Macaque Prefrontal Cortex Research Articles

Attractor dynamics in morph-shape working memory in macaque prefrontal cortex

Attractor dynamics in morph-shape working memory in macaque prefrontal cortex

Neural population dynamics of human working memory

The activity of neurons in macaque prefrontal cortex (PFC) persists during working memory (WM) delays, providing a mechanism for memory.1,2,3,4,5,6,7,8,9,10,11 Although theory,11,12 including formal network models,13,14 assumes that WM codes are stable over time, PFC neurons exhibit dynamics inconsistent with these assumptions.15,16,17,18,19 Recently, multivariate reanalyses revealed the coexistence of both stable and dynamic WM codes in macaque PFC.20,21,22,23 Human EEG studies also suggest that WM might contain dynamics.24,25 Nonetheless, how WM dynamics vary across the cortical hierarchy and which factors drive dynamics remain unknown. To elucidate WM dynamics in humans, we decoded WM content from fMRI responses across multiple cortical visual field maps.26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48 We found coexisting stable and dynamic neural representations of WM during a memory-guided saccade task. Geometric analyses of neural subspaces revealed that early visual cortex exhibited stronger dynamics than high-level visual and frontoparietal cortex. Leveraging models of population receptive fields, we visualized and made the neural dynamics interpretable. We found that during WM delays, V1 population initially encoded a narrowly tuned bump of activation centered on the peripheral memory target. Remarkably, this bump then spread inward toward foveal locations, forming a vector along the trajectory of the forthcoming memory-guided saccade. In other words, the neural code transformed into an abstraction of the stimulus more proximal to memory-guided behavior. Therefore, theories of WM must consider both sensory features and their task-relevant abstractions because changes in the format of memoranda naturally drive neural dynamics.

Characterizing the spatial organization of population codes in macaque prefrontal cortex during visuospatial tasks

Characterizing the spatial organization of population codes in macaque prefrontal cortex during visuospatial tasks

Neural responses in macaque prefrontal cortex are linked to strategic exploration.

Humans have been shown to strategically explore. They can identify situations in which gathering information about distant and uncertain options is beneficial for the future. Because primates rely on scarce resources when they forage, they are also thought to strategically explore, but whether they use the same strategies as humans and the neural bases of strategic exploration in monkeys are largely unknown. We designed a sequential choice task to investigate whether monkeys mobilize strategic exploration based on whether information can improve subsequent choice, but also to ask the novel question about whether monkeys adjust their exploratory choices based on the contingency between choice and information, by sometimes providing the counterfactual feedback about the unchosen option. We show that monkeys decreased their reliance on expected value when exploration could be beneficial, but this was not mediated by changes in the effect of uncertainty on choices. We found strategic exploratory signals in anterior and mid-cingulate cortex (ACC/MCC) and dorsolateral prefrontal cortex (dlPFC). This network was most active when a low value option was chosen, which suggests a role in counteracting expected value signals, when exploration away from value should to be considered. Such strategic exploration was abolished when the counterfactual feedback was available. Learning from counterfactual outcome was associated with the recruitment of a different circuit centered on the medial orbitofrontal cortex (OFC), where we showed that monkeys represent chosen and unchosen reward prediction errors. Overall, our study shows how ACC/MCC-dlPFC and OFC circuits together could support exploitation of available information to the fullest and drive behavior towards finding more information through exploration when it is beneficial.

Residual dynamics resolves recurrent contributions to neural computation.

Relating neural activity to behavior requires an understanding of how neural computations arise from the coordinated dynamics of distributed, recurrently connected neural populations. However, inferring the nature of recurrent dynamics from partial recordings of a neural circuit presents considerable challenges. Here we show that some of these challenges can be overcome by a fine-grained analysis of the dynamics of neural residuals-that is, trial-by-trial variability around the mean neural population trajectory for a given task condition. Residual dynamics in macaque prefrontal cortex (PFC) in a saccade-based perceptual decision-making task reveals recurrent dynamics that is time dependent, but consistently stable, and suggests that pronounced rotational structure in PFC trajectories during saccades is driven by inputs from upstream areas. The properties of residual dynamics restrict the possible contributions of PFC to decision-making and saccade generation and suggest a path toward fully characterizing distributed neural computations with large-scale neural recordings and targeted causal perturbations.

Geometrical representation of serial order in working memory.

Encoding a sequence relies on one's memory for ordinal succession of events and is critical for episodic memory, spatial navigation, language, and other cognitive functions. Investigating the neural mechanisms underlying sequence working memory in the macaque prefrontal cortex, Xie et al. (Science, 375, 632-639, 2022) uncovered a novel integrated representation of temporal and spatial information in different subspaces of a high-dimensional neural state space, offering broad implications across comparative cognition and neuroscience.

Delay-related activity in marmoset prefrontal cortex.

Persistent delay-period activity in prefrontal cortex (PFC) has long been regarded as a neural signature of working memory (WM). Electrophysiological investigations in macaque PFC have provided much insight into WM mechanisms; however, a barrier to understanding is the fact that a portion of PFC lies buried within the principal sulcus in this species and is inaccessible for laminar electrophysiology or optical imaging. The relatively lissencephalic cortex of the New World common marmoset (Callithrix jacchus) circumvents such limitations. It remains unknown, however, whether marmoset PFC neurons exhibit persistent activity. Here, we addressed this gap by conducting wireless electrophysiological recordings in PFC of marmosets performing a delayed-match-to-location task on a home cage-based touchscreen system. As in macaques, marmoset PFC neurons exhibited sample-, delay-, and response-related activity that was directionally tuned and linked to correct task performance. Models constructed from population activity consistently and accurately predicted stimulus location throughout the delay period, supporting a framework of delay activity in which mnemonic representations are relatively stable in time. Taken together, our findings support the existence of common neural mechanisms underlying WM performance in PFC of macaques and marmosets and thus validate the marmoset as a suitable model animal for investigating the microcircuitry underlying WM.

Effects of contraction bias on the decision process in the macaque prefrontal cortex.

Our representation of magnitudes such as time, distance, and size is not always veridical because it is affected by multiple biases. From a Bayesian perspective, estimation errors are considered to be the result of an optimization mechanism for the behavior in a noisy environment by integrating previous experience with the incoming sensory information. One influence of the distribution of past stimuli on perceptual decisions is represented by the regression toward the mean, a type of contraction bias. Using a spatial discrimination task with 2 stimuli presented sequentially at different distances from the center, we show that this bias is also present in macaques when comparing the magnitude of 2 distances. We found that the contraction of the first stimulus magnitude toward the center of the distribution accounted for some of the changes in performance, even more so than the effect of difficulty related to the ratio between stimulus magnitudes. At the neural level in the dorsolateral prefrontal cortex, the coding of the decision after the presentation of the second stimulus reflected the effect of the contraction bias on the discriminability of the stimuli at the behavioral level.

Decoding distributed oscillatory signals driven by memory and perception in the prefrontal cortex.

Sensory perception and memory recall generate different conscious experiences. Although externally and internally driven neural activities signifying the same perceptual content overlap in the sensory cortex, their distribution in the prefrontal cortex (PFC), an area implicated in both perception and memory, remains elusive. Here, we test whether the local spatial configurations and frequencies of neural oscillations driven by perception and memory recall overlap in the macaque PFC using high-density electrocorticography and multivariate pattern analysis. We find that dynamically changing oscillatory signals distributed across the PFC in the delta-, theta-, alpha-, and beta-band ranges carry significant, but mutually different, information predicting the same feature of memory-recalled internal targets and passively perceived external objects. These findings suggest that the frequency-specific distribution of oscillatory neural signals in the PFC serves cortical signatures responsible for distinguishing between different types of cognition driven by external perception and internal memory.

Geometry of sequence working memory in macaque prefrontal cortex.

How the brain stores a sequence in memory remains largely unknown. We investigated the neural code underlying sequence working memory using two-photon calcium imaging to record thousands of neurons in the prefrontal cortex of macaque monkeys memorizing and then reproducing a sequence of locations after a delay. We discovered a regular geometrical organization: The high-dimensional neural state space during the delay could be decomposed into a sum of low-dimensional subspaces, each storing the spatial location at a given ordinal rank, which could be generalized to novel sequences and explain monkey behavior. The rank subspaces were distributed across large overlapping neural groups, and the integration of ordinal and spatial information occurred at the collective level rather than within single neurons. Thus, a simple representational geometry underlies sequence working memory.

Orthogonal representations for robust context-dependent task performance in brains and neural networks

SummaryHow do neural populations code for multiple, potentially conflicting tasks? Here we used computational simulations involving neural networks to define “lazy” and “rich” coding solutions to this context-dependent decision-making problem, which trade off learning speed for robustness. During lazy learning the input dimensionality is expanded by random projections to the network hidden layer, whereas in rich learning hidden units acquire structured representations that privilege relevant over irrelevant features. For context-dependent decision-making, one rich solution is to project task representations onto low-dimensional and orthogonal manifolds. Using behavioral testing and neuroimaging in humans and analysis of neural signals from macaque prefrontal cortex, we report evidence for neural coding patterns in biological brains whose dimensionality and neural geometry are consistent with the rich learning regime.

A spatially embedded cortical connectome reveals complex transformations

In this issue of Neuron, Xu etal. (2022) use electrical microstimulation of macaque prefrontal cortex combined with functional MRI to map weighted orderly topographic relationships with other association cortex domains, revealing a spatially embedded large-scale organization likely to be functionally important.

Ultrasound modulation of macaque prefrontal cortex selectively alters credit assignment-related activity and behavior.

Credit assignment is the association of specific instances of reward to the specific events, such as a particular choice, that caused them. Without credit assignment, choice values reflect an approximate estimate of how good the environment was when the choice was made—the global reward state—rather than exactly which outcome the choice caused. Combined transcranial ultrasound stimulation (TUS) and functional magnetic resonance imaging in macaques demonstrate credit assignment–related activity in prefrontal area 47/12o, and when this signal was disrupted with TUS, choice value representations across the brain were impaired. As a consequence, behavior was no longer guided by choice value, and decision-making was poorer. By contrast, global reward state–related activity in the adjacent anterior insula remained intact and determined decision-making after prefrontal disruption.

CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.

Similarities in response non-linearities in macaque lateral prefrontal cortex visual neurons during in vivo and in vitro experiments. Implications for normalization models.

Similarities in response non-linearities in macaque lateral prefrontal cortex visual neurons during in vivo and in vitro experiments. Implications for normalization models.

Between persistently active and activity-silent frameworks: novel vistas on the cellular basis of working memory.

Recent work has revealed important new discoveries on the cellular mechanisms of working memory (WM). These findings have motivated several seemingly conflicting theories on the mechanisms of short‐term memory maintenance. Here, we summarize the key insights gained from these new experiments and critically evaluate them in light of three hypotheses: classical persistent activity, activity‐silent, and dynamic coding. The experiments discussed include the first direct demonstration of persistently active neurons in the human medial temporal lobe that form static attractors with relevance to WM, single‐neuron recordings in the macaque prefrontal cortex that show evidence for both persistent and more dynamic types of WM representations, and noninvasive neuroimaging in humans that argues for activity‐silent representations. A key insight that emerges from these new results is that there are several neural mechanisms that support the maintenance of information in WM. Finally, based on established cognitive theories of WM, we propose a coherent model that encompasses these seemingly contradictory results. We propose that the three neuronal mechanisms of persistent activity, activity‐silent, and dynamic coding map well onto the cognitive levels of information processing (within focus of attention, activated long‐term memory, and central executive) that Cowan's WM model proposes.

Minimax-optimal decoding of movement goals from local field potentials using complex spectral features

Objective. We consider the problem of predicting eye movement goals from local field potentials (LFP) recorded through a multielectrode array in the macaque prefrontal cortex. The monkey is tasked with performing memory-guided saccades to one of eight targets during which LFP activity is recorded and used to train a decoder. Approach. Previous reports have mainly relied on the spectral amplitude of the LFPs as decoding feature, while neglecting the phase without proper theoretical justification. This paper formulates the problem of decoding eye movement intentions in a statistically optimal framework and uses Gaussian sequence modeling and Pinsker’s theorem to generate minimax-optimal estimates of the LFP signals which are used as decoding features. The approach is shown to act as a low-pass filter and each LFP in the feature space is represented via its complex Fourier coefficients after appropriate shrinking such that higher frequency components are attenuated; this way, the phase information inherently present in the LFP signal is naturally embedded into the feature space. Main results. We show that the proposed complex spectrum-based decoder achieves prediction accuracy of up to at superficial cortical depths near the surface of the prefrontal cortex; this marks a significant performance improvement over conventional power spectrum-based decoders. Significance. The presented analyses showcase the promising potential of low-pass filtered LFP signals for highly reliable neural decoding of intended motor actions.

Muscarinic M1 Receptor Overstimulation Disrupts Working Memory Activity for Rules in Primate Prefrontal Cortex

Acetylcholine release in the prefrontal cortex (PFC),acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer's disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses. We hypothesized that M1R blockade and stimulation would disrupt and enhance rule representation in WM, respectively. Unexpectedly, M1R blockade did not consistently affect PFC neuronal rule selectivity. Moreover, M1R stimulation suppressed PFC activity, and at higher doses, degraded rule representations. Our results suggest that, in primates, the deleterious effects of general muscarinic blockade on PFC WM activity are not mediated by M1Rs, while their overstimulation deteriorates PFC rule maintenance.

Nonmonotonic spatial structure of interneuronal correlations in prefrontal microcircuits

Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in nonmonotonic correlation structures. Here, we show such a spatially nonmonotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A nonmonotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes.

Neuromodulation of Prefrontal Cortex in Non-Human Primates by Dopaminergic Receptors during Rule-Guided Flexible Behavior and Cognitive Control.

The prefrontal cortex (PFC) is indispensable for several higher-order cognitive and executive capacities of primates, including representation of salient stimuli in working memory (WM), maintenance of cognitive task set, inhibition of inappropriate responses and rule-guided flexible behavior. PFC networks are subject to robust neuromodulation from ascending catecholaminergic systems. Disruption of these systems in PFC has been implicated in cognitive deficits associated with several neuropsychiatric disorders. Over the past four decades, a considerable body of work has examined the influence of dopamine on macaque PFC activity representing spatial WM. There has also been burgeoning interest in neuromodulation of PFC circuits involved in other cognitive functions of PFC, including representation of rules to guide flexible behavior. Here, we review recent neuropharmacological investigations conducted in our laboratory and others of the role of PFC dopamine receptors in regulating rule-guided behavior in non-human primates. Employing iontophoresis, we examined the effects of local manipulation of dopaminergic subtypes on neuronal activity during performance of rule-guided pro- and antisaccades, an experimental paradigm sensitive to PFC integrity, wherein deficits in performance are reliably observed in many neuropsychiatric disorders. We found dissociable effects of dopamine receptors on neuronal activity for rule representation and oculomotor responses and discuss these findings in the context of prior studies that have examined the role of dopamine in spatial delayed response tasks, attention, target selection, abstract rules, visuomotor learning and reward. The findings we describe here highlight the common features, as well as heterogeneity and context dependence of dopaminergic neuromodulation in regulating the efficacy of cognitive functions of PFC in health and disease.