Functional specialization of mPFC–BLA and mPFC–NAc pathways in affective state representation

Key findings from this study

• The study found that mPFC→NAc neurons showed significantly greater pattern decorrelation during center exploration and sniffing compared to mPFC→BLA neurons.
• The authors report that center-ON neurons were particularly abundant in the mPFC→BLA pathway and exhibited heightened activity during anxiety-associated behaviors.
• The researchers demonstrate that chronic positively valenced contexts enhanced mPFC→NAc activity while negatively valenced conditions boosted mPFC→BLA activity.
• The study found that mPFC→NAc neurons displayed significant pattern decorrelation during social interactions, suggesting specialized encoding of social preference.

Overview

This study examined functional specialization of two medial prefrontal cortex projection pathways in mice during affective behaviors. The authors used in vivo calcium imaging to record activity of mPFC neurons projecting to the basolateral amygdala versus nucleus accumbens during emotional tasks. The research aimed to distinguish how these two pathways, traditionally considered functionally similar, encode distinct affective states. The authors focused on neural activity patterns during anxiety-like, exploratory, and social behaviors. Chronic emotional manipulations were applied to test pathway-specific plasticity under positive versus negative valence conditions.

Methods and approach

The authors delivered retrograde AAV encoding GCaMP6m to the BLA and NAc of female mice, labeling mPFC neurons projecting to each target. A miniaturized microscope recorded calcium activity from identified neurons across behavioral sessions. The open field test assessed anxiety-like and exploratory behaviors, categorizing center time, corner time, wall-sniffing, and grooming. Principal component analysis evaluated population-level activity patterns. The authors tracked individual neurons across sessions to compare pathway responses. A social competition paradigm elicited affective states to probe pathway-specific plasticity. Chronic emotional state manipulations tested how positive versus negative valence contexts affected each pathway.

Results

During the open field test, mPFC→BLA and mPFC→NAc neurons exhibited similar overall firing rates across behaviors, with no main effect of pathway on transient rates. Principal component analysis revealed that both pathways encoded corner behavior similarly, with high correlation between population activity patterns. However, mPFC→NAc neurons showed significantly greater decorrelation from baseline corner states during center exploration and sniffing compared to mPFC→BLA neurons. Center-ON neurons, particularly abundant in the mPFC→BLA pathway, displayed heightened activity during center exploration, a behavior associated with heightened anxiety. The mPFC→NAc pathway demonstrated enhanced pattern decorrelation during social interactions, suggesting specialized encoding of social preference. Chronic emotional state manipulations differentially affected the pathways: positively valenced contexts increased mPFC→NAc activity, while negatively valenced conditions boosted mPFC→BLA activity. These findings reveal that despite superficial similarity in firing patterns, the two pathways exhibit distinct variability signatures and decorrelation dynamics aligned with their proposed roles in aversive versus appetitive behavioral regulation.

Implications

The findings challenge the assumption that mPFC→BLA and mPFC→NAc pathways function similarly in emotional processing. The differential decorrelation patterns suggest specialized encoding strategies: mPFC→BLA neurons may maintain stable representations during aversive states, while mPFC→NAc neurons dynamically reorganize activity during approach and social behaviors. The enrichment of center-ON neurons in the mPFC→BLA pathway supports a role in anxiety-related behavioral regulation, consistent with prior optogenetic studies linking this pathway to fear and anxiety. The enhanced decorrelation in mPFC→NAc neurons during social interactions points to a computational mechanism for processing social preference, extending beyond simple reward encoding. The differential response to chronic emotional contexts indicates pathway-specific plasticity mechanisms that may underlie affective state transitions. These correlational patterns provide targets for causal interventions but do not yet establish whether these pathways actively shape emotional states or merely reflect them. Future manipulations of specific neural ensembles identified here could determine whether decorrelation dynamics causally contribute to behavioral outcomes. The results suggest that ensemble-level analysis reveals functional specialization obscured by traditional bulk manipulation approaches.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.