Biology subjects

Sachs, A. J.

Publications and source records attributed to Sachs, A. J..

5 recordsLinked to original sources

bioRxiv2025

Subanesthetic Ketamine Disrupts Predictive Signaling in the Prefrontal Cortex

Corollary discharge (CD) signals allow the brain to predict and suppress the sensory consequences of its own actions, providing stability to perception and thought. Disruption of these predictive mechanisms has long been hypothesized to contribute to the disorganization of experience in schizophrenia, yet direct circuit-level evidence has been lacking. Here, we show that ketamine, a dissociative N-methyl-D-aspartate receptor (NMDAR) antagonist, at subanesthetic doses, selectively disrupts CD signaling in the lateral prefrontal cortex (LPFC)--a region thought to be the seed of mental representations and one of the most affected areas in schizophrenia. We recorded activity from 1,342 neurons in LPFC areas 8a and 9/46 of macaques performing a visuospatial working-memory task in a virtual environment, before and after subanesthetic ketamine administration. Ketamine impaired performance and increased overall firing rates but markedly suppressed saccade-related responses carrying CD signals. This led to decreased discriminability of eye movement signals. This finding links two major ideas in neuroscience research: the role of disrupted glutamate signaling and the failure of the brains predictive models. It provides evidence for how these mechanisms may interact in the prefrontal cortex to disturb the sense of reality.

neuroscience↗

bioRxiv2022

Neural sequences in primate prefrontal cortex encode working memory in naturalistic environments

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 subjects 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.

neuroscience↗

bioRxiv2022

Stable working memory and perceptual representations in macaque lateral prefrontal cortex during naturalistic vision in virtual environments

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. Significance StatementWe 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.

neuroscience↗

bioRxiv2021

Different neural codes serve long and short-term memory functions in primate Hippocampus and Lateral Prefrontal Cortex during virtual navigation

The hippocampus (HPC) and the lateral prefrontal cortex (LPFC) are two cortical areas of the primate brain deemed essential to cognition. Here we hypothesize that the codes mediating neuronal communication in 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 navigated through a maze using a joystick and selected one of two targets in the arms of the maze according to a learned context-color rule. We found that neurons and neuronal populations in both regions encode similar information about the task. Moreover, we demonstrate that many HPC neurons concentrate spikes into bursts, whereas most layer II/III LPFC neurons sparsely distribute spikes over time. As the animals learned the task HPC neurons, but not LPFC neurons, increased their burst rate as a function of performance. When integrating spike rates over short intervals, HPC neuronal ensembles reached maximum decoded information with fewer neurons than LPFC ensembles. 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, layers II/III LPFC pyramidal cells fire spikes more sparsely distributed in time and over a larger number of neurons. The latter would facilitate broadcasting of signals loaded in short term memory across neuronal populations without necessarily triggering fast synaptic plasticity.

neuroscience↗

bioRxiv2020

Naturalistic coding of working memory in primate prefrontal cortex

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 memory1. Studies in non-human primates have shown that LPFC lesions impair working memory2 and that LPFC neuronal activity encodes working memory representations3. However, such studies have used simple displays and constrained gaze while subjects held information in working memory3, which put into question their ethological validity4,5. 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.

neuroscience↗