The rules governing behavior often vary with behavioral contexts. As a result, an action rewarded in one context may be discouraged in another. Animals and humans are capable of switching between behavioral strategies under different contexts and acting adaptively according to the variable rules, a flexibility that is thought to be mediated by the prefrontal cortex (PFC). However, how the PFC orchestrates the context-dependent switch of strategies remains unclear. Here we show that pathway-specific projection neurons in the medial PFC (mPFC) differentially contribute to context-instructed strategy selection. In mice trained in a decision-making task in which a previously established rule and a newly learned rule are associated with distinct contexts, the activity of mPFC neurons projecting to the dorsomedial striatum (mPFC-DMS) encodes the contexts and further represents decision strategies conforming to the old and new rules. Moreover, mPFC-DMS neuron activity is required for the context-instructed strategy selection. In contrast, the activity of mPFC neurons projecting to the ventral midline thalamus (mPFC-VMT) does not discriminate between the contexts, and represents the old rule even if mice have adopted the new one. Furthermore, these neurons act to prevent the strategy switch under the new rule. Our results suggest that mPFC-DMS neurons promote flexible strategy selection guided by contexts, whereas mPFC-VMT neurons favor fixed strategy selection by preserving old rules.

Brains can gracefully weed out irrelevant stimuli to guide behavior. This feat is believed to rely on a progressive selection of task-relevant stimuli across the cortical hierarchy, but the specific across-area interactions enabling stimulus selection are still unclear. Here, we propose that population gating, occurring within A1 but controlled by top-down inputs from mPFC, can support across-area stimulus selection. Examining single-unit activity recorded while rats performed an auditory context-dependent task, we found that A1 encoded relevant and irrelevant stimuli along a common dimension of its neural space. Yet, the relevant stimulus encoding was enhanced along an extra dimension. In turn, mPFC encoded only the stimulus relevant to the ongoing context. To identify candidate mechanisms for stimulus selection within A1, we reverse-engineered low-rank RNNs trained on a similar task. Our analyses predicted that two context-modulated neural populations gated their preferred stimulus in opposite contexts, which we confirmed in further analyses of A1. Finally, we show in a two-region RNN how population gating within A1 could be controlled by top-down inputs from PFC, enabling flexible across-area communication despite fixed inter-areal connectivity.

Working memory involves the short-term maintenance of information and is critical in many tasks. The neural circuit dynamics underlying working memory remain poorly understood, with different aspects of prefrontal cortical (PFC) responses explained by different putative mechanisms. By mathematical analysis, numerical simulations, and using recordings from monkey PFC, we investigate a critical but hitherto ignored aspect of working memory dynamics: information loading. We find that, contrary to common assumptions, optimal information loading involves inputs that are largely orthogonal, rather than similar, to the persistent activities observed during memory maintenance. Using a novel, theoretically principled metric, we show that PFC exhibits the hallmarks of optimal information loading and we find that such dynamics emerge naturally as a dynamical strategy in task-optimized recurrent neural networks. Our theory unifies previous, seemingly conflicting theories of memory maintenance based on attractor or purely sequential dynamics, and reveals a normative principle underlying the widely observed phenomenon of dynamic coding in PFC.

Flow is defined as an altered state of consciousness with excessive attention and enormous sense of pleasure, when engaged in a challenging task, first postulated by a psychologist, the late M. Csikszentmihayli. The main focus of this talk will be “Team Flow,” but there were two lines of previous studies in our laboratory as its background. First is inter-body and inter-brain coordination/synchrony between individuals. Considering various rhythmic echoing/synchronization phenomena in animal behavior, it could be regarded as the biological, sub-symbolic and implicit origin of social interactions. The second line of precursor research is on the state of Solo Flow in game playing. We employed attenuation of AEP (Auditory Evoked Potential) to task-irrelevant sound probes as an objective-neural indicator of such a Flow status, and found that; 1) Mutual link between the ACC & the TP is critical, and 2) overall, top-down influence is enhanced while bottom-up causality is attenuated. Having these as the background, I will present our latest study of Team Flow in game playing. We found that; 3) the neural correlates of Team Flow is distinctively different from those of Solo Flow nor of non-flow social, 4) the left medial temporal cortex seems to form an integrative node for Team Flow, receiving input related to Solo Flow state from the right PFC and input related to social state from the right IFC, and 5) Intra-brain (dis)similarity of brain activity well predicts (dis)similarity of skills/cognition as well as affinity for inter-brain coherence.

During primate evolution, prefrontal cortex (PFC) expanded substantially relative to other cortical areas. The expansion of PFC circuits likely supported the increased cognitive abilities of humans and anthropoids to sample information about their environment, evaluate that information, plan, and decide between different courses of action. What quantities do these circuits compute as information is being sampled towards and a decision is being made? And how can they be related to anatomical specialisations within and across PFC? To address this, we recorded PFC activity during value-based decision making using single unit recording in non-human primates and magnetoencephalography in humans. At a macrocircuit level, we found that value correlates differ substantially across PFC subregions. They are heavily shaped by each subregion’s anatomical connections and by the decision-maker’s current locus of attention. At a microcircuit level, we found that the temporal evolution of value correlates can be predicted using cortical recurrent network models that temporally integrate incoming decision evidence. These models reflect the fact that PFC circuits are highly recurrent in nature and have synaptic properties that support persistent activity across temporally extended cognitive tasks. Our findings build upon recent work describing economic decision making as a process of attention-weighted evidence integration across time.

Norepinephrine (NE) is a neuromodulator that is released from projections of the locus coeruleus via extra-synaptic vesicle exocytosis. Tonic fluctuations in NE are involved in brain states, such as sleep, arousal, and attention. Previously, NE in the PFC was thought to be a homogenous field created by bulk release, but it remains unknown whether phasic (fast, short-term) fluctuations in NE can produce a spatially heterogeneous field, which could then structure cell firing at a fine spatial scale. To understand how spatiotemporal dynamics of norepinephrine (NE) release in the prefrontal cortex affect neuronal firing, we performed a novel in-vivo two-photon imaging experiment in layer ⅔ of the prefrontal cortex using a green fluorescent NE sensor and a red fluorescent Ca2+ sensor, which allowed us to simultaneously observe fine-scale neuronal and NE dynamics in the form of spatially localized fluorescence time series. Using generalized linear modeling, we found that the local NE field differs from the global NE field in transient periods of decorrelation, which are influenced by proximal NE release events. We used optical flow and pattern analysis to show that release and reuptake events can occur at the same location but at different times, and differential recruitment of release and reuptake sites over time is a potential mechanism for creating a heterogeneous NE field. Our generalized linear models predicting cellular dynamics show that the heterogeneous local NE field, and not the global field, drives cell firing dynamics. These results point to the importance of local, small-scale, phasic NE fluctuations for structuring cell firing. Prior research suggests that these phasic NE fluctuations in the PFC may play a role in attentional shifts, orienting to sensory stimuli in the environment, and in the selective gain of priority representations during stress (Mather, Clewett et al. 2016) (Aston-Jones and Bloom 1981).

Low-dimensional population dynamics can be observed in neural activity recorded from the prefrontal cortex (PFC) of subjects performing simple cognitive tasks. Many studies have shown that recurrent neural networks (RNNs) trained on the same tasks can reproduce qualitatively these state space trajectories, and have used them as models of how neuronal dynamics implement task computations. The PFC is also viewed as a conductor that organizes the communication between cortical areas and provides contextual information. It is then not clear what is its role in solving simple cognitive tasks. Do the low-dimensional trajectories observed in the PFC really correspond to the computations that it performs? Or do they indirectly reflect the computations occurring within the cortical areas projecting to the PFC? To address these questions, we modelled cortical areas with a modular RNN and equipped it with a PFC-like cognitive system. When trained on cognitive tasks, this multi-system brain model can reproduce the low-dimensional population responses observed in neuronal activity as well as classical RNNs. Qualitatively different mechanisms can emerge from the training process when varying some details of the architecture such as the time constants. In particular, there is one class of models where it is the dynamics of the cognitive system that is implementing the task computations, and another where the cognitive system is only necessary to provide contextual information about the task rule as task performance is not impaired when preventing the system from accessing the task inputs. These constitute two different hypotheses about the causal role of the PFC in solving simple cognitive tasks, which could motivate further experiments on the brain.

In an ever-changing environment, uncertainty is omnipresent. To deal with this, organisms have evolved mechanisms that allow them to take advantage of environmental regularities in order to make decisions robustly and adjust their behavior efficiently, thus maximizing their chances of survival. In this talk, I will present behavioral evidence that animals perform model-based state inference to predict environmental state changes and adjust their behavior rapidly, rather than slowly updating choice values. This model-based inference process can be described using Bayesian change-point models. Furthermore, I will show that neural populations in the prefrontal cortex accurately predict behavioral switches, and that the activity of these populations is associated with Bayesian estimates. In addition, we will see that learning leads to the emergence of a high-dimensional representational subspace that can be reused when the animals re-learn a previously learned set of action-value associations. Altogether, these findings highlight the role of the PFC in representing a belief about the current state of the world.

I am interested in developing a neurally mechanistic understanding of how primate brains represent the world through its visual system and how such representations enable a remarkable set of intelligent behaviors. In this talk, I will primarily highlight aspects of my current research that focuses on dissecting the brain circuits that support core object recognition behavior (primates’ ability to categorize objects within hundreds of milliseconds) in non-human primates. On the one hand, my work empirically examines how well computational models of the primate ventral visual pathways embed knowledge of the visual brain function (e.g., Bashivan*, Kar*, DiCarlo, Science, 2019). On the other hand, my work has led to various functional and architectural insights that help improve such brain models. For instance, we have exposed the necessity of recurrent computations in primate core object recognition (Kar et al., Nature Neuroscience, 2019), one that is strikingly missing from most feedforward artificial neural network models. Specifically, we have observed that the primate ventral stream requires fast recurrent processing via ventrolateral PFC for robust core object recognition (Kar and DiCarlo, Neuron, 2021). In addition, I have been currently developing various chemogenetic strategies to causally target specific bidirectional neural circuits in the macaque brain during multiple object recognition tasks to further probe their relevance during this behavior. I plan to transform these data and insights into tangible progress in neuroscience via my collaboration with various computational groups and building improved brain models of object recognition. I hope to end the talk with a brief glimpse of some of my planned future work!

During primate evolution, prefrontal cortex (PFC) expanded substantially relative to other cortical areas. The expansion of PFC circuits likely supported the increased cognitive abilities of humans and anthropoids to plan, evaluate, and decide between different courses of action. But what do these circuits compute as a decision is being made, and how can they be related to anatomical specialisations within and across PFC? To address this, we recorded PFC activity during value-based decision making using single unit recording in non-human primates and magnetoencephalography in humans. At a macrocircuit level, we found that value correlates differ substantially across PFC subregions. They are heavily shaped by each subregion’s anatomical connections and by the decision-maker’s current locus of attention. At a microcircuit level, we found that the temporal evolution of value correlates can be predicted using cortical recurrent network models that temporally integrate incoming decision evidence. These models reflect the fact that PFC circuits are highly recurrent in nature and have synaptic properties that support persistent activity across temporally extended cognitive tasks. Our findings build upon recent work describing economic decision making as a process of attention-weighted evidence integration across time.

Among mammals, excellent color vision has evolved only in certain non-human primates. And yet, color is often assumed to be just a low-level stimulus feature with a modest role in encoding and recognizing objects. The rationale for this dogma is compelling: object recognition is excellent in grayscale images (consider black-and-white movies, where faces, places, objects, and story are readily apparent). In my talk I will discuss experiments in which we used color as a tool to uncover an organizational plan in inferior temporal cortex (parallel, multistage processing for places, faces, colors, and objects) and a visual-stimulus functional representation in prefrontal cortex (PFC). The discovery of an extensive network of color-biased domains within IT and PFC, regions implicated in high-level object vision and executive functions, compels a re-evaluation of the role of color in behavior. I will discuss behavioral studies prompted by the neurobiology that uncover a universal principle for color categorization across languages, the first systematic study of the color statistics of objects and a chromatic mechanism by which the brain may compute animacy, and a surprising paradoxical impact of memory on face color. Taken together, my talk will put forward the argument that color is not primarily for object recognition, but rather for the assessment of the likely behavioral relevance, or meaning, of the stuff we see.

Cortical circuits receive multiple inputs from upstream populations with non-overlapping stimulus tuning preferences. Both the feedforward and recurrent architectures of the receiving cortical layer will reflect this diverse input tuning. We study how population-wide neuronal variability propagates through a hierarchical cortical network receiving multiple, independent, tuned inputs. We present new analysis of in vivo neural data from the primate visual system showing that the number of latent variables (dimension) needed to describe population shared variability is smaller in V4 populations compared to those of its downstream visual area PFC. We successfully reproduce this dimensionality expansion from our V4 to PFC neural data using a multi-layer spiking network with structured, feedforward projections and recurrent assemblies of multiple, tuned neuron populations. We show that tuning-structured connectivity generates attractor dynamics within the recurrent PFC current, where attractor competition is reflected in the high dimensional shared variability across the population. Indeed, restricting the dimensionality analysis to activity from one attractor state recovers the low-dimensional structure inherited from each of our tuned inputs. Our model thus introduces a framework where high-dimensional cortical variability is understood as ``time-sharing’’ between distinct low-dimensional, tuning-specific circuit dynamics.

The Arnsten lab studies molecular influences on the higher cognitive circuits of the dorsolateral prefrontal cortex (dlPFC), in order to understand mechanisms affecting working memory at the cellular and behavioral levels, with the overarching aim of identifying the actions that render the dlPFC so vulnerable in cognitive disorders. Her lab has shown that the dlPFC has unique neurotransmission and neuromodulation compared to the classic actions found in the primary visual cortex, including mechanisms to rapidly weaken PFC connections during uncontrollable stress. Reduced regulation of these stress pathways due to genetic or environmental insults contributes to dlPFC dysfunction in cognitive disorders, including calcium dysregulation and tau phosphorylation in the aging association cortex. Understanding these unique mechanisms has led to the development of a new treatment, IntunivTM, for a variety of PFC disorders.