Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.
Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.
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DOI：
10.1002/hipo.22535
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发表时间：
2016-04
期刊：
影响因子：
3.5
通讯作者：
Bizon JL
中科院分区：
文献类型：
--
作者：
Montgomery KS;Edwards G 3rd;Levites Y;Kumar A;Myers CE;Gluck MA;Setlow B;Bizon JL
β-淀粉样蛋白升高和海马突触功能受损是阿尔茨海默病 (AD) 的最早表现之一。然而，人类和动物模型中采用的大多数认知评估对这种早期疾病病理不敏感。海马功能的一个关键方面是它在情景记忆中的作用，这涉及到时间上一致的感觉信息（例如，景象、气味和声音）的结合，以创建特定学习时期的表示。这些不同的感官刺激之间可以形成灵活的关联，从而能够在各种环境中“迁移”新的学习内容。目前的研究采用了关联“迁移学习”任务的小鼠模拟，该任务此前曾被用于识别人类前驱 AD 的风险。该任务的啮齿动物版本评估了一系列复合歧视问题中与食物奖励相关的刺激特征的学习迁移。预测食物奖励的相关特征在问题中保持不变，但不相关的特征（即上下文）发生了变化。实验1证明，双侧海马有鹅膏蕈酸损伤的C57BL6/J小鼠能够与对照小鼠一样区分两种刺激；然而，受损小鼠无法将这种学习转移或应用到新的问题配置中。实验 2 使用 APPswePS1 淀粉样变性小鼠模型表明，在海马中由 β 淀粉样蛋白诱导的细微突触缺陷的小鼠中，迁移学习的严重损害是明显的。最后，实验 3 证实，在 APPswePS1 小鼠中观察到的相同迁移学习障碍在 Tg-SwDI 小鼠（另一种淀粉样变性模型）中也很明显。总之，这些数据表明，即使存在微妙的海马功能障碍，将学习关联推广到新环境的能力也会受到破坏，并表明，在不同物种中，海马依赖性学习的这一方面可能有助于早期识别 AD 样病理。
Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer’s disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the “transfer” of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative “transfer learning” task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswePS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.