Stable Working Memory and Perceptual Representations in Macaque Lateral Prefrontal Cortex during Naturalistic Vision.

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 male rhesus macaques using multielectrode 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 used 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 behavior of the animals. Neural decoding of the 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.SIGNIFICANCE STATEMENT We show that lateral prefrontal cortex 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 into the use of virtual environments to construct behavioral tasks for electrophysiological experiments.

View cells in the hippocampus and prefrontal cortex of macaques during virtual navigation.

Cells selectively activated by a particular view of an environment have been found in the primate hippocampus (HPC). Whether view cells are present in other brain areas, and how view selectivity interacts with other variables such as object features and place remain unclear. Here, we explore these issues by recording the responses of neurons in the HPC and the lateral prefrontal cortex (LPFC) of rhesus macaques performing a task in which they learn new context-object associations while navigating a virtual environment using a joystick. We measured neuronal responses at different locations in a virtual maze where animals freely directed gaze to different regions of the visual scenes. We show that specific views containing task relevant objects selectively activated a proportion of HPC units, and an even higher proportion of LPFC units. Place selectivity was scarce and generally dependent on view. Many view cells were not affected by changing the object color or the context cue, two task relevant features. However, a small proportion of view cells showed selectivity for these two features. Our results show that during navigation in a virtual environment with complex and dynamic visual stimuli, view cells are found in both the HPC and the LPFC. View cells may have developed as a multiarea specialization in diurnal primates to encode the complexities and layouts of the environment through gaze exploration which ultimately enables building cognitive maps of space that guide navigation.

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

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.

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

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.

Distinct neural codes in primate hippocampus and lateral prefrontal cortex during associative learning in virtual environments.

The hippocampus (HPC) and the lateral prefrontal cortex (LPFC) are two cortical areas of the primate brain deemed essential to cognition. Here, we hypothesized that the codes mediating neuronal communication in the HPC and LPFC microcircuits have distinctively evolved to serve plasticity and memory function at different spatiotemporal scales. We used a virtual reality task in which animals selected one of the two targets in the arms of the maze, according to a learned context-color rule. Our results show that during associative learning, HPC principal cells concentrate spikes in bursts, enabling temporal summation and fast synaptic plasticity in small populations of neurons and ultimately facilitating rapid encoding of associative memories. On the other hand, layer II/III LPFC pyramidal cells fire spikes more sparsely distributed over time. The latter would facilitate broadcasting of signals loaded in short-term memory across neuronal populations without necessarily triggering fast synaptic plasticity.

Neural Substrates of Visual Perception and Working Memory: Two Sides of the Same Coin or Two Different Coins?

Visual perception occurs when a set of physical signals emanating from the environment enter the visual system and the brain interprets such signals as a percept. Visual working memory occurs when the brain produces and maintains a mental representation of a percept while the physical signals corresponding to that percept are not available. Early studies in humans and non-human primates demonstrated that lesions of the prefrontal cortex impair performance during visual working memory tasks but not during perceptual tasks. These studies attributed a fundamental role in working memory and a lesser role in visual perception to the prefrontal cortex. Indeed, single cell recording studies have found that neurons in the lateral prefrontal cortex of macaques encode working memory representations via persistent firing, validating the results of lesion studies. However, other studies have reported that neurons in some areas of the parietal and temporal lobe-classically associated with visual perception-similarly encode working memory representations via persistent firing. This prompted a line of enquiry about the role of the prefrontal and other associative cortices in working memory and perception. Here, we review evidence from single neuron studies in macaque monkeys examining working memory representations across different areas of the visual hierarchy and link them to studies examining the role of the same areas in visual perception. We conclude that neurons in early visual areas of both ventral (V1-V2-V4) and dorsal (V1-V3-MT) visual pathways of macaques mainly encode perceptual signals. On the other hand, areas downstream from V4 and MT contain subpopulations of neurons that encode both perceptual and/or working memory signals. Differences in cortical architecture (neuronal types, layer composition, and synaptic density and distribution) may be linked to the differential encoding of perceptual and working memory signals between early visual areas and higher association areas.

Customizable cap implants for neurophysiological experimentation.

BACKGROUND: Several primate neurophysiology laboratories have adopted acrylic-free, custom-fit cranial implants. These implants are often comprised of titanium or plastic polymers, such as polyether ether ketone (PEEK). Titanium is favored for its mechanical strength and osseointegrative properties whereas PEEK is notable for its lightweight, machinability, and MRI compatibility. Recent titanium/PEEK implants have proven to be effective in minimizing infection and implant failure, thereby prolonging experiments and optimizing the scientific contribution of a single primate. NEW METHOD: We created novel, customizable PEEK 'cap' implants that contour to the primate's skull. The implants were created using MRI and/or CT data, SolidWorks software and CNC-machining. RESULTS: Three rhesus macaques were implanted with a PEEK cap implant. Head fixation and chronic recordings were successfully performed. Improvements in design and surgical technique solved issues of granulation tissue formation and headpost screw breakage. COMPARISON WITH EXISTING METHODS: Primate cranial implants have traditionally been fastened to the skull using acrylic and anchor screws. This technique is prone to skin recession, infection, and implant failure. More recent methods have used imaging data to create custom-fit titanium/PEEK implants with radially extending feet or vertical columns. Compared to our design, these implants are more surgically invasive over time, have less force distribution, and/or do not optimize the utilizable surface area of the skull. CONCLUSIONS: Our PEEK cap implants served as an effective and affordable means to perform electrophysiological experimentation while reducing surgical invasiveness, providing increased strength, and optimizing useful surface area.