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Neurons in the primate lateral prefrontal cortex (LPFC) encode working memory (WM) representations via sustained firing, a phenomenon hypothesized to arise from recurrent dynamics within ensembles of interconnected neurons. Here, we tested this hypothesis by using microelectrode arrays to examine spike count correlations (rsc) in LPFC neuronal ensembles during a spatial WM task. We found a pattern of pairwise rsc during WM maintenance indicative of stronger coupling between similarly tuned neurons and increased inhibition between dissimilarly tuned neurons. We then used a linear decoder to quantify the effects of the high-dimensional rsc structure on information coding in the neuronal ensembles. We found that the rsc structure could facilitate or impair coding, depending on the size of the ensemble and tuning properties of its constituent neurons. A simple optimization procedure demonstrated that near-maximum decoding performance could be achieved using a relatively small number of neurons. These WMoptimized subensembles were more signal correlation (rsignal)- diverse and anatomically dispersed than predicted by the statistics of the full recorded population of neurons, and they often contained neurons that were poorly WM-selective, yet enhanced coding fidelity by shaping the ensemble’s rsc structure. We observed a pattern of rsc between LPFC neurons indicative of recurrent dynamics as a mechanism forWM-related activity and that the rsc structure can increase the fidelity ofWMrepresentations. Thus,WMcoding in LPFC neuronal ensembles arises from a complex synergy between single neuron coding properties and multidimensional, ensemblelevel phenomena.

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. The neural codes underlying working memory are not fully understood. Here the authors recorded neurons in the lateral prefrontal cortex of male macaque monkeys, during a working memory task, and identify activation sequences that encode target locations in the task.

To demonstrate a method to calculate phase amplitude coupling (PAC) quickly and robustly for realtime applications. We designed and implemented a multirate PAC algorithm with efficient filter bank processing and efficient computation of PAC for many frequency-pair combinations. We tested the developed algorithm for computing PAC on simulated data and on intraoperative neural recording data obtained during deep brain stimulation (DBS) electrode implantation surgery. A combination of parallelized frequency-domain filtering and modulation index for PAC estimation provided robust results that could be calculated in real time on modest computing hardware. The standard methods for calculating PAC can be optimized for quick and robust performance. These results demonstrated that PAC can be extracted in real time and is suitable for neurofeedback applications.

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.

Working memory is the ability to briefly remember and manipulate information after it becomes unavailable to the senses. The mechanisms supporting working memory coding in the primate brain remain controversial. Here we demonstrate that microcircuits in layers 2/3 of the primate lateral prefrontal cortex dynamically represent memory content in a naturalistic task through sequential activation of single neurons. We simultaneously recorded the activity of hundreds of neurons in the lateral prefrontal cortex of macaque monkeys during a naturalistic visuospatial working memory task set in a virtual environment. We found that the sequential activation of single neurons encoded trajectories to target locations held in working memory. Neural sequences were not a mere successive activation of cells with memory fields at specific spatial locations, but an abstract representation of the subject's trajectory to the target. Neural sequences were less correlated to target trajectories during perception and were not found during working memory tasks lacking the spatiotemporal structure of the naturalistic task. Finally, ketamine administration distorted neural sequences, selectively decreasing working memory performance. Our results indicate that neurons in the lateral prefrontal cortex causally encode working memory in naturalistic conditions via complex and temporally precise activation patterns. Competing Interest Statement The authors have declared no competing interest.

The primate lateral prefrontal cortex (LPFC) is considered fundamental for temporarily maintaining and manipulating mental representations that serve behavior, a cognitive function known as working memory. Studies in non-human primates have shown that LPFC lesions impair working memory and that LPFC neuronal activity encodes working memory representations. However, such studies have used simple displays and constrained gaze while subjects held information in working memory, which put into question their ethological validity. Currently, it remains unclear whether LPFC microcircuits can support working memory function during natural behavior. We tested macaque monkeys in a working memory navigation task in a life-like virtual environment while their gaze was unconstrained. We show that LPFC neuronal populations robustly encode working memory representations in these conditions. Furthermore, low doses of the NMDA receptor antagonist, ketamine, impaired working memory performance while sparing perceptual and motor skills. Ketamine decreased the firing of narrow spiking inhibitory interneurons and increased the firing of broad spiking cells reducing population decoding accuracy for remembered locations. Our results show that primate LPFC generates robust neural codes for working memory in naturalistic settings and that such codes rely upon a fine balance between the activation of excitatory and inhibitory neurons. Competing Interest Statement L.P. reports personal fees from Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work.

Primates use perceptual and mnemonic visuospatial representations to perform everyday functions. Neurons in the lateral prefrontal cortex (LPFC) have been shown to encode both of these representations during tasks where eye movements are strictly controlled and visual stimuli are reduced in complexity. This raises the question of whether perceptual and mnemonic representations encoded by LPFC neurons remain robust during naturalistic vision — in the presence of a rich visual scenery and during eye movements. Here we investigate this issue by training macaque monkeys to perform working memory and perception tasks in a visually complex virtual environment that requires navigation using a joystick and allows for free visual exploration of the scene. We recorded the activity of 3950 neurons in the LPFC (areas 8a and 9/46) of two rhesus macaques using multi-electrode arrays, and measured eye movements using video tracking. We found that navigation trajectories to target locations and eye movement behavior differed between the perception and working memory tasks suggesting that animals employed different behavioral strategies. Single neurons were tuned to target location during cue encoding and working memory delay and neural ensemble activity was predictive of the animals’ behavior. Neural decoding of target location was stable throughout the working memory delay epoch. However, neural representations of similar target locations differed between the working memory and perception tasks. These findings indicate that during naturalistic vision, LPFC neurons maintain robust and distinct neural codes for mnemonic and perceptual visuospatial representations. We show that LPFC neurons encode working memory and perceptual representations during a naturalistic task set in a virtual environment. We show that despite eye movement and complex visual input, neurons maintain robust working memory representations of space which are distinct from neuronal representations for perception. We further provide novel insight on the use of virtual environments to construct behavioral tasks for electrophysiological experiments.

Primates use perceptual and mnemonic visuospatial representations to perform everyday functions. Neurons in the lateral prefrontal cortex (LPFC) have been shown to encode both of these representations during tasks where eye movements are strictly controlled and visual stimuli are reduced in complexity. This raises the question of whether perceptual and mnemonic representations encoded by LPFC neurons remain robust during naturalistic vision - in the presence of a rich visual scenery and during eye movements. Here we investigate this issue by training macaque monkeys to perform working memory and perception tasks in a visually complex virtual environment that requires navigation using a joystick and allows for free visual exploration of the scene. We recorded the activity of 3950 neurons in the LPFC (areas 8a and 9/46) of two rhesus macaques using multi-electrode arrays, and measured eye movements using video tracking. We found that navigation trajectories to target locations and eye movement behavior differed between the perception and working memory tasks suggesting that animals employed different behavioral strategies. Single neurons were tuned to target location during cue encoding and working memory delay and neural ensemble activity was predictive of the animals' behavior. Neural decoding of target location was stable throughout the working memory delay epoch. However, neural representations of similar target locations differed between the working memory and perception tasks. These findings indicate that during naturalistic vision, LPFC neurons maintain robust and distinct neural codes for mnemonic and perceptual visuospatial representations. Competing Interest Statement The authors have declared no competing interest.

CB Commercial initially showed Sears the Columbia building for another purpose, but Sears took that deal to New Jersey, only to come back to the Columbia building when it was looking for a distribution center site, he said. Mark Wasserman, Maryland's secretary of economic and employment development, said the state did not offer Sears any financial incentives to move here. But he and Mr. [Eugene V. Ryan] said a law created by the General Assembly last year, allowing companies to operate 53-foot double-trailer trucks on Maryland's roads, was essential to landing the Sears deal. Neither Rouse nor Sears would divulge financial details of the deal, which Rouse said has a five-year term, with Sears having options to renew.

The woman, who shares the house with her boyfriend and 4-year-old daughter, was asleep on a living room sofa when the abductor entered the home, Sergeant [Gary Gardner] said. Howard police have provided descriptions of the suspect and his vehicle to police departments in neighboring counties, Sergeant Gardner said. The abductor reportedly released the woman in Laytonsville, a Montgomery County town about 11 miles south of Mount Airy, police said.