以Aβ为靶点治疗阿尔茨海默症（AD）的药物都没通过临床前期测试，亟待寻找早期诊断和防治AD的新靶点。轻度认知障碍（MCI）与突触及神经环路异常早于Aβ斑出现已引起关注，但AAIC于2016年呼吁关注更早出现的包括情绪、社交和冲动控制等异常的轻度行为障碍（MBI），强调通过痴呆前的行为找到早期诊断的指标，但对MBI的界定及其生物标记物的研究尚不清晰，与MBI相关的神经环路的研究更是匮乏。前额叶皮层是AD患者最早受损的脑区，前额叶—纹状体环路在脑高级功能中作用重要。本项目将在3-5月龄AD小鼠模型，1）确定痴呆前期MBI的表征及年龄段；2）揭示前额叶—纹状体环路电活动的异常及其与MBI的关系；3）揭示前额叶—纹状体环路电活动异常的机理，尤其是GABA信号通路异常的分子机制； 4）干预GABA通路的靶点改善前额叶—纹状体环路活动和MBI；为用于AD早期诊断的MBI标准的确定及干预靶点提供依据。

The hallmark of Alzheimer's disease (AD) is characterized by accumulation of extracellular beta-amyloid (Aβ) plaques in the brain. Although much focus has been giving to Aβ in trying to understand the pathogenesis and treatment of AD, All anti-Aβ treatment showed failed clinical trials thus far. Though MCI and abnormal neuronal circuits have been suggested to be the early symptoms of AD, the Alzheimer’s Association International Conference 2016 (AAIC 2016) introduced and described a new condition or patient status, Mild Behavioral Impairment (MBI), that may be a forerunner of neurodegeneration and progression to mild cognitive impairment (MCI) or dementia, and propose utility of the MBI‐Checklist once it is refined. However the MBI-C, underlying neural circuits and biomarkers remain largely unknown. Prefrontal cortex (PFC) is the early target in AD pathogeneesis, and PFC-striatum (Str) pathway plays important role in higher brain function and behavior. The study aims to elucidate 1) Predemential MBI in 3-5 months old AD mice that have not display any abnormal cognition to help the development of MBI-C. 2) Evaluate the oscillative and synaptic activities in the PFC-Str pathway. 3) Uncover the molecular and cellular mechanisms underlying MBI and abnormal electrical activities, with an emphasis of GABAergic signaling pathway. 4) Rescue MBI and PFC-Str electrical activity by targeting GABAergic pathway. In the end, we will establish experimental evidences and mechanisms of MBI, providing with potential biomarker and target for early diagnosis and treatment of AD.