Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

Abstract

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are nega9vely affected in the future. Stress responses are established by an interplay between gene9cs, environment, and life experiences. Psychosocial stress is par9cularly impacAul during adolescence, a cri9cal period for the development of mood disorders. In this study we compared two established, selec9vely-bred Sprague Dawley rat lines, the “internalizing” bred Low Responder (bLR) line versus the “externalizing” bred High Responder (bHR) line, to inves9gate how gene9c temperament and adolescent environment impact future responses to social interac9ons and psychosocial stress, and how these determinants of stress response interact. Animals were exposed to social and environmental enrichment in adolescence prior to experiencing social defeat and were then assessed for social interac9on and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interac9on, less submission during defeat, and resilience to the prolonged effects of social stress on cor9costerone, while enrichment caused bHR animals to show greater aggression during defeat and during a neutral social encounter, and decreased anxiety-like behavior. To gain insight into the development of social resilience in the anxious phenotype bLRs, RNA-seq was conducted on the hippocampus and nucleus accumbens, two brain regions that mediate stress regula9on and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory ac9vity were enriched with differen9al expression in both regions, with a par9cularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inocula9ng experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipula9ng their environment has transla9onal implica9ons, as it underscores the feasibility of interven9on strategies targeted at gene9cally vulnerable adolescent popula9ons.

Resource: A Curated Database of Brain-Related Functional Gene Sets (Brain.GMT)

“…For [14], the referenced fGSEA results are from worksheet 2 ("Directional_Test") in Supplemental Table S5. For [15], the referenced fGSEA results are from worksheets 2 and 3 ("SortbyEE" and "SortbySD") from both Tables S4 and S5, with the false discovery rate defined by the minimum FDR from the Model 1 and Model 2 analyses ("EE_Min_AdjPval" and "SD_MIN_AdjPval). For [16], the referenced fGSEA results are from the code release accompanying the publication (https://github.com/hagenaue/HDRF_MetaAnalysis_Downstream).…”

“…The table is split into three for the purpose of fitting easily on a page. We have now used the Brain.GMT custom gene set database to improve our interpretation of differential expression results within three publications [14][15][16] and one unpublished study (Rhoads et al, in preparation). Each of these studies focused on rodent (rat, mouse) models of mood disorder, behavioral temperament, or stress response.…”

“…The full methods used to produce the transcriptional profiling results referenced in our paper are described in detail in their respective publications [14][15][16]…”

“…To improve the interpretation of brain-derived differential expression results, we compiled a custom gene set database (Brain.GMT) focused on sets of genes associated with brain function, brain cell-types, brain co-expression networks, and regional gene expression signatures. We initially constructed Brain.GMT as part of projects using hippocampal [13][14][15][16] and nucleus accumbens tissue [15] from rodent models of neuropsychiatric disorders. To rapidly compare our results to existing literature, we also constructed gene sets using differential expression results from related publications and differential expression databases.…”

“…To rapidly compare our results to existing literature, we also constructed gene sets using differential expression results from related publications and differential expression databases. This paper serves as detailed methodological documentation to accompany our transcriptional profiling studies using Brain.GMT [13][14][15][16]. Since we have found Brain.GMT to be exceptionally useful, we also provide detailed guidance to accompany its public release for use by other researchers.…”