This study investigated the role of signal transducer and activator of transcription 3 (STAT3) in the midbrain serotonergic system, focusing on its relevance to emotional behavior in mice. Using germline genetic and viral-mediated approaches to selectively knock down raphe STAT3 expression, researchers found that mice lacking serotonergic STAT3 exhibited reduced negative behavioral reactivity and blunted responses to amphetamine sensitization. These alterations were accompanied by changes in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of genes associated with neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 replicated the behavioral changes observed in STAT3 knockout mice, suggesting that DR STAT3 disruption in adult mice is sufficient to produce these effects. The findings indicate that DR STAT3 acts as a molecular gate for controlling behavioral reactivity, linking upstream STAT3 activators, serotonergic neurotransmission, and psychopathology.

Sonali N. Reisinger, Spyros Sideromenos, Orsolya Horvath, Sophia Derdak, Ana Cicvaric, Francisco J. Monje, Martin Bilban, Martin Häring, Micaela Glat, Daniela D. Pollak