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）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损的发育轨迹及潜在机制仍知之甚少。本研究依托已得到充分表征的儿童脑损伤小鼠模型，近期证实：在出生后第21天（postnatal day, p21，对应人类幼儿阶段）接受脑损伤的小鼠，其社交互动缺陷会随发育进程持续至成年期，且程度显著。基于上述发现，本研究提出假设：这类社交缺陷依赖于损伤发生时的脑成熟状态，并伴随异常的社交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，本研究对比了两组小鼠的行为学与神经解剖学结局：分别在儿童期（p21）及青春期（p35）接受创伤性脑损伤的小鼠。于成年期采用居住者-入侵者范式，评估小鼠的社交性行为（包括社交探究与爬跨行为）；同时通过尿液气味标记测试与超声波发声（ultrasonic vocalizations, USVs）检测，作为社交沟通的评估指标，以补充上述行为学结果。本研究证实，p21期接受脑损伤的小鼠会出现社交性行为缺陷：于成年期表现为对陌生雌性小鼠的爬跨行为减少，且气味标记行为降低。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，除了在三箱社交偏好任务中出现社交识别能力丧失外，成年期几乎未表现出社交缺陷，具有显著的韧性。损伤后小鼠的超声波发声总量增加，且更倾向于发出高频超声波发声，这一表现依赖于刺激类型与既往社交经历。尽管曾有假说认为白质体积变化是社交功能障碍的潜在机制，但本研究发现：p21与p35期接受脑损伤的小鼠，至成年期时胼胝体（corpus callosum）的萎缩程度并无显著差异。但p21期损伤小鼠的海马组织（hippocampal tissue）丢失量显著高于p35期损伤小鼠，这提示p21期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，本研究结果表明发育中的大脑对社交功能障碍具有年龄依赖性易感性，且损伤发生年龄越小，成年后的社交与社交性行为结局越差。