Wild mice with different social network sizes vary in brain gene expression

Background Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. Results We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. Conclusions Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa. RNA-seq dataset from three brain regions (hypothalamus, prefrontal cortex and hippocampus) from wild mice presenting consistently extreme (large/high or small/low) social network sizes. Males and females from each type are included.研究背景 恰当的社交互动可通过影响交配、领地防御、后代抚育等多个过程，进而影响动物的适合度。目前诸多旨在揭示社交行为神经生物学基础的研究，多聚焦于九肽类物质 (nonapeptides)，包括血管升压素、催产素及其同源物，以及性互动或亲子互动相关的行为。此外，过往相关研究多在人工实验室条件下开展动物实验，而实验室中行为反应的后果或许不如自然环境中那般关键，这可能会掩盖部分生理反应。本研究于繁殖期外对野生小家鼠的社交互动进行自动化记录，以筛选出以自我为中心的社交网络规模 (egocentric network sizes)（以每日遇到的不同伙伴的数量为表征指标）分布两端的个体。随后采用RNA测序 (RNA-seq)，对社交网络规模存在自然极端差异的这些小鼠的前额叶皮层、海马体及下丘脑的基因表达神经差异进行无偏评估。 研究结果 本研究发现，与极端社交网络规模相关的神经基因组通路存在性别差异。在雌性个体中，社交网络规模大小与个体间差异表达的基因多达数百个；而在雄性个体中，差异表达基因极少。对于雄性而言，前额叶皮层中的X染色体失活通路是区分社交网络规模大小个体的最优判别通路。在雌性个体中，社交网络规模较小的个体，其下丘脑中多巴胺能生成与转运通路呈现上调表达。此外，相较于社交网络规模较大的雌性个体，社交网络规模较小的雌性个体，其海马神经元的细胞外基质沉积水平更高。 研究结论 在传统模式生物的自然栖息地中开展社交行为自然变异的神经机制研究，可为理解其他类群的社交行为变异提供全新的研究靶点。本研究的RNA测序 (RNA-seq) 数据集来源于野生小家鼠的三个脑区：下丘脑、前额叶皮层与海马体，这些小鼠均呈现出稳定的极端社交网络规模（大/高或小/低），涵盖了每种类型的雄性与雌性个体。