Summary: STAT3 is a key molecular regulator within the serotonergic system that helps control emotional reactivity. These findings connect immune signaling, serotonin transmission and affective disorders such as depression.
Source: Medical University of Vienna
Many studies now indicate that inflammatory processes contribute to the development and progression of psychiatric conditions. Among the immune-related pathways of interest, the interleukin‑6/STAT3 signaling cascade has emerged as particularly relevant to disorders such as depression, schizophrenia and bipolar disorder.
A team at the Medical University of Vienna, led by Daniela Pollak in the Division of Neurophysiology and Neuropharmacology, has published new research in Molecular Psychiatry showing that STAT3 acts as an important molecular mediator within the brain’s serotonergic system. Their work identifies a mechanistic link between immune signaling, serotonin neurotransmission and behavioral outcomes relevant to affective disorders.
STAT3 is a signal transducer and activator of transcription that becomes active following phosphorylation by Janus kinases in response to a wide range of triggers, both immunogenic and non‑immunogenic. Prior research from this group and others suggested that STAT3 influences neuronal function, and earlier work demonstrated that STAT3 can regulate expression of the serotonin transporter gene.
Because alterations in serotonergic transmission — the communication between neurons that use serotonin as a neurotransmitter — are closely linked to the pathophysiology of depression and other mood disorders, the researchers focused on how STAT3 signaling interacts with serotonergic neurons and whether it influences emotional behaviour.
STAT3 deficiency reduces emotional reactivity
To investigate the role of STAT3 in emotional regulation, the investigators selectively inhibited STAT3 within the midbrain serotonergic system, a central hub for emotion regulation, using mouse models. They used both a germline genetic knockout (STAT3 KO) and viral-mediated knockdown approaches to reduce STAT3 expression specifically in serotonergic neurons of the dorsal raphe.
When STAT3 was selectively removed from serotonergic neurons in the midbrain, mice showed consistently reduced negative emotional reactivity in behavioral tests and a blunted neurochemical response to amphetamine. Because the same behavioral profile was observed in both genetic and adult viral knockdown models, the team could rule out developmental artifacts and conclude that acute disruption of STAT3 in the adult dorsal raphe is sufficient to alter emotional behaviour.
Further analyses revealed altered neuronal activity patterns in midbrain serotonergic cells of STAT3‑deficient animals and changes in gene expression networks that are relevant to neuropsychiatric disease. These molecular and physiological alterations support the behavioral observations and point to specific transcriptional programs downstream of STAT3 that may influence vulnerability to affective disorders.
Pollak and colleagues conclude that STAT3 functions as a molecular gate within the dorsal raphe serotonergic system, modulating behavioural reactivity and linking upstream immune signals to serotonin neurotransmission and affective pathology. This work therefore provides mechanistic evidence connecting immune‑related signaling pathways with neural circuits that regulate emotion.
About this genetics and psychology research news
Source: Medical University of Vienna
Contact: Thorsten Medwedeff – Medical University of Vienna
Image: The image is in the public domain.
Original Research: Open access.
“STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology” by Sonali N. Reisinger, Spyros Sideromenos, Orsolya Horvath, Sophia Derdak, Ana Cicvaric, Francisco J. Monje, Martin Bilban, Martin Häring, Micaela Glat & Daniela D. Pollak. Published in Molecular Psychiatry. DOI: 10.1038/s41380-020-00904-2
Abstract
STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology
STAT3 signaling is activated by phosphorylation through Janus kinases in response to diverse immunogenic and non‑immunogenic stimuli. A growing body of evidence implicates STAT3 in neural functions relevant to behaviour in both health and disease, but its broad DNA‑binding activity and pleiotropic transcriptional effects have made its precise role in psychopathology difficult to define. In this study, the authors examined the midbrain serotonergic system — a central regulator of emotion — and selectively reduced STAT3 expression in the raphe using both germline genetic deletion and viral knockdown. Mice lacking serotonergic STAT3 displayed reduced negative behavioural reactivity and a diminished sensitising response to amphetamine, along with altered midbrain serotonergic neuronal firing and transcriptional changes in gene networks linked to neuropsychiatric disorders. Viral knockdown in adult dorsal raphe reproduced the behavioural phenotype seen in genetic knockouts, indicating that disruption of STAT3 signaling in adulthood is sufficient to produce these effects rather than being a consequence of developmental changes. Overall, the data position dorsal raphe STAT3 as a molecular gate that controls behavioural reactivity and provides a mechanistic bridge between upstream STAT3 activators, serotonin neurotransmission and psychopathology.