Contributions of hippocampal oxytocin receptors to social recognition

海马催产素受体对社会认可的贡献

• 批准号: 10286210
• 负责人: Amar Sahay
• 金额: $ 31.36万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-15 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286210
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Anterior; Antiepileptic Agents; Behavioral; Brain region; Calcium; Calcium-Binding Proteins; Cells; Cognition; Data; Discrimination; Down-Regulation; Equilibrium; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Hippocampus (Brain); Human; Hyperactivity; Image; Individual; Inflammation; Interneurons; Knock-in Mouse; Levetiracetam; Medial; Memory; Memory impairment; Molecular; Mus; Myoepithelial cell; National Institute of Mental Health; Neocortex; Neurons; Oxytocin Receptor; Parents; Parvalbumins; Pathologic; Pattern; Photons; Role; Senile Plaques; Social Interaction; Stimulus; Stratum Lucidum; Temporal Lobe; Testing; Therapeutic; Viral; Work; age related; aged; attenuation; awake; base; calbindin; cingulate cortex; cognitive change; dentate gyrus; entorhinal cortex; granule cell; hippocampal pyramidal neuron; human old age (65+); imaging study; improved; in vivo; inhibitory neuron; long term memory; mild cognitive impairment; mossy fiber; mouse model; neural circuit; neuron loss; optogenetics; parent grant; recruit; relating to nervous system; social; social cognition; tau Proteins; trend; vesicular glutamate transporter 1; β-amyloid burden

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.

项目摘要 在阿尔茨海默病(AD)的内侧颞叶神经元丢失之前，有 大量的病理变化，包括ABeta和tau的变化，炎症和 与轻度阿尔茨海默病相关的小胶质细胞功能和神经回路/突触功能障碍 认知障碍(MCI)。功能磁共振成像研究记录了海马区的过度活动和 齿状回(DG)-CA3依赖功能的改变，如模式分离-模式 MCI和老化期间的完成率平衡。在行为上，这表现为间歇性(包括 社交)记忆不精确。在电路水平上，DG-CA3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 已被证明可以减少DG-CA3多动症并改善MCI患者的认知能力 改善AD模型小鼠E-I失衡。重要的是，直接光遗传刺激 小白蛋白篮子细胞的减少或神经活动的化学生成减弱降低淀粉样蛋白负荷 在AD的多个小鼠模型中。这些来自人类和老鼠研究的观察结果表明 减少神经元过度活动和募集GABA能抑制作用可能直接 调节淀粉样斑块负荷和记忆损伤。在这里，我们将在我们的 初步数据，并将调查促进PV INS招募的分子因素， Ablim3可能被利用来增加APPNL-F的DG-CA3环路的前馈抑制 敲入小鼠阿尔茨海默病模型，降低淀粉样蛋白负荷，减少CA1多动，改善 社交记忆的精确度。总之，拟议的AIMS将利用正在进行的调查工作 DG-CA3回路中的催产素受体如何调节父母的社会记忆精确度 NIMH RO1同时传达了一个新的方向，可能会照亮治疗潜力 利用Ablim3抑制海马DG-CA3过度活动，减轻淀粉样蛋白负荷，并 提高AD中社会记忆的精确度。