Data from: Sociosexual and communication deficits after traumatic injury to the developing murine brain

Despite the life-long implications of social and communication dysfunction after pediatric traumatic brain injury, there is a poor understanding of these deficits in terms of their developmental trajectory and underlying mechanisms. In a well-characterized murine model of pediatric brain injury, we recently demonstrated that pronounced deficits in social interactions emerge across maturation to adulthood after injury at postnatal day (p) 21, approximating a toddler-aged child. Extending these findings, we here hypothesized that these social deficits are dependent upon brain maturation at the time of injury, and coincide with abnormal sociosexual behaviors and communication. Age-dependent vulnerability of the developing brain to social deficits was addressed by comparing behavioral and neuroanatomical outcomes in mice injured at either a pediatric age (p21) or during adolescence (p35). Sociosexual behaviors including social investigation and mounting were evaluated in a resident-intruder paradigm at adulthood. These outcomes were complemented by assays of urine scent marking and ultrasonic vocalizations as indices of social communication. We provide evidence of sociosexual deficits after brain injury at p21, which manifest as reduced mounting behavior and scent marking towards an unfamiliar female at adulthood. In contrast, with the exception of the loss of social recognition in a three-chamber social approach task, mice that received TBI at adolescence were remarkably resilient to social deficits at adulthood. Increased emission of ultrasonic vocalizations (USVs) as well as preferential emission of high frequency USVs after injury was dependent upon both the stimulus and prior social experience. Contrary to the hypothesis that changes in white matter volume may underlie social dysfunction, injury at both p21 and p35 resulted in a similar degree of atrophy of the corpus callosum by adulthood. However, loss of hippocampal tissue was greater after p21 compared to p35 injury, suggesting that a longer period of lesion progression or differences in the kinetics of secondary pathogenesis after p21 injury may contribute to observed behavioral differences. Together, these findings indicate vulnerability of the developing brain to social dysfunction, and suggest that a younger age-at-insult results in poorer social and sociosexual outcomes.尽管儿童创伤性脑损伤（pediatric traumatic brain injury, pTBI）后出现的社交与沟通功能障碍会对个体产生终身影响，但目前学界对这类缺陷的发展轨迹及潜在机制仍知之甚少。在经过充分表征的儿童脑损伤小鼠模型中，我们近期的研究证实，在出生后第21天（postnatal day, p21，对应人类幼儿阶段）实施脑损伤后，小鼠的社交互动缺陷会随发育持续至成年阶段。基于上述发现，本研究提出假设：此类社交缺陷取决于损伤发生时大脑的成熟阶段，且会伴随异常的社会性行为与社交沟通表现。为探究发育中大脑对社交缺陷的年龄依赖性易感性，本研究通过对比分别在幼儿期（p21）或青春期（p35）接受脑损伤的小鼠的行为学与神经解剖学结局展开研究。研究于小鼠成年阶段采用居住者-入侵者实验范式，评估其社会探索、爬跨等社会性行为；同时通过尿液气味标记与超声波发声（ultrasonic vocalizations, USVs）实验，作为社交沟通的检测指标，补充验证上述行为学结果。本研究证实，p21阶段接受脑损伤的小鼠在成年后会出现社会性行为缺陷，具体表现为爬跨行为减少，且对陌生雌性小鼠的气味标记行为降低。与之形成对比的是，青春期接受创伤性脑损伤（traumatic brain injury, TBI）的小鼠，除在三箱社交接触实验中出现社交识别能力缺失外，成年后几乎未表现出社交缺陷，展现出较强的抵抗性。损伤后小鼠的超声波发声（USVs）总量增加，且更倾向于发出高频USVs，该变化同时受刺激类型与既往社交经验的影响。与"白质体积变化是社交功能障碍潜在机制"的假设相悖，p21与p35阶段接受脑损伤的小鼠，在成年后均出现了程度相近的胼胝体萎缩。但p21阶段损伤的小鼠海马组织丢失量显著高于p35阶段损伤组，这提示p21损伤后更长的病变进展周期，或继发性发病机制的动力学差异，可能是导致两组小鼠行为学差异的原因。综上，本研究结果证实发育中的大脑对社交功能障碍存在年龄依赖性易感性，且损伤发生时年龄越小，小鼠成年后的社交与社会性行为结局越差。