Behavioral studies have shown spatial working memory impairment with aging in several animal species, including humans. Persistent activity of layer 3 pyramidal dorsolateral prefrontal cortex (dlPFC) neurons during delay periods of working memory tasks is important for encoding memory of the stimulus. In vitro studies have shown that these neurons undergo significant age-related structural and functional changes, but the extent to which these changes affect neural mechanisms underlying spatial working memory is not understood fully. Here, we confirm previous studies showing impairment on the Delayed Recognition Span Task in the spatial condition (DRSTsp), and increased in vitro action potential firing rates (hyperexcitability), across the adult life span of the rhesus monkey. We use a bump attractor model to predict how empirically observed changes in the aging dlPFC affect performance on the Delayed Response Task (DRT), and introduce a model of memory retention in the DRSTsp. Persistent activity—and, in turn, cognitive performance—in both models was affected much more by hyperexcitability of pyramidal neurons than by a loss of synapses. Our DRT simulations predict that additional changes to the network, such as increased firing of inhibitory interneurons, are needed to account for lower firing rates during the DRT with aging reported in vivo. Synaptic facilitation was an essential feature of the DRSTsp model, but it did not compensate fully for the effects of the other age-related changes on DRT performance. Modeling pyramidal neuron hyperexcitability and synapse loss simultaneously led to a partial recovery of function in both tasks, with the simulated level of DRSTsp impairment similar to that observed in aging monkeys. This modeling work integrates empirical data across multiple scales, from synapse counts to cognitive testing, to further our understanding of aging in non-human primates.

中文翻译：

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网络模型预测 dlPFC 中的锥体神经元过度兴奋和突触丧失导致恒河猴与年龄相关的空间工作记忆障碍

行为研究表明，包括人类在内的几种动物物种会随着年龄的增长而出现空间工作记忆障碍。在工作记忆任务的延迟期间，第 3 层锥体背外侧前额叶皮层 (dlPFC) 神经元的持续活动对于编码刺激的记忆很重要。体外研究表明，这些神经元经历了与年龄相关的显着结构和功能变化，但这些变化对空间工作记忆的神经机制的影响程度尚不完全清楚。在这里，我们证实了之前的研究表明，在恒河猴的成年期，空间条件下的延迟识别跨度任务 (DRSTsp) 受损，并增加了体外动作电位放电率（过度兴奋）。我们使用碰撞吸引器模型来预测根据经验观察到的老化 dlPFC 的变化如何影响延迟响应任务 (DRT) 的性能，并在 DRSTsp 中引入记忆保留模型。在两种模型中，持续活动——以及认知表现——受到锥体神经元过度兴奋的影响比突触损失要大得多。我们的 DRT 模拟预测，需要对网络进行额外的更改，例如增加抑制性中间神经元的放电，以解释 DRT 期间随着体内老化报告的较低放电率。突触促进是 DRSTsp 模型的一个基本特征，但它并没有完全补偿其他与年龄相关的变化对 DRT 性能的影响。同时模拟锥体神经元过度兴奋和突触丢失导致两项任务的功能部分恢复，模拟的 DRSTsp 损伤水平类似于在衰老猴子中观察到的水平。这项建模工作整合了多个尺度的经验数据，从突触计数到认知测试，以进一步了解非人类灵长类动物的衰老。