Contributions of hippocampal oxytocin receptors to social recognition

项目摘要 在阿尔茨海默病（AD）的内侧颞叶神经元损失之前， 许多病理变化，包括ABeta和tau的改变、炎症和 小胶质细胞功能和神经回路/突触功能障碍，与轻度 认知障碍（MCI）。功能磁共振成像研究记录了海马活动过度， 齿状回（DG）-CA 3依赖性功能的改变，例如模式分离-模式 MCI和老化期间的完成余额。在行为上，这表现为偶发性（包括 社会）记忆不精确。在电路水平上，DG-CA 3中的兴奋-抑制（E-I）失衡 与这些认知变化有关。此外，抗癫痫药物左乙拉西坦 已显示可降低患有MCI的个体中的DG-CA 3活动过度并改善认知 改善AD小鼠模型的E-I失衡。重要的是，直接光遗传学刺激 或神经活性的化学发生衰减降低淀粉样蛋白负荷 在多种AD小鼠模型中。这些来自人类和小鼠研究的观察结果表明， 减少神经元过度活跃和募集GABA能抑制可能直接 调节淀粉样斑块负荷和记忆障碍。在这里，我们将建立在我们的 初步数据，并将研究促进PV IN募集的分子因子， Ablim 3，可用于增加APPNL-F的DG-CA 3电路中的前馈抑制 敲入AD小鼠模型，降低淀粉样蛋白负荷，降低CA 1活动过度，并改善 社会记忆精确度总之，拟议的目标将利用正在进行的努力， DG-CA 3回路中的催产素受体如何调节父母的社会记忆精度 NIMH Ro 1同时传达了一个新的方向，可以照亮治疗潜力， 利用Ablim 3抑制海马DG-CA 3过度活跃，减少淀粉样蛋白负荷， 提高AD患者社会记忆精度。

Project Summary Prior to neuronal loss in the medial temporal lobe in Alzheimer's disease (AD), there are numerous pathological changes including alterations in ABeta and tau, inflammation and microglial functions and neural circuit/synaptic dysfunction that are associated with a mild cognitive impairment (MCI). fMRI studies have documented hippocampal hyperactivity and alterations in dentate gyrus (DG)-CA3 dependent functions such as pattern separation-pattern completion balance in MCI and during aging. Behaviorally, this manifests as episodic (including social) memory imprecision. At a circuit level, excitation-inhibition (E-I) imbalance in DG-CA3 are associated with these cognitive changes. Furthermore, the antiepileptic drug levetiracetam has been shown to decrease DG-CA3 hyperactivity and improve cognition in individuals with MCI and ameliorate E-I imbalance in AD mouse models. Importantly, direct optogenetic stimulation of parvalbumin basket cells or chemogenetic attenuation of neural activity decreases amyloid load in multiple mouse models of AD. These observations from human and mouse studies suggest that decreasing neuronal hyperactivity and recruiting GABAergic inhibition may directly modulate amyloid plaque burden and memory impairment. Here, we will build on our preliminary data and will investigate how a molecular factor that promotes recruitment of PV INs, Ablim3, maybe harnessed to increase feed-forward inhibition in DG-CA3 circuit of the APPNL-F knock-in mouse model of AD, decrease amyloid load, reduce CA1 hyperactivity, and improve social memory precision. Together, the proposed Aims will leverage ongoing efforts investigating how oxytocin receptors in DG-CA3 circuitry modulate social memory precision in the parent NIMH Ro1 while conveying a new direction that may illuminate the therapeutic potential of harnessing Ablim3 to dampen hippocampal DG-CA3 hyperactivity, reduce amyloid burden and improve social memory precision in AD.