RESUMO
BACKGROUND: Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown. METHODS: To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse. RESULTS: RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/- heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/- mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/- mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity. CONCLUSIONS: This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.
Assuntos
Anquirinas/genética , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Transtorno Bipolar/genética , Cloreto de Lítio/farmacologia , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Animais , Anquirinas/fisiologia , Transtornos de Ansiedade/sangue , Transtornos de Ansiedade/tratamento farmacológico , Corticosterona/sangue , Giro Denteado/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Estresse Psicológico/sangue , Estresse Psicológico/tratamento farmacológicoRESUMO
Neurobehavioural analysis of mouse phenotypes requires the monitoring of mouse behaviour over long periods of time. In this study, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviours. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviours of two standard inbred and two non-standard mouse strains. From these data, we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor-based automated approaches and enable an adaptable, comprehensive, high-throughput, fine-grained, automated analysis of mouse behaviour.
