# Counterbalancing O‐GlcNAcylation and STAT3 Phosphorylation in Ventral Tegmental Area Dopaminergic Neurons Mediates Behavioral Adaptations to Acute Restraint Stress

## TL;DR

This study shows how stress affects brain cells by changing two chemical signals that help control mood and reward sensitivity.

## Contribution

The paper reveals a new counterbalancing mechanism between O-GlcNAcylation and STAT3 phosphorylation in dopaminergic neurons during stress.

## Key findings

- Acute stress increases STAT3 phosphorylation, which reduces neuronal activity and reward sensitivity.
- O-GlcNAcylation counteracts these effects, helping maintain emotional balance.
- STAT3 phosphorylation promotes GABBR2 and GABRB3 upregulation, contributing to anxiety and reduced reward-seeking.

## Abstract

Acute stressors, significant risk factors for mood disorders, increase anxiety and reduce reward sensitivity. However, the underlying neuroadaptive mechanisms remain unclear. Here, it is shown that acute restraint stress upregulates Signal Transducer and Activator of Transcription 3 (STAT3) signaling and O‐GlcNAcylation in ventral tegmental area (VTA) dopaminergic (DAergic) neurons. Multi‐omics analyses in O‐linked N‐acetylglucosamine transferase (OGT) conditional knockout (cKO) mice reveal a counterbalancing mechanism between O‐GlcNAcylation and STAT3Ser727 phosphorylation. In vivo fiber‐optic recordings and behavioral experiments demonstrate that STAT3Ser727 phosphorylation mediates the suppression of DAergic neuronal activity and reward sensitivity, as well as the increased anxiety induced by acute restraint stress. Conversely, the upregulation of O‐GlcNAcylation in the VTA DAergic neurons prevents these effects. Furthermore, Gabbr2 and Gabrb3 expression is upregulated in the VTA of Ogt cKO mice, whereas the phosphorylation of STAT3Ser727 in the DAergic neurons is required for the upregulation of Gabbr2 and Gabrb3 induced by acute restraint stress. These findings highlight the dynamic and counterbalancing post‐translational modifications occurring in the VTA to maintain dopaminergic and emotional homeostasis, offering new insights into neuronal and behavioral responses to acute stress.

Acute restraint stress enhances STAT3Ser727 phosphorylation in dopaminergic neurons in mice. This modification promotes the upregulation of GABBR2 and GABRB3, reduces neuronal activity, and contributes to anxiety‐like behavior and diminished reward‐seeking following stress exposure. Meanwhile, O‐GlcNAcylation is upregulated in the VTA, counteracting STAT3 phosphorylation and mitigating stress‐induced neuronal and behavioral changes to help maintain emotional homeostasis.