Abstract
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.
Highlights
Survivors of childhood traumatic brain injury (TBI) have an elevated risk of long-term social dysfunction [1,2], with substantial implications for reintegration into society and quality of life [3]
After surgery at p21, sham-operated mice spent a total of 224.5618.1 sec investigating the intruding male over a 5 min period, compared to TBI mice that spent 32% less time engaged in social investigation (152.168.51 sec; unpaired t-test, t18 = 3.75, p = 0.002)
Emission of ultrasonic vocalizations after pediatric TBI is both stimulus and experience-dependent Based upon the application of USVs as a potential measure of social communication in mouse models of communication disorders, we investigated whether USVs were altered after TBI at p21, the injury age after which we have seen the most robust social deficits emerge by adulthood
Summary
Survivors of childhood traumatic brain injury (TBI) have an elevated risk of long-term social dysfunction [1,2], with substantial implications for reintegration into society and quality of life [3]. Brain injury at a young age is consistently predictive of poorer language and non-verbal communication [6,7,8], which may complicate the ongoing development of social skills [9]. These consequences persist up to 20 years after severe TBI during childhood [10,11,12], and compromise many areas of language competence including syntax, semantics and pragmatics [13]. A younger age-at-insult has been highlighted as a risk factor for social dysfunction [6], leading to the hypothesis that impairments after childhood TBI may reflect a disturbance in brain development and the failure to acquire age-appropriate skills [16,17]
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