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

   https://doi.org/10.1038/s41380-021-01082-5  

   Roussy, Megan; Luna, Rogelio; Duong, Lyndon; Corrigan, Benjamin; Gulli, Roberto A.; Nogueira, Ramon; Moreno-Bote, Rubén; Sachs, Adam J.; Palaniyappan, Lena; Martinez-Trujillo, Julio C. (May 2021, Molecular Psychiatry)

   null (Ed.)

   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. 

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2. Resolving a paradox about how vision is transformed into familiarity

   https://doi.org/10.1101/2025.06.13.659490  

   Bohn, Simon; Hacker, Catrina M; Jannuzi, Barnes_G L; Meyer, Travis; Hay, Madison L; Rust, Nicole C (December 2025, bioRxiv)

   Summary While humans and other primates are generally good at remembering the images they have seen, they systematically remember some images better than others (“image memorability”). Here, we leverage image memorability to resolve a puzzle around how the brain transforms seeing into familiarity. Namely, the neural signal driving familiarity reports is thought to be repetition suppression, an overall reduction in the vigor of the population response in brain regions, including inferotemporal cortex (ITC). However, within ITC, more memorable images evoke higher firing rates than less memorable ones, even when they are repeated. These two observations conflict: ifreducedfiring leads to stronger memory signaling, then why are the images that inducegreaterfiring more memorable? To investigate this “familiarity-memorability paradox”, we compared neural activity in ITC and the hippocampus (HC) as two macaque monkeys performed a single-exposure image familiarity task. We found a resolution to the paradox, reflected in two pieces of evidence. First, memory and memorability were not completely overlapping in ITC, suggesting that familiarity signals could be extracted independently of memorability modulation. Second, responses in HC reflected a transformation of ITC responses that extracted memory, leaving behind stimulus-evoked firing modulation. This transformation could be accounted for by a linear decoder that selectively extracts memory and preserves larger ITC memory signals for more memorable images. These results resolve the familiarity-memorability paradox by demonstrating that ITC familiarity signals are a component (but not the entirety) of repetition suppression, and they establish the existence of a previously undescribed medial temporal lobe computation. SignificanceNeural representations of image memorability create a paradox: familiarity reports are thought to derive fromreducedfiring in inferotemporal cortex (ITC), but more memorable images evoke more vigorous responses there. To resolve this contradiction, we compared ITC with an area downstream, the hippocampus (HC), as macaque monkeys performed a single-exposure familiarity task. We found evidence for a computation between ITC and HC that selectively extracts ITC memory signals. This transformation could be explained by a linear decoder that preserves larger memory signals for more memorable images. This work resolves the familiarity-memorability paradox by showing that ITC memory signals have been misunderstood, and it reveals a previously undescribed role for the medial temporal lobe in familiarity behavior. 

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3. Sharpened visual memory representations are reflected in inferotemporal cortex

   https://doi.org/10.1523/JNEUROSCI.0833-25.2025  

   Jannuzi, Barnes GL; Hacker, Catrina M; Bohn, Simon; Meyer, Travis; Hay, Madison L; Rust, Nicole C (January 2026, The Journal of Neuroscience)

   Humans and other primates can robustly report whether they've seen specific images before, even when those images are extremely similar to ones they've previously seen. Multiple lines of evidence suggest that pattern separation computations in the hippocampus (HC) contribute to this behavior by shaping the fidelity of visual memory. However, unclear is whether HC uniquely determines memory fidelity or whether computations in other brain areas also contribute. To investigate, we recorded neural signals from inferotemporal cortex (ITC) and HC of two rhesus monkeys (1 male, 1 female) as they performed a memory task in which they judged whether images were novel or exactly repeated in the presence of visually similar lure images with a range of visual similarities. We found behavioral evidence for sharpening, reflected as memory performance that was nonlinearly transformed relative to a benchmark defined by visual representations in ITC. As expected, we found that behavioral sharpening aligned with visual memory representations in HC. Surprisingly, and unaccounted for by HC pattern separation proposals, we also found neural correlates of behavioral sharpening reflected in ITC. These results, coupled with further analysis of the data, suggest that ITC contributes to shaping the fidelity of visual memory in the transformation from visual processing to memory storage and signaling. Significance StatementVisual recognition memories are stored with remarkable visual fidelity, allowing humans and other primates to distinguish images they have encountered from visually similar images they have not. This fidelity has long been attributed to computations in the hippocampus that sharpen visual representations before memory storage (pattern separation). Unclear is how this proposal aligns with other evidence that visual memories are stored within high-level visual cortex itself, before signals reach the hippocampus. Here we demonstrate that, like the hippocampus, inferotemporal cortex also reflects sharpened visual memory representations, suggesting that visual cortex contributes to shaping the visual fidelity of visual memory. 

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

   https://doi.org/10.1038/s41467-024-48664-9  

   Busch, Alexandra; Roussy, Megan; Luna, Rogelio; Leavitt, Matthew L; Mofrad, Maryam H; Gulli, Roberto A; Corrigan, Benjamin; Mináč, Ján; Sachs, Adam J; Palaniyappan, Lena; et al (December 2024, Nature Communications)

   Abstract Working memory (WM) is the ability to maintain and manipulate information ‘in mind’. The neural codes underlying WM have been a matter of debate. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of male macaque monkeys during a visuospatial WM task that required navigation in a virtual 3D environment. Here, we demonstrate distinct neuronal activation sequences (NASs) that encode remembered target locations in the virtual environment. This NAS code outperformed the persistent firing code for remembered locations during the virtual reality task, but not during a classical WM task using stationary stimuli and constraining eye movements. Finally, blocking NMDA receptors using low doses of ketamine deteriorated the NAS code and behavioral performance selectively during the WM task. These results reveal the versatility and adaptability of neural codes supporting working memory function in the primate lateral prefrontal cortex. 

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5. Comparative analysis reveals distinctive epigenetic features of the human cerebellum

   https://doi.org/10.1371/journal.pgen.1009506  

   Guevara, Elaine E.; Hopkins, William D.; Hof, Patrick R.; Ely, John J.; Bradley, Brenda J.; Sherwood, Chet C. (May 2021, PLOS Genetics)

   Gojobori, Takashi (Ed.)

   Identifying the molecular underpinnings of the neural specializations that underlie human cognitive and behavioral traits has long been of considerable interest. Much research on human-specific changes in gene expression and epigenetic marks has focused on the prefrontal cortex, a brain structure distinguished by its role in executive functions. The cerebellum shows expansion in great apes and is gaining increasing attention for its role in motor skills and cognitive processing, including language. However, relatively few molecular studies of the cerebellum in a comparative evolutionary context have been conducted. Here, we identify human-specific methylation in the lateral cerebellum relative to the dorsolateral prefrontal cortex, in a comparative study with chimpanzees ( Pan troglodytes ) and rhesus macaques ( Macaca mulatta ). Specifically, we profiled genome-wide methylation levels in the three species for each of the two brain structures and identified human-specific differentially methylated genomic regions unique to each structure. We further identified which differentially methylated regions (DMRs) overlap likely regulatory elements and determined whether associated genes show corresponding species differences in gene expression. We found greater human-specific methylation in the cerebellum than the dorsolateral prefrontal cortex, with differentially methylated regions overlapping genes involved in several conditions or processes relevant to human neurobiology, including synaptic plasticity, lipid metabolism, neuroinflammation and neurodegeneration, and neurodevelopment, including developmental disorders. Moreover, our results show some overlap with those of previous studies focused on the neocortex, indicating that such results may be common to multiple brain structures. These findings further our understanding of the cerebellum in human brain evolution. 

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