Freezing responses during threat memory retrieval reflect trait-like anxiety endophenotypes in inbred mice

Trait anxiety is one of the major contributors to susceptibility to stress-induced and anxiety disorders in humans. Although vulnerability to stress-induced pathologies is clearly highly individual, animal models still largely fail to account for it. Using the threat imminence continuum theory, we designed and validated an experimental pipeline in mice centred around auditory aversive conditioning. Harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy enabled us to operationalize trait anxiety. We identified sustained freezing during prolonged retrieval sessions as a behavioural marker of an anxiety endophenotype in both males and females. RNA-sequencing of key defence circuit brain regions revealed massive differences in transcriptomes of phasic and sustained responders, correlating with transcriptomic signatures of psychiatric disorders such as PTSD and schizophrenia. We provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility. Overall design: Comparative gene expression profiling analysis of RNA-seq data for different fear conditioning phenotypes in four brain regions of wild-type mice