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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE223269 | GEO | 2024/04/09

REPOSITORIES: GEO

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Project description:Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The ârisk-avoidanceâ and âhypoactivityâ traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the âincreased stress-reactivityâ trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations. Compared three generations of male offspring from wild-type and 5HT1A-R-/+ Swiss Webster mothers with two replicates per sample. Included as well is F2 embryo transfer from wild-type and het parents in wild-type surogates

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

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