Altered Heterosynaptic Plasticity Impairs Visual Discrimination Learning in Adenosine A1 Receptor Knock-Out Mice
Altered Heterosynaptic Plasticity Impairs Visual Discrimination Learning in Adenosine A1 Receptor Knock-Out Mice
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DOI：
10.1523/jneurosci.3073-20.2021
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发表时间：
2021-05-26
影响因子：
5.3
通讯作者：
Volgushev, Maxim
中科院分区：
文献类型：
--
作者：
Chasse, Renee;Malyshev, Alexey;Volgushev, Maxim
理论和模型研究表明，异突触的可塑性-在诱导过程中不活跃的突触的变化-促进了Hebbian型系统中的细粒度区分学习，并有助于实现稳健的重复学习能力。缺乏选择性操作的工具阻碍了对异突触可塑性在行为中所起作用的实验分析。在这里，我们通过测试对腺苷A1受体(A1Rs)的实验操作造成的异突触可塑性损害的行为后果的特定预测来绕过这一障碍。我们先前的工作表明，阻断腺苷A1受体会损害脑片的异突触可塑性，当在计算机模型中实施时，选择性地损害连续任务的重复学习。基于这项工作，我们预测A1R基因敲除(KO)小鼠将表现出(1)异突触可塑性受损和(2)在连续任务中学习的行为缺陷。通过脑片电生理实验和动物行为学测试，我们发现，与野生型对照相比，A1R KO小鼠视皮层神经元突触可塑性受损，视觉辨别学习能力明显下降。A1R基因敲除的缺陷在重新学习过程中特别明显，随着对日益复杂的顺序视觉辨别任务的学习，这种缺陷变得越来越明显。这些行为结果证实了我们的模型预测，并为异突触可塑性在生物体水平学习中的作用提供了第一个实验证据。此外，这些结果表明，异突触可塑性是干预的一个新的潜在目标，可能有助于在现有记忆的背景下加强新的学习。
Theoretical and modeling studies demonstrate that heterosynaptic plasticity-changes at synapses inactive during induction-facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about the behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1Rs). Our prior work demonstrated that the blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work, we predict that A1R knock-out (KO) mice will express (1) impairment of heterosynaptic plasticity and (2) behavioral deficits in learning on sequential tasks. Using electrophysiological experiments in slices and behavioral testing of animals of both sexes, we show that, compared with wild-type controls, A1R KO mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R knockouts were seen specifically during relearning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in organism-level learning. Moreover, these results identify heterosynaptic plasticity as a new potential target for interventions that may help to enhance new learning on a background of existing memories.