Re-engineering excitation-inhibition connectivity to rejuvenate memory circuits in aging

 描述(由申请人提供)：情景记忆障碍是衰老和阿尔茨海默病早期的标志。情景记忆的形成需要海马齿状回(DG)-CA3回路中两个不同的助记过程的平衡，即模式分离和模式完成。然而，DG中的模式分离对于通过最大限度地减少干扰来区分相似经验是必不可少的，而CA3中的模式完成有助于基于部分线索提取记忆。对啮齿动物和人类的研究表明，在年龄增长和轻度认知障碍的个体中，模式分离-完成平衡被打破。尽管在衰老过程中发现了内侧颞叶的结构和功能变化，但模式分离-完成失衡背后的神经生物学机制却知之甚少。这项拟议的研究旨在将DG-CA3回路中前馈兴奋抑制(E-I)平衡的连通性变化与衰老过程中出现的编码和记忆缺陷联系起来，并确定DG-CA3回路中前馈E-I平衡的分子恢复是否足以逆转与年龄相关的损害。检验这些假说的关键是我们识别了一种新的连接分子调节器，它是前馈E-I平衡的基础，不影响成熟齿状颗粒神经元的输入特异性。利用新开发的病毒系统双向调节齿状颗粒神经元中这一分子代理的水平，我们将以前所未有的空间精度重新设计前馈兴奋和抑制基础的连接性，并询问其对成年期和老年期网络水平模式分离机制以及编码和记忆精度的影响。这些研究可能会深入了解DG-CA3回路在衰老过程中编码和记忆精确度的基本机制，以及它们可能如何被靶向逆转与年龄相关的认知障碍。

 DESCRIPTION (provided by applicant): Impairments in episodic memory are a hallmark of aging and early stages of Alzheimer's disease. Episodic memory formation requires a balance of two distinct mnemonic processes, pattern separation and pattern completion in the dentate gyrus (DG)-CA3 circuit of the hippocampus. Whereas, pattern separation in DG is essential to distinguish between similar experiences by minimizing interference, pattern completion in CA3 facilitates the retrieval of memories based on partial cues. Studies in rodents and humans have suggested that pattern separation-completion balance is disrupted in aging and in individuals with mild cognitive impairment. Although structural and functional alterations have been identified within the medial temporal lobe during aging, the neurobiological mechanisms underlying pattern separation-completion imbalance are poorly understood. The proposed research aims to causally link changes in connectivity underlying feed-forward excitation-inhibition (E-I) balance in the DG-CA3 circuit with encoding and memory deficits seen in aging and determine whether molecular restoration of feed-forward E-I balance in DG-CA3 circuitry is sufficient to reverse age-related impairments. Critical to testing these hypotheses is our identification of a novel molecular regulator of connectivity underlying feed-forward E-I balance that does not affect input specificity of mature dentate granule neurons. Using newly developed viral systems to bi-directionally regulate levels of this molecular agency in dentate granule neurons, we will re-engineer connectivity underlying feed-forward excitation and inhibition with unprecedented spatial precision and interrogate its impact on network level pattern separation mechanisms and encoding and memory precision in adulthood and in aging. These studies may generate insights into fundamental mechanisms underlying encoding and memory precision in DG-CA3 circuit in aging and how they may be targeted for reversing age-related cognitive impairments.