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Prefrontal cortex modulates sensory signals in extrastriate visual cortex, in part via its direct projections from the frontal eye field (FEF), an area involved in selective attention. We find that working memory-related activity is a dominant signal within FEF input to visual cortex. Although this signal alone does not evoke spiking responses in areas V4 and MT during memory, the gain of visual responses in these areas increases, and neuronal receptive fields expand and shift towards the remembered location, improving the stimulus representation by neuronal populations. These results provide a basis for enhancing the representation of working memory targets and implicate persistent FEF activity as a basis for the interdependence of working memory and selective attention.
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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.
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- PAR ID:
- 10249634
- Date Published:
- Journal Name:
- Molecular Psychiatry
- ISSN:
- 1359-4184
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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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.more » « less
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The ability to use past experience to effectively guide decision-making declines in older adulthood. Such declines have been theorized to emerge from either impairments of striatal reinforcement learning systems (RL) or impairments of recurrent networks in prefrontal and parietal cortex that support working memory (WM). Distinguishing between these hypotheses has been challenging because either RL or WM could be used to facilitate successful decision-making in typical laboratory tasks. Here we investigated the neurocomputational correlates of age-related decision-making deficits using an RL-WM task to disentangle these mechanisms, a computational model to quantify them, and magnetic resonance spectroscopy to link them to their molecular bases. Our results reveal that task performance is worse in older age, in a manner best explained by working memory deficits, as might be expected if cortical recurrent networks were unable to sustain persistent activity across multiple trials. Consistent with this, we show that older adults had lower levels of prefrontal glutamate, the excitatory neurotransmitter thought to support persistent activity, compared to younger adults. Individuals with the lowest prefrontal glutamate levels displayed the greatest impairments in working memory after controlling for other anatomical and metabolic factors. Together, our results suggest that lower levels of prefrontal glutamate may contribute to failures of working memory systems and impaired decision-making in older adulthood.more » « less
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ImportanceThe risk of mental disorders is consistently associated with variants inCACNA1C(L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders. ObjectiveTo examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices. Design, Setting, and ParticipantsThe design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques. Main Outcomes and MeasuresOutcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments. ResultsLayer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated byCALB1(calbindin), and high levels ofCACNA1C(Cav1.2),GRIN2B(NMDA receptor GluN2B), andKCNN3(SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress. Conclusions and RelevanceThe layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants inCACNA1Cwere associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41380-021-01082-5
