利用标记活化神经元研究吗啡激活的伏隔核神经元在成瘾中的作用

The nucleus accumbens is the key brain structure for addiction. Exposure to addictive drugs causes an increase in dopamine release in the brain, leading to neuronal activation and changes in synaptic plasticity in the nucleus accumbens, which are considered as an important mechanism of addiction. However, due to the heterogeneity of the nucleus accumbens, different neural subpopulations respond to rewarding or aversive stimuli differently. It has not been tested whether direct manipulate the activity of nucleus accumbens neurons respond to drugs could affect addiction. We found a neural subpopulation in the nucleus accumbens respond to rewarding stimuli specifically, and speculate that the activation of this neural ensemble may trigger rewarding behavior; the repetitive- and hyper-activation of this neural ensembles may mediate addiction. This project intends to utilize activity dependent tool RAM to label and manipulate the subpopulation of neurons activated by morphine, investigate the neural circuit, as well as the rewarding behavior induced by activation of this neural ensemble; and further observe the potential therapeutic effect by inhibiting this neural ensemble in addiction. This project is important for elaborating the circuit basis of addiction in the nucleus accumbens, and exploring new targets and approaches for addiction treatment.

伏隔核是成瘾的核心脑区。成瘾药物暴露引起脑内多巴胺释放增加，导致伏隔核中神经元活化及突触可塑性改变，被认为是成瘾的重要机制。然而，由于伏隔核神经元的异质性，不同亚群神经元对奖赏或厌恶刺激有着不同的响应。前人的工作中并未探索过直接操纵被成瘾药物所激活的伏隔核神经元活性对于成瘾的作用。我们已发现伏隔核中存在一群特异性响应吗啡的神经元，并推测其活化可能驱动奖赏行为，而这群神经元的重复及过度激活则可能介导个体的成瘾。本课题拟通过活化神经元依赖工具RAM标记并操纵伏隔核中被吗啡所激活的神经元亚群，探索该神经元亚群的神经环路，及激活引起小鼠的奖赏行为；并进一步观察在成瘾过程中抑制伏隔核中改亚群神经元对吗啡成瘾的潜在治疗作用。本课题的开展对于阐明基于伏隔核中成瘾相关的神经环路机制，寻找新的成瘾治疗靶点与方法具有重要意义。

伏隔核是成瘾的核心脑区。成瘾药物暴露引起脑内多巴胺释放增加，导致伏隔核神经元活化及突触可塑性改变，这些变化被认为是成瘾的重要机制。我们发现伏隔核中存在一群特异性响应吗啡的神经元，其投射与被足底电击所激活的神经元不同。相较于足底电击响应神经元，吗啡所激活的神经元更多地投射往奖赏中枢腹侧被盖区；而二者投射往伏隔核最大的下游腹侧苍白球的比例类似。对吗啡暴露小鼠的干预实验中，我们发现混合抗生素可以显著减少吗啡诱导的小鼠成瘾相关行为。对照实验显示，混合抗生素干预不影响小鼠的空间记忆能力、运动能力、焦虑水平，以及吗啡的药代动力学。进一步研究显示，显示抗生素干预降低伏隔核以及腹侧被盖区的c-fos表达，且多巴胺神经递质探针的光纤记录提示伏隔核中多巴胺递质释放量减少。本课题探索了伏隔核中成瘾相关的神经环路机制，并对动物中进行吗啡诱导的药物相关行为进行了干预，进而为寻找新的成瘾临床干预以及药物开发靶点提供了重要线索。.