星型胶质细胞介导的BLP-vCA1神经环路损伤在阿尔茨海默病抑郁和空间记忆障碍中的作用及干预机制研究

Depression and memory deficit are early clinical manifestations of Alzheimer’s disease (AD), and the former has been shown to accelerate memory deficit and the progression of AD. However, the mechanisms remain unclear. In recent study, we found that AD transgenic mice accompanied by depression-like despair behavior exhibited more severe spatial working memory deficits as well as deposit of Aβ-amyloid (Aβ) in posterior part of basolateral amygdala (BLP). We identified an excitatory input from BLP to ventral hippocampal CA1 (vCA1). Activation of BLP-vCA1 input can rescue despair emotion impaired-spatial learning and memory. Inhibition of the inputs can induce significant encoding deficit during spatial working memory. In addition, functional inhibition of astrocyte-specific GABA transporter GAT3/4 not only ameliorated despair emotion but also spatial working memory impairment of AD transgenic mice. These data suggested the detrimental effects of depression on working memory and a vital role of BLP-vCA1 input and GAT3/4 in the pathogenesis of AD. This study is aimed to investigate and elucidate the effects of depression-aggravated spatial working memory deficit and the underlying mechanisms, including the relationship among Aβ, BLP-vCA1 input impairment, AD-like depression and spatial working memory deficit; whether and how Aβ impairs BLP-vCA1 input via GAT3/4, therefore leading to a consequence of AD-like depression-aggravated spatial working memory deficit. Furthermore, whether activation of BLP-vCA1 input and/or inhibition of GABA transporter can rescue AD-like depression and/or its aggravated working memory deficit will be dissected. The accomplishment of this project will be expected to contribute to the discovery of new idea and novel molecular targets for efficient prevention and treatment of AD.

抑郁和记忆障碍是阿尔茨海默病（AD）早期表现，前者可加速、加重记忆损伤，但机制不明。申请者发现：伴抑郁绝望情绪的AD转基因小鼠工作记忆损伤严重且与杏仁核基底外侧核后部（BLP）β-淀粉样肽（Aβ）沉积相关；激活BLP至腹侧海马CA1（vCA1）环路能逆转绝望情绪所致记忆障碍，抑制该环路降低工作记忆的编辑能力；抑制BLP内星型胶质细胞GABA转运体(GAT3/4)具有改善抑郁和工作记忆障碍的双重效应，提示：抑郁对工作记忆的损伤及BLP-vCA1环路、GAT3/4在AD发病和防治中起重要作用。本项目将探讨AD样抑郁产生及其加重工作记忆损伤的机制，包括Aβ与抑郁、BLP-vCA1环路损伤、工作记忆障碍间的关系；Aβ是否通过GAT3/4损伤BLP-vCA1环路，并在AD样抑郁加重工作记忆障碍中发挥关键作用；增强该环路或抑制GAT3/4能否改善抑郁和或记忆损伤。该项目将为AD防治提供新思路和新靶标。

阿尔茨海默病(AD)是最为常见的神经退行性疾病。临床上，AD患者常表现有焦虑、抑郁等负性情绪，是加重AD认知障碍的风险因素。杏仁核与海马是调控焦虑和抑郁的重要脑区，亦是AD易累脑区。AD病程中，杏仁核较海马更早发生Aβ沉积。本研究项目围绕杏仁核基底外侧核-海马神经环路展开研究，利用环路示踪、光遗传学技术、在体钙信号记录等技术深入解析杏仁核基底外侧核-海马神经环路异质性，揭示杏仁核基底外侧核后部（pBLA）与腹侧海马CA1（vCA1）神经环路具有抗焦虑、抑郁作用；明确了pBLA-vCA1神经环路损伤在AD样焦虑/抑郁中的关键作用；通过蛋白质组学检测，我们描绘了Aβ病变下pBLA内异常蛋白质网络图谱，并发现GAT3/4是Aβ损伤pBLA-vCA1神经环路的关键分子。本课题研究成果有助于深入理解AD的发病机制，并为抗AD治疗提供新的靶标。