Beaver Jasmin N, Nicodemus Marissa M, Spalding Isabella R, Dutta Sohini, Jasnow Aaron M, Gilman T Lee
Department of Psychological Sciences.
Brain Health Research Institute.
bioRxiv. 2024 Sep 10:2024.08.12.607663. doi: 10.1101/2024.08.12.607663.
Mice offer a wealth of opportunities for investigating brain circuits regulating multiple behaviors, largely due to their genetic tractability. Social behaviors are of translational relevance, considering both mice and humans are highly social mammals, and disruptions in human social behavior are key symptoms of myriad neuropsychiatric disorders. Stresses related to social experiences are particularly influential in the severity and maintenance of neuropsychiatric disorders like anxiety disorders, and trauma and stressor-related disorders. Yet, induction and study of social stress in mice is disproportionately focused on males, influenced heavily by their natural territorial nature. Conspecific-elicited stress (i.e., defeat), while ethologically relevant, is quite variable and predominantly specific to males, making rigorous and sex-inclusive studies challenging. In pursuit of a controllable, consistent, high throughput, and sex-inclusive paradigm for eliciting social stress, we have discovered intriguing sex-specific social aversions that are dependent upon the sex of both experimental and conspecific mice. Specifically, we trained male and female F1 129S1/SvlmJ × C57BL/6J mice to associate (via classical conditioning) same or different sex C57BL/6J conspecifics with a mild, aversive stimulus. Upon subsequent testing for social interaction 24 h later, we found that males socially conditioned better to male conspecifics by exhibiting reduced social interaction, whereas females socially conditioned better to male conspecifics. Serum corticosterone levels inversely corresponded to social avoidance after different sex, but not same sex, conditioning, suggesting corticosterone-mediated arousal could influence cross sex interactions. While our paradigm has further optimization ahead, these current findings reveal why past pursuits to develop same sex female social stress paradigms may have met with limited success. Future research should expand investigation of utilizing male mouse conspecifics to instigate social stress across sexes.
小鼠为研究调节多种行为的脑回路提供了丰富的机会，这主要归功于它们在基因方面的可操作性。考虑到小鼠和人类都是高度社会化的哺乳动物，且人类社会行为的破坏是众多神经精神疾病的关键症状，社会行为具有转化相关性。与社会经历相关的压力在焦虑症、创伤及与应激源相关的疾病等神经精神疾病的严重程度和持续时间方面具有特别重要的影响。然而，小鼠社会压力的诱导和研究在很大程度上集中于雄性，这在很大程度上受到其天然领地性的影响。同种引发的压力（即挫败）虽然在行为学上具有相关性，但变化很大且主要针对雄性，这使得严谨且包含两性的研究具有挑战性。为了寻求一种可控、一致、高通量且包含两性的引发社会压力的范式，我们发现了有趣的性别特异性社会厌恶现象，这种现象取决于实验小鼠和同种小鼠的性别。具体而言，我们训练雄性和雌性F1 129S1/SvlmJ × C57BL/6J小鼠（通过经典条件反射）将同性或异性C57BL/6J同种小鼠与轻度厌恶刺激联系起来。在24小时后进行后续社会互动测试时，我们发现雄性通过减少社会互动对雄性同种小鼠的社会条件反射更好，而雌性对雄性同种小鼠的社会条件反射更好。血清皮质酮水平与不同性别而非相同性别条件反射后的社会回避呈负相关，这表明皮质酮介导的唤醒可能会影响跨性别互动。虽然我们的范式还有进一步优化的空间，但目前的这些发现揭示了过去开发同性雌性社会压力范式可能成效有限的原因。未来的研究应扩大利用雄性小鼠同种个体引发跨性别社会压力的研究。
