Abstract
The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Globally, 350 million people suffer from major depressive disorder (MDD), which is estimated to constitute the number one cause of disease burden by 2030
signal transducer and activator of transcription 3 (STAT3) fluorescence intensity was quantified within 5-HT-labelled cells and revealed a significant reduction of STAT3 within serotonergic neurons of the knockout mice SertCre/+; Stat3fl/fl (KO) dorsal raphe (DR)
Integrating behavioural, electrophysiological and molecular units of analysis, we aimed to shed light on the functional consequences following the disruption of STAT3 signalling in the DR under consideration of neurodevelopmental aspects
Summary
350 million people suffer from major depressive disorder (MDD), which is estimated to constitute the number one cause of disease burden by 2030. MDD is not the only severe mental illness presenting with an epidemic propagation. 60 million people worldwide are confronted with a diagnosis of bipolar depression (BP) and patients suffering from schizophrenia (SCZ) are estimated at 21 million (available from: http://www.who.com). Efforts originating from the Research Domain Criteria concept, launched by the National Institute of Mental Health in 2008 [1], suggest a research program focused on the investigation of individual constructs of behaviour and brain function, rather than. Others have suggested a bottom-up strategy, centred on the identification and exploration of individual aetiological factors, to be more effective [2]
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