# Separate BNST Microcircuits Targeted by Direct Versus Amygdala-Relayed Prefrontal Inputs Mediate Dissociable Phenotypes After Isolation

## TL;DR

This study identifies two separate brain circuits in mice that control different behaviors like anxiety and social skills, which could help explain why these conditions often occur together.

## Contribution

The study reveals distinct BNST microcircuits mediating dissociable behavioral outcomes via direct and BLA-relayed PFC inputs.

## Key findings

- BLA relays PFC signals to BNST, driving anxiety, depression, and social deficits.
- Indirect BLA-relayed pathway affects emotional behaviors without altering social behavior.
- Direct PFC → BNST pathway specifically restores social recognition without affecting emotional behaviors.

## Abstract

Anxiety, depression, and social impairment exhibit high clinical comorbidity, yet their underlying shared neural circuitry remains poorly defined. Using a mouse model of chronic social isolation combined with circuit tracing and chemogenetic tools, we identified a key role for the basolateral amygdala (BLA) in relaying prefrontal cortex (PFC) signals to the bed nucleus of the stria terminalis (BNST) to drive behavioral changes. Further circuit dissection identified two distinct BNST microcircuits segregated by their input sources: one receives indirect PFC input relayed through the BLA (PFC → BLA → BNST), while the other is innervated by direct PFC projections (PFC → BNST). Chemogenetic inhibition of BLA neurons in the indirect pathway ameliorated anxiety-like behavior, depression-like behavior, and social deficits. Within the BNST, however, inhibition of neurons in PFC → BLA → BNST pathway selectively alleviated affective phenotypes without altering social behavior. In contrast, inhibition of neurons in PFC → BNST pathway specifically restored social recognition while leaving emotional behaviors intact. Thus, the BLA integrates PFC-derived signals to broadly modulate behavior, while downstream BNST microcircuits dissociate these influences. The indirect, BLA-relayed pathway within the BNST specifically drives affective symptoms, whereas the direct PFC → BNST pathway selectively governs social recognition. This dissociable circuit model offers a new framework for understanding clinical comorbidity and may inform targeted interventions for distinct symptom dimensions.