Department of Psychological Sciences, University of Connecticut, Storrs, Connecticut 06269.
Murine Behavioral Neurogenetics Facility and Institute of Brain and Behavioral Sciences, University of Connecticut, Storrs, Connecticut 06269.
J Neurosci. 2021 May 26;41(21):4631-4640. doi: 10.1523/JNEUROSCI.3073-20.2021. Epub 2021 Apr 13.
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. Understanding how interacting forms of synaptic plasticity mediate learning is fundamental for neuroscience. Theory and modeling revealed that, in addition to Hebbian-type associative plasticity, heterosynaptic changes at synapses that were not active during induction are necessary for stable system operation and fine-grained discrimination learning. However, lacking tools for selective manipulation prevented behavioral analysis of heterosynaptic plasticity. Here we circumvent this barrier: from our prior experimental and computational work we predict differential behavioral consequences of the impairment of Hebbian-type versus heterosynaptic plasticity. We show that, in adenosine A1 receptor knock-out mice, impaired synaptic plasticity in visual cortex neurons is coupled with specific deficits in learning sequential, increasingly complex visual discrimination tasks. This provides the first evidence linking heterosynaptic plasticity to organism-level learning.
理论和建模研究表明，在诱导过程中不活跃的突触的异突触可塑性变化促进了赫布型系统中的精细辨别学习，并有助于实现重复学习的稳健能力。缺乏选择性操作工具阻碍了对异突触可塑性在行为中作用的实验分析。在这里，我们通过实验操纵腺苷 A1 受体来测试关于异突触可塑性的行为后果的具体预测，从而规避了这一障碍。我们之前的工作表明，阻断腺苷 A1 受体可损害脑片的异突触可塑性，并且当在计算机模型中实现时，可选择性地损害序列任务上的重复学习。基于这项工作，我们预测 A1R 敲除 (KO) 小鼠将表现出 (1) 异突触可塑性受损和 (2) 序列任务学习中的行为缺陷。通过在切片中的电生理实验和对两性动物的行为测试，我们表明与野生型对照相比，A1R KO 小鼠的视觉皮层神经元中的突触可塑性受损，并且在视觉辨别学习中存在明显的缺陷。在重新学习过程中，A1R 敲除的缺陷特别明显，随着序列视觉辨别任务复杂性的增加，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机体水平学习中的作用提供了第一个实验证据。此外，这些结果将异突触可塑性确定为一种新的潜在靶点，可能有助于在现有记忆的背景下增强新的学习。理解相互作用的突触可塑性如何介导学习对于神经科学来说是至关重要的。理论和建模揭示，除了赫布型联想可塑性之外，在诱导过程中不活跃的突触的异突触变化对于稳定的系统运行和精细的辨别学习也是必需的。然而，缺乏选择性操作工具阻碍了对异突触可塑性的行为分析。在这里，我们规避了这个障碍：从我们之前的实验和计算工作中，我们预测了赫布型和异突触可塑性受损的不同行为后果。我们表明，在腺苷 A1 受体敲除小鼠中，视觉皮层神经元的突触可塑性受损与序列、越来越复杂的视觉辨别任务学习中的特定缺陷有关。这为将异突触可塑性与机体水平学习联系起来提供了第一个证据。
