The role of the septo-hippocampal cholinergic circuit in regulating hippocampal function

项目摘要 随着人口老龄化，阿尔茨海默病(AD)的患病人数将继续增长。 与阿尔茨海默病(一种神经退行性疾病)相关的主要问题之一是渐进性记忆衰退 这是由于海马区功能缺陷引起的，包括海马区神经发生和 海马区网络活动。广泛的海马体功能的一个主要调节回路被称为隔膜- 海马神经元(SHC)，在AD时易变性。充分的证据表明 SHC胆碱能成分的退变与痴呆的严重程度呈正相关 记忆障碍。海马神经发生和海马网动力学在脑损伤中起重要作用 调节适当的记忆功能。我们的发现表明，调节SHC可以增加海马区 阿尔茨海默病小鼠3个月阶段的神经发生和DG网络动力学受损，突出了 这一关键时期的重要性。我将检验SHC对成人胆碱能调节的假设 阿尔茨海默病患者神经发生和DG动力学受损，刺激胆碱能回路可恢复 神经发生水平和DG动力学。我将使用携带5个AD相关转基因的小鼠模型 (5xFAD)，并在疾病早期(3个月)测试1)成人的SHC胆碱能控制 AD小鼠的神经发生和2)SHC胆碱能控制AD小鼠的齿状回动力学。完成 拟议的工作将建立一种电路特异性机制，调节海马神经发生和 阿尔茨海默病患者的海马区网络动力学研究。最终，模仿已识别的电路机制的基本特征 可能构成一种修复退化大脑的新策略。

Project Summary As our population ages, the number of people inflicted with Alzheimer’s disease (AD) will continue to grow. One of the major problems associated with AD, a neurodegenerative disorder, is progressive memory decline that arises as a result of defective hippocampal functions including hippocampal neurogenesis and hippocampal network activity. A major regulatory circuit of broad hippocampal function is known as the Septo- Hippocampal Circuit (SHC), which is susceptible to degeneration in AD. Ample evidence has shown degeneration of the cholinergic component of the SHC correlates positively with the severity of dementia and memory dysfunction. Hippocampal neurogenesis and hippocampal network dynamics play a crucial role in regulating proper memory function. Our findings suggest that modulating the SHC can increase hippocampal neurogenesis and that DG network dynamics are impaired at the 3 month stage in AD mice, highlighting the importance of this critical time period. I will test the hypothesis that SHC cholinergic regulation of adult neurogenesis and DG dynamics is impaired in AD and that stimulation of the cholinergic circuit can restore neurogenesis levels and DG dynamics. I will use a mouse model that harbors 5 AD related transgenes (5xFAD) and test the early stage of the disease (3 months) for 1) SHC cholinergic control of adult neurogenesis in AD mice and 2) SHC cholinergic control of dentate gyrus dynamics in AD mice. Completion of proposed work will establish a circuit specific mechanism that regulates hippocampal neurogenesis and hippocampal network dynamics in AD. Ultimately, mimicking basic features of identified circuitry mechanisms may constitute a novel strategy to repair the degenerated brain.