STAT3S727 Phosphorylation in VTA Dopaminergic Neurons Competed by O-GlcNAcylation Regulates Acute Stress-Induced Anxiety and Reward Inhibition [RNA-Seq Ogt]

Acute stress can inhibit the activity of dopaminergic neurons in the ventral tegmental area (VTA), leading to increased anxiety and reduced sensitivity to natural rewards. However, the molecular mechanisms underlying this effect remain unclear. Our study shows that acute restraint stress increases the phosphorylation of the transcription factor STAT3 at Ser727 and Tyr705 in VTA dopaminergic neurons, enhancing its transcriptional activity. This modulation contributes to the inhibition of dopaminergic neuron activity, heightened anxiety, and reduced reward sensitivity. Furthermore, acute stress also promotes O-GlcNAcylation in VTA neurons, which competes with STAT3 Ser727 but not Tyr705 phosphorylation and modulates its transcriptional activity, leading to alterations in GABA receptor expression. This reveals a complex molecular feedback mechanism where O-GlcNAcylation regulates STAT3 activity to maintain brain homeostasis during acute stress responses. To explore the differential gene signaling pathway changes in VTA dopaminergic neurons caused by Ogt knockdown.Ogt flox+/Y and Ogt flox-/Y mice were injected with AAV-TH-Cre and AAV-Flex-NBL10 in the VTA, and ribosome-associated mRNA expressing NBL10-HA was enriched and subjected to RNA sequencing.