Interplay between persistent activity and activity-silent dynamics in prefrontal cortex during working memory

Abstract

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative, "activity-silent" substrates for memory.Using monkey and human electrophysiology, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in PFC. This interaction allows memory reactivation, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in PFC. Just prior to the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model integrating activity-based and activity-silent mechanisms. Finally, single-pulse TMS applied to human prefrontal cortex prior to trial start enhanced serial biases, demonstrating the causal role of prefrontal reactivations in determining working memory behavior.1 Both attractor dynamics 24,28 and activity-silent 13,22,27 mechanisms have been proposed to carry stimulus-selective information from one trial to the next to effect serial biases.However, dependencies of serial biases with delay and ITI durations [24][25][26] , which demonstrate their relationship with memory maintenance, are largely consistent with activity-silent, and not activity-based mechanisms 13,22,27 . Here, we sought to specify the interaction of activity-based and activity-silent prefrontal cortex (PFC) mechanisms in supporting serial biases while subjects performed a spatial working memory task that engages attractor dynamics in prefrontal cortex 6 . We compared the encoding properties of brain activity in delay and inter-trial intervals (ITI) to identify the mechanistic basis of the memory trace that spans consecutive trials. We used behavioral and electrophysiological data collected in monkeys and humans, with prefrontal multiple-unit recordings in monkeys, and scalp electroencephalography (EEG) in humans. Between successive persistent activity mnemonic codes, we found an activity-silent code in PFC that carried stimulus information through inter-trial periods. In addition, we found correlational and causal evidence that fixation-period PFC reactivation from this activity-silent trace enhances attractive serial biases. These findings underscore the behavioral relevance of the dynamic interplay between attractor and subthreshold network dynamics in PFC and reconcile these seemingly conflicting mechanisms: their interplay could be the basis of closely associated memory storage processes operating at different time scales, possibly serving different behavioral purposes 29,30 . ResultsWe trained four rhesus monkeys to perform an oculomotor delayed response task (ODR).The task consisted of remembering spatial locations at fixed eccentricity while maintaining fixation during a ...

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

“…A prevailing idea associates NMDAR hypofunction in schizophrenia primarily to synapses onto GABAergic interneurons 20 , while the role of NMDARs in working memory has been emphasized in synapses between pyramidal neurons 1,2,18 . Alternatively, NMDARs could be involved in mechanisms directly associated with the generation of serial biases, such as short-term plasticity 15,19,27 . To assess these mechanistic explanations comparatively, we simulated consecutive trials of a spatial working memory task in a spiking neural network model of the prefrontal cortex 18 (Fig.…”

“…Prefrontal cortex not only holds working memory contents in an activity-based code 14,17 , but also keeps long-lasting latent (possibly synaptic) memory traces that produce serial dependence 15 .…”

“…10; Methods ). As proposed by previous studies 15,19,27 we modeled serial dependence as an effect of short-term plasticity that builds up at delay-active excitatory synapses and maintains information during the ITI in a subthreshold stimulus representation not reflected in firing rate selectivity ( Fig. 2b, Methods ).…”

“…However, while proactive interference is mainly discussed in the context of cognitive control, the limited complexity of our task restricts possible interpretations of reduced between-trial interference and supports the role of reduced residual memory traces. Moreover, thanks to our task's well-studied single-neuron correlates 14,15 and biophysical models 15,17,18 and the comparison with anti-NMDAR encephalitis patients, we provide a specific mechanistic model of synaptic deficits leading to reduced previous-trial interference in schizophrenia.…”

“…1b) as a read-out of passive information maintenance across trials. Neural correlates of this task have been identified in monkey prefrontal cortex 14,15 , inspiring computational models that can capture key aspects of neural dynamics and behavior [15][16][17][18][19] . The biophysical detail of these models permits to investigate how NMDAR hypofunction at different synaptic sites affects circuit dynamics and working memory.Candidate mechanisms are a disturbed balance between cortical excitation and inhibition (E/I balance), as it is observed in schizophrenia and in studies using NMDAR antagonists (e.g.…”