mPFC

The medial prefrontal cortex replays generalized sequences

Whilst spatial navigation is a function ascribed to the hippocampus, flexibly adapting to a change in rule depends on the medial prefrontal cortex (mPFC). Single-units were recorded from the hippocampus and mPFC of rats shifting between a spatially- and cue-guided rule on a plus-maze. The mPFC population coded for the relative position between start and goal arm. During awake immobility periods, the mPFC replayed organized sequences of generalized positions which positively correlated with rule-switching performance. Conversely, hippocampal replay negatively correlated with performance and occurred independently of mPFC replay. Sequential replay in the hippocampus and mPFC may thus serve different functions.

Prefrontal top-down projections control context-dependent strategy selection

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.

Flexible selection of task-relevant features through population gating

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.

Dissecting the neural circuits underlying prefrontal regulation of reward and threat responsivity in a primate

Gaining insight into the overlapping neural circuits that regulate positive and negative emotion is an important step towards understanding the heterogeneity in the aetiology of anxiety and depression and developing new treatment targets. Determining the core contributions of the functionally heterogenous prefrontal cortex to these circuits is especially illuminating given its marked dysregulation in affective disorders. This presentation will review a series of studies in a new world monkey, the common marmoset, employing pathway-specific chemogenetics, neuroimaging, neuropharmacology and behavioural and cardiovascular analysis to dissect out prefrontal involvement in the regulation of both positive and negative emotion. Highlights will include the profound shift of sensitivity away from reward and towards threat induced by localised activations within distinct regions of vmPFC, namely areas 25 and 14 as well as the opposing contributions of this region, compared to orbitofrontal and dorsolateral prefrontal cortex, in the overall responsivity to threat. Ongoing follow-up studies are identifying the distinct downstream pathways that mediate some of these effects as well as their differential sensitivity to rapidly acting anti-depressants.

From single cell to population coding during defensive behaviors in prefrontal circuits

Coping with threatening situations requires both identifying stimuli predicting danger and selecting adaptive behavioral responses in order to survive. The dorso medial prefrontal cortex (dmPFC) is a critical structure involved in the regulation of threat-related behaviour, yet it is still largely unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks in order to successfully drive adaptive responses. Over the past years, we used a combination we used a combination of extracellular recordings, neuronal decoding approaches, and state of the art optogenetic manipulations to identify key neuronal elements and mechanisms controlling defensive fear responses. I will present an overview of our recent work ranging from analyses of dedicated neuronal types and oscillatory and synchronization mechanisms to artificial intelligence approaches used to decode the activity or large population of neurons. Ultimately these analyses allowed the identification of high dimensional representations of defensive behavior unfolding within prefrontal networks.

A Network for Computing Value Equilibrium in the Human Medial Prefrontal Corte

Humans and other animals make decisions in order to satisfy their goals. However, it remains unknown how neural circuits compute which of multiple possible goals should be pursued (e.g., when balancing hunger and thirst) and how to combine these signals with estimates of available reward alternatives. Here, humans undergoing fMRI accumulated two distinct assets over a sequence of trials. Financial outcomes depended on the minimum cumulate of either asset, creating a need to maintain “value equilibrium” by redressing any imbalance among the assets. Blood-oxygen-level-dependent (BOLD) signals in the rostral anterior cingulate cortex (rACC) tracked the level of imbalance among goals, whereas the ventromedial prefrontal cortex (vmPFC) signaled the level of redress incurred by a choice rather than the overall amount received. These results suggest that a network of medial frontal brain regions compute a value signal that maintains value equilibrium among internal goals.

Dynamical population coding during defensive behaviours in prefrontal circuits

Coping with threatening situations requires both identifying stimuli predicting danger and selecting adaptive behavioral responses in order to survive. The dorso medial prefrontal cortex (dmPFC) is a critical structure involved in the regulation of threat-related behaviour, yet it is still largely unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks in order to successfully drive adaptive responses. To address these questions, we used a combination of extracellular recordings, neuronal decoding approaches, and optogenetic manipulations to show that threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. These data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations and discriminates threat- from non-threat cues, it does not predict action outcome. In contrast, transient dmPFC population activity prior to action initiation reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity critically constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of active fear responses relies on a dynamic process of information linking threats with defensive actions unfolding within prefrontal networks.

Dynamical population coding during defensive behaviours in prefrontal circuits

Coping with threatening situations requires both identifying stimuli predicting danger and selecting adaptive behavioral responses in order to survive. The dorso medial prefrontal cortex (dmPFC) is a critical structure involved in the regulation of threat-related behaviour, yet it is still largely unclear how threat-predicting stimuli and defensive behaviours are associated within prefrontal networks in order to successfully drive adaptive responses. To address these questions, we used a combination of extracellular recordings, neuronal decoding approaches, and optogenetic manipulations to show that threat representations and the initiation of avoidance behaviour are dynamically encoded in the overall population activity of dmPFC neurons. These data indicate that although dmPFC population activity at stimulus onset encodes sustained threat representations and discriminates threat- from non-threat cues, it does not predict action outcome. In contrast, transient dmPFC population activity prior to action initiation reliably predicts avoided from non-avoided trials. Accordingly, optogenetic inhibition of prefrontal activity critically constrained the selection of adaptive defensive responses in a time-dependent manner. These results reveal that the adaptive selection of active fear responses relies on a dynamic process of information linking threats with defensive actions unfolding within prefrontal networks.

AGE-DEPENDENT CONTROL OF SLEEP HOMEOSTASIS BY LAYER 5 MPFC NEURONS

FENS Forum 2026

NEURAL SIGNATURES OF VMPFC–AMYGDALA CONNECTIVITY UNDERLYING LONGITUDINAL ANXIETY DYNAMICS AND POSITIVE AFFECT STABILITY

FENS Forum 2026

IMPACT ON TRANSCALLOSAL, LONG RANGE AND LOCAL MPFC EXCITATORY INPUTS BY EARLY POSTNATAL NMDA RECEPTOR ABLATION

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ELEVATED MATERNAL IMMUNE SIGNALING ALTERS CELL-SPECIFIC TRANSCRIPTOMIC PROFILES IN VMPFC–AMYGDALA CIRCUITRY IN NONHUMAN PRIMATE OFFSPRING

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CHRONIC STRESS REPROGRAMS SYNAPTIC AND TRANSCRIPTIONAL SIGNATURES OF THE MPFC-VTA CIRCUITRY TO IMPAIR COGNITION

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NEURONAL CIRCUITRY AND CELLULAR ORGANIZATION OF THE MOUSE CLAUSTRUM IN RELATION TO THE MPFC, AMYGDALA, AND CORTICAL LAYER 6B

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SEROTONERGIC Α-SYNUCLEINOPATHY DISRUPTS VMPFC–RAPHE CIRCUIT ACTIVITY AND CONNECTIVITY, PROMOTING AN ANXIETY-LIKE PHENOTYPE IN FEMALE MICE

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FREQUENCY-SPECIFIC OSCILLATORY DYNAMICS AND FUNCTIONAL CONNECTIVITY IN MPFC–NAC CIRCUITS DURING SOCIAL INTERACTION IN MALE MICE

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CIRCUIT-SPECIFIC ACTIVATION OF THE DORSAL CA1 - MPFC PATHWAY AS A MECHANISM FOR DOPAMINE DYSREGULATION IN SCHIZOPHRENIA RELEVANT BEHAVIORS

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TASK-EVOKED OXYGEN SUPPLY AND UTILIZATION DYNAMICS IN HUMAN MPFC DURING VIRTUAL SPATIAL NAVIGATION MEASURED WITH A HIGH-SENSITIVITY WEARABLE FNIRS

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HYPERACTIVE GSK3 SIGNALING FAILS TO PRESERVE MPFC NEURONAL EXCITABILITY IN MICE SUSCEPTIBLE TO CHRONIC SOCIAL DEFEAT STRESS

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FUNCTIONAL NEURONAL ENSEMBLES ENCODE AND STORE SAFETY MEMORY IN THE DMPFC

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mGluR5-mediated deactivation of mPFC via somatostatin-positive interneuron in neuropathic pain mice

FENS Forum 2024

Plasticity-related alterations in the mPFC of a dual-hit model of schizophrenia in rat

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The role of local and long-range mPFC connections in the consolidation of memories

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The role of the mPFC pyramidal neurons in mediating social choice

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Altered circadian clock gene expression in the mPFC of mouse model of depression and its modulation by rapid antidepressant treatments

BLA-mPFC-DMS circuitry: The gateway to the effect of fear on action control

Shedding light on object location recall: Optogenetic priming of the HIP-mPFC pathway for object-location memory

FENS Forum 2024

The HIP-mPFC network is a neural resource of object recognition memory

The role of mPFC spatial coding in supporting a contextual association task

The roles of the human orbitofrontal cortex, vmPFC, and anterior cingulate cortex connectome in emotion and memory

Stability of task representations in mouse mPFC across different behaviors

FENS Forum 2024

Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression

FENS Forum 2024

Cerebellar neuronal activity during emotional control and the role of cerebellar-mPFC pathway in fear learning

FENS Forum 2024

The circadian molecular clock in mPFC modulates the depressive phenotype and represents a potential treatment pathway

FENS Forum 2024

Early postnatal NMDA receptor ablation differentially impacts on transcallosal and long-range mPFC inputs

FENS Forum 2024