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.

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDARdependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.

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The collagenous constituents of mature bone of 30 individuals 22-93 years of age were studied by post-mortem morphological and biochemical analysis. Morphometric evaluation of the second lumbar vertebral body revealed striking interindividual differences in bone mass, mean trabecular density and mean trabecular thickness. Collagen extracted from vertebral trabecular bone by limited pepsin digestion consisted mainly of collagen I (92%) and collagen V (8%). Immunohistochemistry revealed a distinct distribution of these two collagen types within the bone matrix. The degree of lysyl hydroxylation of the alpha 2(I) collagen chain correlated inversely with the trabecular bone volume (TBV) and with the mean trabecular plate density. This correlation was statistically significant for the entire study group as well as for the female and male subgroups. Within the female subgroup, the lysyl hydroxylation/TBV ratio was higher in postmenopausal than in premenopausal women and was highest in women with established osteoporosis. No significant correlation was found between the level of lysyl hydroxylation and the age of the patients. The alpha 1(I) collagen chain showed a nearly constant degree of lysyl hydroxylation in all 30 samples. The results provide convincing evidence that morphometric changes associated with osteopenia in adult bone are accompanied by an altered level of lysyl hydroxylation of the alpha 2(I)-chain of collagen I. The biochemical alterations observed may be responsible for the deposition of a deficient bone matrix in osteopenic conditions.

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Highlights• People with schizophrenia have quantitative working memory (WM) deficits • WM deficits cannot be readily mapped on the stability of continuous attractors • Different attractor models yield inconsistent behavioral predictions upon changes in E/I ratio • Grouping different perturbations under E/I ratio can be inadequate for some deficits • Insufficient experimental and computational understanding precludes model selection • We need data showing NMDAR-dependence of rate tuning and correlated noise in WM circuits

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 ...

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