NMDA受体拮抗剂和DISC1对猕猴脑网络认知发展的作用机制

NMDA receptor antagonists were used to mimic the schizophrenia in animals. NMDA receptors mediate DISC1 (Disrupted In Schizophrenia) which is associated with increased risk of mental disorders including schizophrenia. NMDA receptor is a potential target of DISC1. Researches on DISC1 mainly have been studied in rodents. However, rodents are lack of well developed prefrontal cortex (PFC) which leads a limitation to study the function of DISC1 in PFC while human’s dorsolateral prefrontal cortex (dlPFC) dysfunction and dysconnectome has been found in schizophrenia. Monkeys have a similar PFC as humans. Our previous study has found that 14-day treatment of NMDA antagonist, PCP (phencyclidine) tended to accelerated brain maturation during late infancy and changed their cognition which showed a mimic of schizophrenia. In the current program, a dual hit model will be established in PCP-treated rhesus monkeys by using “PCP + late stress” method to study the brain connectome, the behaviors including cognition during the development. The possible role of DISC1 in dlPFC will be studied in the monkeys at key time window of the development. It is important to reveal the mechanism of DISC1 in dlPFC function. The data may supply the insight into the role of DISC1 in schizophrenia, and other mental disorders including depression and bipolar disorder. In addition, this study will supply the first data for the further transgenic study in monkeys to establish non-human primate models of human mental diseases.

NMDA受体拮抗剂可用于制备精神分裂症样动物模型，并调控小鼠突触内DISC1水平。DISC1和几种精神疾病的发展相关，NMDA受体是其潜在作用靶点之一。目前研究对象集中在缺乏高度发育的前额叶的啮齿类动物，而精神分裂症患者的显著特点是背外侧前额叶功能失调和脑网络异常。猕猴的前额叶和人类非常相似。我们前期工作发现NMDA受体拮抗剂PCP可加速婴猴大脑发育，并导致成年猕猴认知功能异常，提示可模拟精神分裂症。本项目将采用“PCP+后期应激”方法，从大脑发育的角度继续探讨精神分裂症样猕猴模型的脑网络、行为认知改变，并研究DISC1是否在发育的关键时间节点参与前额叶的神经分子调控。研究DISC1在前额叶中的作用对解析精神分裂症的发病机制和治疗策略意义重大，本研究可望揭示精神分裂症的DISC1基因机制，为未来制备转基因非人灵长类疾病模型奠定基础。同时对抑郁症、双相情感障碍等疾病研究具有重要指导意义。

精神分裂症在人群发病率约为1%，因为缺乏合适的动物模型，给发病机制和治疗研究带来困难。PCP（phencyclidine）为NMDA受体非竞争性拮抗剂，可用于动物实验模拟精神分裂症。本研究采用“PCP+物理、化学两种后期应激”法，在猕猴上探讨非人灵长类拟精神分裂症动物模型。首先采用不同的行为学手段，研究了模型猕猴工作记忆、迂回反应、反转学习等高级认知功能的变化与NMDA受体相关性。并在关键时间节点，多次采集脑影像学数据，采集血液组织，进行分子生物学实验。结果发现低剂量PCP+物理、化学应激在一般行为和学习记忆上反应更强，可作为模拟精神分裂症的猕猴候选模型；低剂量PCP组左侧上扣带回（SCg）和右侧颞中回白质（MTG）发育轨迹与对照组存在显著差异；低剂量PCP组和对照组相比有较多的基因表达差异。项目执行期间，建立了基于视觉信息辨别的触摸屏高级认知任务系统及功能脑成像扫描平台。并在该系统上训练了PCP猕猴，进行NMDA受体药物、DISC1调减药物对随机反转学习及脑功能影像学的作用等研究。此外，在基于灵长类动物模型的潜在干预手段研究上也获得一定的研究成果。共发表标注项目研究论文7篇，申请4项发明专利，其中1项可用于检测猕猴神经功能的专利获授权，正在进行成果转化。该研究可揭示精神分裂症的NMDA受体及DISC1基因调控机制，为临床精神神经疾病寻找治疗、预防策略提供理论基础。对精神分裂症之外的其他精神或神经疾病（抑郁症、双相情感障碍、孤独症等）的研究也具有重要指导意义。