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Sociosexual and communication deficits after traumatic injury to the developing murine brain.

Semple BD, Noble-Haeusslein LJ, Jun Kwon Y, Sam PN, Gibson AM, Grissom S, Brown S, Adahman Z, Hollingsworth CA, Kwakye A, Gimlin K, Wilde EA, Hanten G, Levin HS, Schenk AK - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America; Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.

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.

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Loss of social novelty preference at adulthood is unique to TBI at p35.Independent of injury, all mice spent equal time in the left and right side chambers during habituation (stage 1; a). During stage 2 (b), both sham and TBI mice showed a similar preference for spending more time in the chamber containing the stimulus mouse, compared to the empty chamber (2-way ANOVA overall effect of stimulus, *p<0.05). In stage 3 (c), sham mice showed a strong preference for spending more time with stimulus mouse 2 compared to mouse 1, indicating social recognition or memory of ‘now-familiar’ stimulus 1 (2-way ANOVA post-hoc, ****p<0.0001). In contrast, TBI mice injured at p35 spent equivalent time with both stimulus mice (post-hoc, n.s.), indicating a lack of preference for social novelty.
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pone-0103386-g003: Loss of social novelty preference at adulthood is unique to TBI at p35.Independent of injury, all mice spent equal time in the left and right side chambers during habituation (stage 1; a). During stage 2 (b), both sham and TBI mice showed a similar preference for spending more time in the chamber containing the stimulus mouse, compared to the empty chamber (2-way ANOVA overall effect of stimulus, *p<0.05). In stage 3 (c), sham mice showed a strong preference for spending more time with stimulus mouse 2 compared to mouse 1, indicating social recognition or memory of ‘now-familiar’ stimulus 1 (2-way ANOVA post-hoc, ****p<0.0001). In contrast, TBI mice injured at p35 spent equivalent time with both stimulus mice (post-hoc, n.s.), indicating a lack of preference for social novelty.

Mentions: We have previously identified deficits in sociability and social novelty recognition after TBI at p21 using the three-chamber social approach task [19]. Here, we also applied this paradigm to mice injured at adolescence (p35), to further elucidate age-dependent consequences to social deficits. As expected, both sham and TBI mice spent comparable time in each empty outer chamber during stage 1 habituation (figure 3a; 2-way RM ANOVA no effect of injury F1, 32 = 0.03, p = 0.868; no effect of chamber side, F1, 32 = 0.58, p = 0.452). Stage 2 (figure 3b) subsequently provided test mice with the choice between chambers containing either a novel stimulus male mouse or an empty cup. Here, both sham and TBI mice showed a similar preference for social proximity, spending more time in the chamber containing the stimulus mouse compared to the empty cup (2-way RM ANOVA overall effect of stimulus F1, 32 = 6.64, p = 0.015; no effect of injury F1, 32 = 0.130, p = 0.721; Bonferroni's post-hoc, n.s.).


Sociosexual and communication deficits after traumatic injury to the developing murine brain.

Semple BD, Noble-Haeusslein LJ, Jun Kwon Y, Sam PN, Gibson AM, Grissom S, Brown S, Adahman Z, Hollingsworth CA, Kwakye A, Gimlin K, Wilde EA, Hanten G, Levin HS, Schenk AK - PLoS ONE (2014)

Loss of social novelty preference at adulthood is unique to TBI at p35.Independent of injury, all mice spent equal time in the left and right side chambers during habituation (stage 1; a). During stage 2 (b), both sham and TBI mice showed a similar preference for spending more time in the chamber containing the stimulus mouse, compared to the empty chamber (2-way ANOVA overall effect of stimulus, *p<0.05). In stage 3 (c), sham mice showed a strong preference for spending more time with stimulus mouse 2 compared to mouse 1, indicating social recognition or memory of ‘now-familiar’ stimulus 1 (2-way ANOVA post-hoc, ****p<0.0001). In contrast, TBI mice injured at p35 spent equivalent time with both stimulus mice (post-hoc, n.s.), indicating a lack of preference for social novelty.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126664&req=5

pone-0103386-g003: Loss of social novelty preference at adulthood is unique to TBI at p35.Independent of injury, all mice spent equal time in the left and right side chambers during habituation (stage 1; a). During stage 2 (b), both sham and TBI mice showed a similar preference for spending more time in the chamber containing the stimulus mouse, compared to the empty chamber (2-way ANOVA overall effect of stimulus, *p<0.05). In stage 3 (c), sham mice showed a strong preference for spending more time with stimulus mouse 2 compared to mouse 1, indicating social recognition or memory of ‘now-familiar’ stimulus 1 (2-way ANOVA post-hoc, ****p<0.0001). In contrast, TBI mice injured at p35 spent equivalent time with both stimulus mice (post-hoc, n.s.), indicating a lack of preference for social novelty.
Mentions: We have previously identified deficits in sociability and social novelty recognition after TBI at p21 using the three-chamber social approach task [19]. Here, we also applied this paradigm to mice injured at adolescence (p35), to further elucidate age-dependent consequences to social deficits. As expected, both sham and TBI mice spent comparable time in each empty outer chamber during stage 1 habituation (figure 3a; 2-way RM ANOVA no effect of injury F1, 32 = 0.03, p = 0.868; no effect of chamber side, F1, 32 = 0.58, p = 0.452). Stage 2 (figure 3b) subsequently provided test mice with the choice between chambers containing either a novel stimulus male mouse or an empty cup. Here, both sham and TBI mice showed a similar preference for social proximity, spending more time in the chamber containing the stimulus mouse compared to the empty cup (2-way RM ANOVA overall effect of stimulus F1, 32 = 6.64, p = 0.015; no effect of injury F1, 32 = 0.130, p = 0.721; Bonferroni's post-hoc, n.s.).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America; Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia.

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.

Show MeSH
Related in: MedlinePlus