biostudies-literatureMiller JANIMH NIH HHSNational Institute of Mental HealthNational Institutes of Health3805-3819.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC9768795biostudies-literatureUnknown110(22)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.NeuronLong-term learning transforms prefrontal cortex representations during working memory.PMC9768795F32 MH111204RO1 MH63901F32 MH106280R01 MH063901F32MH106280F32MH111204Tambini AKiyonaga AD'Esposito MMiller JAfalseLong-term learning transforms prefrontal cortex representations during working memory.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.2022-01-01T00:00:00Z2022 Nov2025-04-18T18:13:54.185Z2025-04-07T05:52:07.95ZS-EPMC97687953624076810.1016/j.neuron.2022.09.019