The Effect of Adolescent Environmental Enrichment and Social Defeat on the Nucleus Accumbens and Hippocampus in a Selectively Bred Model with Anxious Phenotype (bLR Rats): RNAseq data

Stress is a major influence on mental health status; the ways that individuals respond to or copes with stressors determine whether they are negatively affected in the future. Stress responses are established by an interplay between genetics, environment, and life experiences. Psychosocial stress is particularly impactful during adolescence, a critical period for the development of mood disorders. In this study we compared two established, selectively-bred Sprague Dawley rat lines, the “internalizingâ€� bred Low Responder (bLR) line versus the “externalizingâ€� bred High Responder (bHR) line, to investigate how genetic temperament and adolescent environment impact future responses to social interactions 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 interaction and anxiety-like behavior. Adolescent enrichment caused bLR rats to display less social avoidance, more social interaction, less submission during defeat, and resilience to the prolonged effects of social stress on corticosterone, 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 regulation and social behavior. Gene sets previously associated with stress, social behavior, aggression and exploratory activity were enriched with differential expression in both regions, with a particularly large effect on gene sets that regulate social behaviors. These findings provide further evidence that adolescent enrichment can serve as an inoculating experience against future stressors. The ability to induce social resilience in a usually anxious line of animals by manipulating their environment has translational implications, as it underscores the feasibility of intervention strategies targeted at genetically vulnerable adolescent populations.压力是影响心理健康状态的核心因素；个体对应激源的应对方式，决定了其未来是否会受到负面影响。应激反应由遗传、环境与生活经历之间的相互作用共同塑造。心理社会应激在青春期阶段影响尤为显著，而青春期是情绪障碍发生发展的关键时期。本研究选取两株已成熟的选择性繁育斯普拉格-道利大鼠（Sprague Dawley rat）品系——「内向型」选育低反应者（Low Responder, bLR）品系与「外向型」选育高反应者（High Responder, bHR）品系，旨在探究遗传气质与青春期环境如何影响个体未来的社交互动与心理社会应激应答，以及应激应答的这些决定因素之间的相互作用机制。实验大鼠在青春期接受社交与环境丰富化干预，随后经历社交挫败，之后对其社交互动能力与类焦虑行为进行评估。青春期丰富化干预可使bLR大鼠表现出更少的社交回避、更强的社交互动能力，在社交挫败过程中更少出现屈服行为，并能抵御社交应激对皮质酮水平的长期影响；而该干预则会使bHR大鼠在社交挫败及中性社交互动场景中表现出更强的攻击行为，同时降低其类焦虑行为表现。为深入探究焦虑表型bLR大鼠的社交韧性发育机制，本研究对介导应激调节与社交行为的两个脑区——海马体（hippocampus）与伏隔核（nucleus accumbens）进行了RNA测序（RNA-seq）分析。此前与应激、社交行为、攻击行为及探索活动相关的基因集在两个脑区中均呈现富集差异表达，其中对调控社交行为的基因集影响尤为显著。本研究结果进一步证实，青春期丰富化干预可作为一种预接种式体验，帮助个体抵御未来的应激源威胁。通过环境调控在本就易焦虑的大鼠品系中诱导社交韧性的可行性，具有重要的转化医学价值，该研究结果凸显了针对遗传易感青春期人群制定干预策略的可行性。