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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. Co-operation of long-term and working memory representations in simultaneous chaining by rhesus monkeys ( Macaca mulatta )

   https://doi.org/10.1177/1747021819838432  

   Templer, Victoria L.; Gazes, Regina Paxton; Hampton, Robert R. (April 2019, Quarterly Journal of Experimental Psychology)

   We studied the memory representations that control execution of action sequences by training rhesus monkeys ( Macaca mulatta) to touch sets of five images in a predetermined arbitrary order (simultaneous chaining). In Experiment 1, we found that this training resulted in mental representations of ordinal position rather than learning associative chains, replicating the work of others. We conducted novel analyses of performance on probe tests consisting of two images “derived” from the full five-image lists (i.e., test B, D from list A→B→C→D→E). We found a “first item effect” such that monkeys responded most quickly to images that occurred early in the list in which they had been learned, indicating that monkeys covertly execute known lists mentally until an image on the screen matches the one stored in memory. Monkeys also made an ordinal comparison of the two images presented at test based on long-term memory of positional information, resulting in a “symbolic distance effect.” Experiment 2 indicated that ordinal representations were based on absolute, rather than on relative, positional information because subjects did not link two lists into one large list after linking training, unlike what occurs in transitive inference. We further examined the contents of working memory during list execution in Experiments 3 and 4 and found evidence for a prospective, rather than a retrospective, coding of position in the lists. These results indicate that serial expertise in simultaneous chaining results in robust absolute ordinal coding in long-term memory, with rapidly updating prospective coding of position in working memory during list execution. 

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3. 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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4. 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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5. Familiarity, Active Memory And Pressure During A Delayed Matching-To-Sample Task In Tufted Capuchin Monkeys (Sapajus [Cebus] Apella)

   https://doi.org/10.26451/abc.12.01.02.2025  

   Sosnowski, Meghan; Brosnan, Sarah (February 2025, Animal Behavior and Cognition)

   Delayed matching-to-sample (DMTS) tasks are commonly used in the field of comparative cognition to study memory, including working memory. However, specific task demands vary across studies and species, and as such, DMTS tasks may engage different memory systems when features such as the available stimulus pool differ. Further, individual or species-wide differences in response to pressure to perform may increase variation within a species. We explored how task features, memory systems, and pressure interact in tufted capuchin monkeys (Sapajus [Cebus] apella) to influence performance on a DTMS task by varying the size of the possible stimulus pool across testing blocks. We also varied the amount of pressure within a testing block by training monkeys to associate a background color change with a more difficult, but more highly rewarded, trial, as we had done in previous work. In accordance with previous literature (Basile & Hampton, 2013), we found that performance greatly decreased when the possible stimulus pool was limited as compared to a large possible stimulus pool, likely because monkeys could not rely on passive familiarity memory to complete the task. However, we found no overall species tendency to fail under pressure in either the limited- or large-set conditions; instead, we found a surprising tendency to thrive under higher pressure. Taken together, our results further highlight the importance of considering DMTS task features when studying specific memory systems in non-human species and suggest that the DTMS task might not be the best paradigm for testing pressure effects without consideration of individual differences. 

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