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摘要：焦虑和抑郁症是人群中最常见的情绪情感障碍，而情绪和情感的神经机制是公认的重大科学问题之一。本研究利用小鼠作为模式动物，研究焦虑和抑郁症的神经环路和分子机理这个关键科学问题，通过多学科交叉，分为三个研究展开，试图从分子到个体多层次研究焦虑和抑郁症行为的神经生物学机制。 本研究第一个子研究是动物焦虑和抑郁行为的细胞生理学研究。五羟色胺（5-HT）系统紊乱会导致焦虑、快感缺失和抑郁，而且5-HT转运体是现有的治疗抑郁得主要靶点，因此在第一个子研究中，研究组成员研究了激活脑内5-HT主要来源的背侧中缝核（DRN）5-HT细胞的行为效果。通过运用光遗传学、清醒动物单细胞记录、药理学、转基因小鼠遗传操作、以及多种行为学分析，发现激活DRN的5-HT细胞产生强烈的奖赏效应，而且此一效应通过5-HT以及谷氨酸这两种神经递质来完成。这些结果证明中缝背核直接介导奖赏效应，而且为从多神经递质的角度分析中缝背核的功能提供了良好的开端；为快感缺失及其相关的抑郁、精神分裂等情绪紊乱和精神疾病症候群的机理和治疗揭示了新的途径。 本研究第二个子研究主要研究生物节律对人类情绪等行为的影响。生物节律包括近日节律（昼夜）、近月节律（潮汐）、近年节律（季节）等等周期在生物体内的表征。我们重点研究对象是近日周期、近年周期，与人类情绪调控的互作。本年度报告中，我们主要在三个方面有明显进展：1. 近年节律对情绪调控的影响方面，我们发现小鼠C3H品系对于模拟人类季节性抑郁症方面有较好的吻合；2. 近日节律对情绪调控的影响方面，我们发现VTA脑区的生物钟基因Bmal1和Clock都有很重要的作用；3. 药物治疗方面，我们运用高通量方面对约9000个化合物进行了筛选，找到了一批生物钟调节相关的化合先导物，可能为通过对生物钟进行调节进而缓解人类情绪疾病提供一种崭新的尝试。 本研究的第三个子研究开展与动物焦虑和抑郁行为相关的神经环路的影像学研究。初步完成了焦虑和抑郁神经环路的影像学研究方法和平台的建立，有效开展了去甲肾上腺素（NE）和肾上腺素（E）神经细胞的全脑连接和投射研究以及光功能成像研究，完成了大脑阿片-促黑素细胞皮质素原（POMC）神经细胞的功能研究。 以上研究在过去的一年中，圆满完成了本研究的年度计划，且为下一年度有效开焦虑和抑郁症的神经生物学研究打下了坚实的基础。
关键词：焦虑， 抑郁， 神经环路， 分子机制，光学成像， 电生理，钙成像，昼夜节律
Neural circuits and molecular mechanisms underlying anxiety and depression
Abstract：Anxiety and depression are common human emotion and mood disorders， and their underlying neural mechanisms remain largely unknown. In this project， we plan to use mouse as the model system to study the neural circuits and molecular mechanisms of anxiety and depression， at the levels ranging from molecules to animal behaviors. The first team carries out the cellular physiological studies of animal anxiety and depression. The malfunctions of the serotonin （5-HT） system are related to anxiety， anhedonia， and depression. We examined the behavioral effects of activating 5-HT neurons in the dorsal raphe nucleus （DRN）， the major source of 5-HT in the forebrain. By combining optogenetics， single-unit recordings， pharmacology， mouse genetic， and behavioral assays， we find that the activation of DRN 5-HT neurons produces strong reward signals that are mediated through the release of 5-HT and glutamate. Our results demonstrate that the DRN directly mediates reward， provides new insights into the intervention of depression and schizophrenia， which often manifest as the disorders of emotion and mood. The second team mainly focus on the interactions between circadian/circannual rhythms and the mood regulation. Here we present some substantial progresses on three aspects. First， we discovered that the C3H mouse strain is particularly suitable for studying seasonal affective disorders （SAD）， highlighting the light-entrainment， or seasonal-mimicking， in mood regulation. Second， we found that the deletion of Bmal1 or Clock gene in the brain VTA area developed a counter-depression effect in mice， suggesting the engagement of the circadian clock in mood regulation. Finally， we have developed a cell-based high-throughput screen assay to identify clock modifier drugs， which are potentially useful to cure or relieve the mood disorders such as depression in humans. The third team is tasked to perform optical imaging studies of the neural circuits. We have established the optical methods and platforms to study the neural circuits underlying anxiety and depression， carried out the preliminary experiments of studying the whole-brain projection patterns as well as calcium imaging of NE/E neurons in the brain. In addition， we have completed the study of the behavioral functions of POMC neurons in the adult brain. In summary， we are smoothly on the track of our research schedules， and are well-positioned to make more exciting findings in the future years.
Keywords：Anxiety， Depression， Neural Circuit， Molecular mechanisms， Optical imaging， Electrophysiology， Calcium imaging， Circadian Rhythm
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关键词：焦虑， 抑郁， 神经环路， 分子机制，光学成像， 电生理，钙成像，昼夜节律
Neural circuits and molecular mechanisms underlying anxiety and depression
Abstract：Anxiety and depression are common human emotion and mood disorders， and their underlying neural mechanisms remain largely unknown. In this project， we plan to use mouse as the model system to study the neural circuits and molecular mechanisms of anxiety and depression， at the levels ranging from molecules to animal behaviors. The first team carries out the cellular physiological studies of animal anxiety and depression. The malfunctions of the serotonin （5-HT） system are related to anxiety， anhedonia， and depression. We examined the behavioral effects of activating 5-HT neurons in the dorsal raphe nucleus （DRN）， the major source of 5-HT in the forebrain. By combining optogenetics， single-unit recordings， pharmacology， mouse genetic， and behavioral assays， we find that the activation of DRN 5-HT neurons produces strong reward signals that are mediated through the release of 5-HT and glutamate. Our results demonstrate that the DRN directly mediates reward， provides new insights into the intervention of depression and schizophrenia， which often manifest as the disorders of emotion and mood. The second team mainly focus on the interactions between circadian/circannual rhythms and the mood regulation. Here we present some substantial progresses on three aspects. First， we discovered that the C3H mouse strain is particularly suitable for studying seasonal affective disorders （SAD）， highlighting the light-entrainment， or seasonal-mimicking， in mood regulation. Second， we found that the deletion of Bmal1 or Clock gene in the brain VTA area developed a counter-depression effect in mice， suggesting the engagement of the circadian clock in mood regulation. Finally， we have developed a cell-based high-throughput screen assay to identify clock modifier drugs， which are potentially useful to cure or relieve the mood disorders such as depression in humans. The third team is tasked to perform optical imaging studies of the neural circuits. We have established the optical methods and platforms to study the neural circuits underlying anxiety and depression， carried out the preliminary experiments of studying the whole-brain projection patterns as well as calcium imaging of NE/E neurons in the brain. In addition， we have completed the study of the behavioral functions of POMC neurons in the adult brain. In summary， we are smoothly on the track of our research schedules， and are well-positioned to make more exciting findings in the future years.
Keywords：Anxiety， Depression， Neural Circuit， Molecular mechanisms， Optical imaging， Electrophysiology， Calcium imaging， Circadian Rhythm
阅读全文链接（需实名注册）：http：//www.nstrs.cn/xiangxiBG.aspx？id=47928&flag=1