STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

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.

Effects of Changyu Daotan Decoction on Depression via Restoration of Mice Hippocampus and Alteration of Expression of Relevant Neurotrophic Factors

“…Patients with severe depression are prone to committing suicide, and it was reported that the prevalence of depression has been increasing year by year [ 1 – 3 ]. Up to now, there are at least about 350 million people suffering from depression, and this horde is likely to grow to be the first in the global disease burden in 2030 [ 4 , 5 ]. However, the pathogenesis of depression is too complicated to be figured out, perhaps related to those factors such as genetics, immunology, psychology, and social environment [ 6 ].…”

Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation

“…Tph2 KO mice show hyperactivity on the exposure to novel environments, and reduced immobility in both forced swimming test and tail suspension test with altered hippocampal neuroplasticity ( Maddaloni et al., 2018 ). Conditional KO of STAT3 in dorsal raphe nuclei reduced immobility in forced swimming test ( Reisinger et al., 2021 ). Local neuroinflammation in dorsal raphe nuclei in interleukin 1β transgenic mice exhibited increased stress-induced locomotion ( Howerton et al., 2014 ).…”

Uncoupling Protein-1 Modulates Anxiety-Like Behavior in a Temperature-Dependent Manner

“…The FST was conducted using an automated movement-tracking software (VideoTrack version 3, Viewpoint) as reported previously ( Reisinger et al, 2020b ). The test lasted for 6 min, and the percentage of immobility during the last 4 min of the test was used as an indicator of despair-like behavior related to depression.…”

“…N numbers, full statistics, and ρ values are reported for each main effect, and all interactions are listed where relevant in the main text; a complete report including sample sizes for each experiment is given Table 1 . Sample sizes were determined according to our own experience, and data provided in the literature ( Kong et al, 2015 ; Dorninger et al, 2019 ; Reisinger et al, 2019 , 2020a , b ; Berger et al, 2020 ; Gabriel et al, 2020 ). All statistical analyses were conducted using GraphPad Prism 7.…”