Neuronal activation sequences in lateral prefrontal cortex encode visuospatial working memory during virtual navigation

Abstract The brain can maintain and flexibly manipulate complex visuospatial information ‘in mind’, an ability known as working memory. The neural codes underlying this function have been a matter of debate. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of monkeys during a visuospatial working memory task that required navigation in a virtual 3D environment. During task trials, animals perceived the location of a transient visual cue, remembered that location for a few seconds, and finally navigated toward it using a joystick to collect a reward. We found time boundary neurons that transiently activated just before the beginning and end of the memory period. Moreover, distinct neuronal activation sequences encoded specific remembered target locations in the virtual 3D environment, as viewed from the subject’s own visual perspective. This sequence code outperformed persistent firing codes for the remembered location during the virtual reality task, but did not occur during a classical working memory task using stationary stimuli and homogeneous displays. Finally, blocking NMDA receptors using low doses of ketamine selectively deteriorated the sequence code during the working memory task. Our results reveal a novel mechanism, NMDA-dependent neural activation sequences, for encoding visuospatial working memory in complex naturalistic environments. They further reveal the versatility and adaptability of neural codes supporting working memory function in the primate lateral prefrontal cortex.