Sociosexual and Communication Deficits after Traumatic Injury to the Developing Murine Brain

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.

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury

“…2,74,89,93,106 In a small subset of CCI rats, a protuberance similar to a leptomeningeal cyst formed several days after injury, and MRI showed findings similar to those in human infants with a leptomeningeal cyst. 82 In P11 CCI, similar deformation of the lateral ventricle has been noted on histological analyses.…”

Social dysfunction after pediatric traumatic brain injury: A translational perspective

“…Across a range of injury models including FPI, CCI, impact acceleration, blast and repetitive closed skull impacts of varying severity, investigators have reported either a reduction in social investigation and social recognition after TBI (Bajwa et al, 2016; Fenn et al, 2013; Klemenhagen et al, 2013; Koliatsos et al, 2011; Pandey et al, 2009; Semple et al, 2012; Semple et al, 2014), or the lack of a difference compared to sham-operated controls (Patel et al, 2014; Shultz et al, 2012; Shultz et al, 2011). Further studies are needed to validate the incorporation of specific social tasks in this context, as the characterization of social outcomes across a range of TBI models will likely enhance our understanding of the complex interaction between neuropathology and functional outcomes.…”

“…Further, at adulthood, TBI mice were more likely to exert social dominance in the tube task compared to sham-operated controls (Semple et al, 2012). Brain-injured mice also present with aberrant social communication, as evidenced by a striking reduction in scent marking behavior at adulthood after pTBI, and abnormal context-dependent ultrasonic vocalizations in response to female stimuli (Semple et al, 2014). Together, these findings reveal an emergence of aberrant social behavior over time after early-life injury, a trajectory that parallels the development of cognitive deficits in this model, as well as social dysfunction reported many years after childhood TBI in patients.…”

Found in translation: Understanding the biology and behavior of experimental traumatic brain injury

“…To address the extent to which the age at injury influences social behaviors, a subsequent study from the same investigators recently compared mice injured at PND 21 or PND 35 (Semple et al, 2014). Mice injured at a young postnatal age (PND 21), when tested at adulthood, exhibited reduced scent marking behavior and an alteration in context-dependent USVs in response to female stimuli.…”

“…Changes in the corpus callosum in terms of volumetric atrophy, microstructural integrity or connectivity (Ewing-Cobbs et al, 2008; Wu et al, 2010; Ewing-Cobbs et al, 2012; Semple et al, 2014) have been associated with poorer social outcomes in both adults and children after TBI (Beauchamp et al, 2009; Ryan et al, 2013). In children, volumetric changes of both grey and white matter structures after injury are likely to reflect not only ongoing neurodegeneration, but also result from the retardation of normal growth trajectories.…”