Interplay between persistent activity and activity-silent dynamics in the prefrontal cortex underlies serial biases in working memory

Abstract

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative, “activity-silent” substrates. 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 reactivations, 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 the human prefrontal cortex between successive trials enhanced serial biases, demonstrating the causal role of prefrontal reactivations in determining working memory behavior.

Prospective Representations in Rat Orbitofrontal Ensembles

“…OFC is likely supported in this by other brain regions, which may hold sustained or dynamic neural activation during the long delay time. However it is likely that maintaining such information across the relatively long delay period used here requires additional mechanisms such as short-term synaptic plasticity, either in OFC or elsewhere, which is not necessarily reflected in increased or decreased neural firing rates (Barbosa et al, 2020;Mongillo, Barak, & Tsodyks, 2008;Stokes, 2015). More investigations are needed in the future to shed light on this important question.…”

Canonical goal-selective representations are absent from prefrontal cortex in a spatial working memory task requiring behavioral flexibility

“…We searched for representations of the current goal encoded in terms of the major forms of delay period activity previously found in other working memory tasks, spatial or non-spatial, involving recordings from the PFC or elsewhere in primates and rodents: activity reflecting the representation at the time of encoding the sample item (Funahashi et al, 1989;Miller et al, 1996;Rainer et al, 1998;Romo et al, 1999;Wu et al, 2020), elevated/suppressed activity in single cells (Fuster & Alexander, 1971;Funahashi et al, 1989;Miller et al, 1996;Rainer et al, 1998;Romo et al, 1999;Kim et al, 2016;Inagaki et al, 2019) or sequential firing patterns across multiple cells that tile the delay period (Baeg et al, 2003;Fujisawa et al, 2008;Pastalkova et al, 2008;Harvey et al, 2012;Ito et al, 2015), oscillatory phase-dependent firing (Siegel et al, 2009;Watrous et al, 2018), and elevated/suppressed covariances in firing among pairs of neurons (Barbosa et al, 2020).…”

“…If the remembered goal is not maintained by activity directly related to activity at the goal itself, it could be (i) transformed into a different, but goal-specific, pattern, potentially dependent on the start location (ii) encoded in egocentric coordinates (i.e. the direction relative to the current start location) (Sarel et al, 2017) instead of in terms of the absolute (allocentric) goal location, (iii) represented by a sequential, instead of tonic, activity pattern and/or (iv) reflected in the phase of spike times or the short timescale interactions between pairs of neurons (Barbosa et al, 2020). We initially tested if any single cell activity in 100-ms-to full-delay-period-sized time bins showed consistent firing differences for allocentric, start-dependent or egocentric goal location ( Figure S3-1).…”

A dopamine gradient controls access to distributed working memory in monkey cortex

“…Unconscious working memory is thought to rely on 'activity-silent' synaptic mechanisms (Stokes 2015;Trübutschek et al 2017). Slow cellular and synaptic processes may not only contribute to such mechanisms but also induce trial-by-trial history-dependent effects (Barbosa et al 2020;Bliss and D'Esposito 2017;Carter and Wang 2007;Pereira and Wang 2015). Previous models of working memory with short-term synaptic plasticity have focused on local activity in the prefrontal cortex (Mongillo et al 2008;Stokes 2015), and thus implicitly imply that it is short-term plasticity in local connections between prefrontal neurons that stores the memory trace.…”