Long-term learning transforms prefrontal cortex representations during working memory

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-11, Vol.110 (22), p.3805-3819.e6
• Main Authors: Miller, Jacob A., Tambini, Arielle, Kiyonaga, Anastasia, D’Esposito, Mark
• Format: Article
• Language: English
• Subjects: Animals; Cognition - physiology; Humans; Learning; long-term memory; Memory, Short-Term - physiology; prefrontal cortex; Prefrontal Cortex - physiology; Reaction Time - physiology; representational similarity; working memory
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2022.09.019

The role of the lateral prefrontal cortex (lPFC) in working memory (WM) is debated. Non-human primate (NHP) electrophysiology shows that the lPFC stores WM representations, but human neuroimaging suggests that the lPFC controls WM content in sensory cortices. These accounts are confounded by differences in task training and stimulus exposure. We tested whether long-term training alters lPFC function by densely sampling WM activity using functional MRI. Over 3 months, participants trained on both a WM and serial reaction time (SRT) task, wherein fractal stimuli were embedded within sequences. WM performance improved for trained (but not novel) fractals and, neurally, delay activity increased in distributed lPFC voxels across learning. Item-level WM representations became detectable within lPFC patterns, and lPFC activity reflected sequence relationships from the SRT task. These findings demonstrate that human lPFC develops stimulus-selective responses with learning, and WM representations are shaped by long-term experience, which could reconcile competing accounts of WM functioning. •Long-term training alters prefrontal cortex function during working memory•Representations for individual stimuli in working memory emerge in prefrontal cortex•Working memory representations are shaped by long-term associative learning•Learning may reconcile debates on the role of prefrontal cortex in working memory Miller et al. densely sampled brain activity with human neuroimaging during working memory across months of learning. Long-term training altered the role of the prefrontal cortex, which developed representations for specific stimuli and associations learned over time. Working memory is shaped by long-term experience, which may help resolve competing accounts of prefrontal functioning.