# Altered acetylcholine modulations and corticoaccumbal pathway in P11-linked social dysfunction

## TL;DR

This study explores how P11 protein affects social behavior and emotional processing in the brain, linking it to depression and potential treatments.

## Contribution

The study identifies P11's role in modulating acetylcholine and dopamine in the corticoaccumbal pathway, impacting social dysfunction in depression.

## Key findings

- Chronic stress alters P11 expression in the corticoaccumbal circuit.
- P11-knockout mice show reduced social motivation and impaired emotion recognition.
- Oxytocin and social buffering therapy can rescue socially impaired behaviors.

## Abstract

Social relationships rely on the willingness to interact with others and the ability to interpret their emotional cues. Major depressive disorder (MDD) often leads to dysfunctional social interactions, marked by reduced social motivation and difficulties in recognizing emotions, yet these issues remain inadequately explored despite their significant impact on quality of life. These social behaviors, interconnected through the corticoaccumbal pathway, balance anxiety and social interaction, but the underlying mechanisms remain poorly understood. Notably, the calcium-binding protein S100A10 (also known as P11), which is dysregulated in MDD patients and influences the response to antidepressants, is prominently expressed in brain structures involved in social and emotional processing. Here, we demonstrate that chronic restraint stress alters P11 expression along the corticoaccumbal circuit. Additionally, our genetic model, P11-knockout mice, exhibit depression-like behavior, including a reduction of social motivation and impaired recognition of conspecific emotions. Using in vivo and ex vivo electrophysiology, we reveal that P11 expression modulates the response of the corticoaccumbal pathway, influencing the balance between anxiety and social interaction, as well as emotion recognition by regulating dopamine and acetylcholine release in the accumbens. Interestingly, we pinpoint the role of different cholinergic structures in anxiety, social motivation, and emotion recognition. Finally, we show that the prosocial compound oxytocin and social buffering therapy were able to rescue the socially impaired behaviors following chronic stress or P11 ablation, opening new avenues for potential treatments.