选择性敲除多巴胺能神经元内NMDA受体对情绪和记忆的调控研究

The neural regulation of emotional perception, learning,and memory is essential for normal behavioral and cognitive functioning. The neurotransmitter dopamine (DA) and its ability to modulate neural regions involved in emotional learning, perception, and memory formation has received considerable research attention as a potential final common pathway to account for the aberrant emotional regulation and psychosis present in a lot of syndrome of emotional disorders, such as anxiety and depression . Recently, increasing evidence points to the dopaminergic amygdala-prefrontal cortical circuit as an important processor of emotional salient information, encoding and expression of memory. But how the perturbances caused by aberrant genetic-environmental interaction within this circuitry lead to dysregulation of emotion and memory remains uncertain. In our preliminary study, we found the mice with dopaminergic neuron-specific NMDAR1 deletion displayed different levels of anxiety-like behaviors dependent on varied features of stress exposures, which indicated that NMDAR played an important role in the dopaminergic modulation of emotion. Considering childhood brain are immaturely developed and vulnerable to adverse environmental insult, here, we want to explore if and how the neurodevelopmental perturbances in the childhood period effect on emotion regulation caused by NMDA induced dopaminergic modulation under either chronic or acute stress, in order to shed light on the cellular mechanism underpinning emotional deregulations.

伴随环境压力增大，近年焦虑、抑郁等疾病患病率增加，且因幼脑发育不完善导致儿童为本病高危人群。目前认为各种遗传和/或环境因素导致前额叶皮质活动降低同时伴随杏仁核等皮质下脑区活动增强，是焦虑、抑郁、多动症等疾病的根本特质，杏仁核基底外侧部到内侧前额叶皮质的神经环路可塑性改变与其发病关系密切。此外，新近发现中脑腹侧背隔核通过多巴胺（DA）系统也参与情绪和记忆调控，机制不清。我们前期通过构建模式小鼠，选择性敲除中脑DA能神经元内NMDA受体后发现小鼠具有焦虑样表型，且应激时出现焦虑加重、恐惧记忆增强。据此，我们期望进一步明确并比较不同年龄阶段DA能神经元内NMDA受体对情绪和记忆的行为学调控特点及神经生物学机制；同时研究不同应激模式与DA能神经元NMDA受体交互影响情绪和记忆的机制，探讨靶向调控多巴胺神经元的NMDA受体作为新型抗焦虑药物研发策略的可能性.

课题组在本项目（项目号：91232706）资助下，发表了9篇标注项目号的SCI论文，培养/联合培养了5名硕士研究生及1名博士后，项目负责人及成员参加国内/国际会议约十余次，其中特邀报告5次。焦虑、抑郁、多动症等疾病常伴有情绪与记忆异常。中脑腹侧背盖的多巴胺（dopamine, DA）系统参与情绪和记忆调控，但机制不清。我们前期通过选择性敲除中脑多巴胺能神经元的N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate，NMDA）受体，发现：小鼠具有焦虑样行为且应激时焦虑加重、恐惧记忆增强。进一步机制研究中，我们发现中脑DA能神经元内NMDA受体可通过BLA-mPFC环路参与调控情绪和记忆认知，存在很强的环境依赖性；此外，多巴胺通路的稳定性尚参与时间相关的抽象记忆调控。.另外，在焦虑研究过程中，我们发现慢性痛引起的焦虑呈现出焦虑类型和时间进程的依赖性。此外，抗炎或镇痛处理能够显著减低慢性疼痛动物的焦虑表型，阻断LTD的干扰肽能够显著逆转焦虑表型的出现，提示特定脑区的LTD可能是上述病理性情绪行为的关键机制。