码恐惧记忆的神经元， 海马体、脑桥核中的可卡因记忆和许多其他形式的记忆。然而，对我们的 然而，这种方法从未应用于关联性吗啡耐受。我们认为，这样做将导致 与其他形式的学习和记忆的重大进展相似。

Project Summary The utility of opiates for treating pain is limited by the development of tolerance, a phenomenon that can lead to dose- escalation and an increased liability for dangerous side effects like dependence and overdose. Interestingly, environmental cues that are paired with opiates can dramatically influence tolerance. Specifically, animals that receive morphine in a particular context exhibit analgesic tolerance that can be eliminated by simply administering the drug in a new environment. The cellular and circuit mechanisms underlying this associative form of tolerance have not been well characterized. However, they are highly relevant clinically as many overdoses occur when addicts take large amounts of opiates in a new place. In this application, we propose to dissect the circuitry underlying associate morphine tolerance using modern behavioral neuroscience tools. Specifically, we will combine optogenetic techniques with transgenic reporter mice to identify the specific neural circuits and cells that mediate associative tolerance. Our central hypothesis is that context-specific representations in the hippocampus become associated with opiate use and produce a compensatory response in the amygdala that prevents the inhibition of pain. To test this idea, we will express light sensitive opsins in the specific neurons that are active during the expression of associative morphine tolerance. We predict that silencing these cells will prevent tolerance in a morphine-paired context. Stimulating these cells, in contrast, should induce tolerance in a novel environment that has never been paired with morphine. A similar strategy has been used to identify and manipulate neurons that encode fear memories in the amygdala, spatial memories in the hippocampus, cocaine memories in the nucleus accumbens and many others forms of memory. However, to our knowledge, this approach has never been applied to associative morphine tolerance. We believe that doing so will lead to significant advances like it has for other forms of learning and memory.