# Subtype-Specific Roles of Anterior Cingulate Cortex Neurons in Pain-Induced Social Deficits in Mice

## TL;DR

This study explores how specific brain cells in mice contribute to social behavior problems caused by chronic pain, revealing that different types of neurons have distinct roles.

## Contribution

The study identifies distinct functional roles of ACC GABAergic and CaMKII+ neurons in pain-induced social deficits, revealing a functional conflict in the ACC.

## Key findings

- GABAergic neurons in the ACC reduce pain hypersensitivity but do not improve social deficits.
- PV+ interneurons regulate both pain and social preference deficits, while SST+ neurons specifically mediate social novelty deficits.
- Inhibiting GABAergic neurons improves social deficits, while inhibiting CaMKII+ neurons reduces pain but partially restores social preference.

## Abstract

Pain is frequently accompanied by impairments in social behavior; however, the neural circuitry underlying pain-induced social deficits remains poorly understood. The aim of the present study was to delineate the distinct functional roles of γ-aminobutyric acid-releasing (GABAergic) neurons and calcium/calmodulin-dependent protein kinase II-positive (CaMKII+) neurons in the anterior cingulate cortex (ACC) in mediating pain-induced social deficits.

Mouse models of inflammatory and neuropathic pain were employed. Optogenetic and chemogenetic approaches, combined with fiber photometry, were used to manipulate and monitor the activity of ACC neuronal subtypes. Social behaviors were assessed using the three-chamber social interaction test. Mechanical and thermal pain sensitivity were evaluated using von Frey filaments and the Hargreaves test, respectively.

Mice with chronic pain exhibited deficits in social preference and novelty. In vivo calcium imaging revealed that, during social interaction under pain conditions, the activity of ACC GABAergic neurons was reduced, whereas that of CaMKII+ neurons was increased. Chemogenetic manipulation demonstrated functional dissociation between these neuronal populations: activation of GABAergic neurons alleviated pain hypersensitivity but failed to rescue social deficits, whereas inhibition of these neurons improved pain-induced social deficits. Conversely, inhibition of CaMKII⁺ neurons attenuated hyperalgesia, while their activation partially restored social preference. Further analyses identified distinct interneuron subtype contributions, with parvalbumin-positive (PV+) neurons regulating both pain and pain-induced social preference deficits, and somatostatin-positive (SST⁺) neurons selectively mediating pain-induced social novelty deficits. These findings indicate that ACC neuronal subtypes exert complementary yet specialized roles in the comorbidity of pain and social deficits.

Distinct ACC neuronal subtypes differentially regulate pain and social behaviors, revealing a functional “conflict” within the ACC whereby modulation of a single neuronal population cannot simultaneously ameliorate both pain and social deficits. These results underscore the necessity of circuit- and subtype-specific intervention strategies to disentangle and therapeutically target pain-related social deficit.