Ketamine Alters Tuning of Neural and Behavioral Spatial Working Memory Precision
bioRxiv Preprint Server – February 10, 2025
Source: bioRxiv
Summary
Memory problems in brain disorders might stem from how brain cells "tune in" to information. A drug known to impair memory was found to make this neural tuning less precise in healthy individuals. Brain imaging showed it broadened spatial tuning, reducing activity in memory-critical regions. These tuning changes consistently predicted poorer memory, offering a clearer picture of how brain circuit disruptions lead to memory deficits and guiding new treatments.
Abstract
Deficits in working memory (WM) are a hallmark of neuropsy-chiatric disorders such as schizophrenia, yet their neurobiological basis remains poorly understood. Glutamate N-methyl-D-aspartate receptors (NMDARs) are critical for spatial WM (sWM), with NMDAR antagonist ketamine known to attenuate task-evoked activation and reduce sWM accuracy. Cortical microcircuit models hypothesize that NMDAR antagonism impairs sWM by broadening neural spatial tuning, but this mechanism has not been directly tested in humans. Using a pharmacological fMRI approach, we showed how ketamine broadened neural spatial tuning, attenuated activation across visual, parietal, and frontal areas, and worsened sWM performance in healthy humans. Ketamine-induced changes in tuning were more consistent across individuals and brain regions than changes in overall activation and correlated with individual differences in sWM performance. These findings provide empirical evidence linking NMDAR antagonism to disruptions in cortical microcircuit dynamics, the resulting neural tuning alterations, and sWM impairments, advancing frameworks for therapeutic development.