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Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks.

ABSTRACT: Ketamine is a dissociative anesthetic drug, which has more recently emerged as a rapid-acting antidepressant. When acutely administered at subanesthetic doses, ketamine causes cognitive deficits like those observed in patients with schizophrenia, including impaired working memory. Although these effects have been linked to ketamine's action as an N-methyl-D-aspartate receptor antagonist, it is unclear how synaptic alterations translate into changes in brain microcircuit function that ultimately influence cognition. Here, we administered ketamine to rhesus monkeys during a spatial working memory task set in a naturalistic virtual environment. Ketamine induced transient working memory deficits while sparing perceptual and motor skills. Working memory deficits were accompanied by decreased responses of fast spiking inhibitory interneurons and increased responses of broad spiking excitatory neurons in the lateral prefrontal cortex. This translated into a decrease in neuronal tuning and information encoded by neuronal populations about remembered locations. Our results demonstrate that ketamine differentially affects neuronal types in the neocortex; thus, it perturbs the excitation inhibition balance within prefrontal microcircuits and ultimately leads to selective working memory deficits.

SUBMITTER: Roussy M

PROVIDER: S-EPMC8760073 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Working memory (WM) provides the stability necessary for high-level cognition. Influential theories typically assume that WM depends on the persistence of stable neural representations, yet increasing evidence suggests that neural states are highly dynamic. Here we apply multivariate pattern analysis to explore the population dynamics in primate lateral prefrontal cortex (PFC) during three variants of the classic memory-guided saccade task (recorded in four animals). We observed the hallmark of dynamic population coding across key phases of a working memory task: sensory processing, memory encoding, and response execution. Throughout both these dynamic epochs and the memory delay period, however, the neural representational geometry remained stable. We identified two characteristics that jointly explain these dynamics: (1) time-varying changes in the subpopulation of neurons coding for task variables (i.e., dynamic subpopulations); and (2) time-varying selectivity within neurons (i.e., dynamic selectivity). These results indicate that even in a very simple memory-guided saccade task, PFC neurons display complex dynamics to support stable representations for WM.SIGNIFICANCE STATEMENT Flexible, intelligent behavior requires the maintenance and manipulation of incoming information over various time spans. For short time spans, this faculty is labeled "working memory" (WM). Dominant models propose that WM is maintained by stable, persistent patterns of neural activity in prefrontal cortex (PFC). However, recent evidence suggests that neural activity in PFC is dynamic, even while the contents of WM remain stably represented. Here, we explored the neural dynamics in PFC during a memory-guided saccade task. We found evidence for dynamic population coding in various task epochs, despite striking stability in the neural representational geometry of WM. Furthermore, we identified two distinct cellular mechanisms that contribute to dynamic population coding.

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Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks.

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