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

 描述（由申请人提供）：情景记忆障碍是老年痴呆症和早期阶段的标志。情景记忆的形成需要两个不同的记忆过程的平衡，模式分离和模式完成在海马齿状回（DG）-CA 3回路。然而，DG中的模式分离对于通过最小化干扰来区分相似的经历是必不可少的，CA 3中的模式完成有助于基于部分线索的记忆检索。对啮齿动物和人类的研究表明，模式分离-完成平衡在衰老和轻度认知障碍的个体中被破坏。虽然结构和功能的改变已被确定在内侧颞叶在老化过程中，模式分离完成不平衡的神经生物学机制知之甚少。该研究旨在将DG-CA 3回路中前馈兴奋-抑制（E-I）平衡的连接变化与衰老中的编码和记忆缺陷联系起来，并确定DG-CA 3回路中前馈E-I平衡的分子恢复是否足以逆转年龄相关的损伤。测试这些假设的关键是我们确定了一个新的前馈E-I平衡，不影响成熟的齿状颗粒神经元的输入特异性连接的分子调节器。使用新开发的病毒系统双向调节齿状颗粒神经元中这种分子机构的水平，我们将以前所未有的空间精度重新设计前馈兴奋和抑制的连接，并询问其对网络水平模式分离机制以及成年和衰老中的编码和记忆精度的影响。这些研究可能会深入了解衰老过程中DG-CA 3回路中编码和记忆精度的基本机制，以及它们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.