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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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Social deficits are associated with white matter atrophy and hippocampal loss.TBI at both a pediatric (a) and adolescent age (b) resulted in a distinct pattern of unilateral cortical and hippocampal loss by adulthood (scale bar = 500 µm). Volumetric analysis of the corpus callosum revealed pronounced volumetric loss of the corpus callosum/external capsule bilaterally after injury at p21 (c; ****p<0.0001, **p<0.01). Similar loss was also evident after injury at adolescence (d; ****p<0.0001, *p<0.05). When expressed as injury-induced tissue loss relative to age-matched sham controls after injury at p21 compared to p35 (e), both cohorts showed ∼50% volume loss of the ipsilateral corpus callosum and ∼20% loss on the side contralateral to injury (n.s.). Volume of the dorsal hippocampus was also quantified, revealing considerable loss of the ipsilateral hippocampus after injury at p21 (f) and p35 (g). When expressed as tissue loss relative to age-matched sham controls (h), greater tissue ipsilateral hippocampus loss was evident after injury at p21 compared to injury at adolescence.
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pone-0103386-g007: Social deficits are associated with white matter atrophy and hippocampal loss.TBI at both a pediatric (a) and adolescent age (b) resulted in a distinct pattern of unilateral cortical and hippocampal loss by adulthood (scale bar = 500 µm). Volumetric analysis of the corpus callosum revealed pronounced volumetric loss of the corpus callosum/external capsule bilaterally after injury at p21 (c; ****p<0.0001, **p<0.01). Similar loss was also evident after injury at adolescence (d; ****p<0.0001, *p<0.05). When expressed as injury-induced tissue loss relative to age-matched sham controls after injury at p21 compared to p35 (e), both cohorts showed ∼50% volume loss of the ipsilateral corpus callosum and ∼20% loss on the side contralateral to injury (n.s.). Volume of the dorsal hippocampus was also quantified, revealing considerable loss of the ipsilateral hippocampus after injury at p21 (f) and p35 (g). When expressed as tissue loss relative to age-matched sham controls (h), greater tissue ipsilateral hippocampus loss was evident after injury at p21 compared to injury at adolescence.

Mentions: As social dysfunction after TBI in patients has been associated with white matter damage, we examined volumetric changes in the corpus callosum/external capsule as a measure of long-term white matter integrity (figure 7). At adulthood after injury at p21 (figure 7c), an overall reduction in the volume of the corpus callosum was evident (2-way RM ANOVA effect of injury F1, 8 = 29.75, p<0.0001), which was dependent upon proximity to the impact site (effect of region F1, 8 = 219.10, p = 0.0006; injury×region interaction F1, 8 = 85.76, p<0.0001). Of note, atrophy of the corpus callosum was observed both ipsilateral to the impact site (Sidak's post-hoc, p<0.0001), as well as contralaterally (p<0.01).


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)

Social deficits are associated with white matter atrophy and hippocampal loss.TBI at both a pediatric (a) and adolescent age (b) resulted in a distinct pattern of unilateral cortical and hippocampal loss by adulthood (scale bar = 500 µm). Volumetric analysis of the corpus callosum revealed pronounced volumetric loss of the corpus callosum/external capsule bilaterally after injury at p21 (c; ****p<0.0001, **p<0.01). Similar loss was also evident after injury at adolescence (d; ****p<0.0001, *p<0.05). When expressed as injury-induced tissue loss relative to age-matched sham controls after injury at p21 compared to p35 (e), both cohorts showed ∼50% volume loss of the ipsilateral corpus callosum and ∼20% loss on the side contralateral to injury (n.s.). Volume of the dorsal hippocampus was also quantified, revealing considerable loss of the ipsilateral hippocampus after injury at p21 (f) and p35 (g). When expressed as tissue loss relative to age-matched sham controls (h), greater tissue ipsilateral hippocampus loss was evident after injury at p21 compared to injury at adolescence.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103386-g007: Social deficits are associated with white matter atrophy and hippocampal loss.TBI at both a pediatric (a) and adolescent age (b) resulted in a distinct pattern of unilateral cortical and hippocampal loss by adulthood (scale bar = 500 µm). Volumetric analysis of the corpus callosum revealed pronounced volumetric loss of the corpus callosum/external capsule bilaterally after injury at p21 (c; ****p<0.0001, **p<0.01). Similar loss was also evident after injury at adolescence (d; ****p<0.0001, *p<0.05). When expressed as injury-induced tissue loss relative to age-matched sham controls after injury at p21 compared to p35 (e), both cohorts showed ∼50% volume loss of the ipsilateral corpus callosum and ∼20% loss on the side contralateral to injury (n.s.). Volume of the dorsal hippocampus was also quantified, revealing considerable loss of the ipsilateral hippocampus after injury at p21 (f) and p35 (g). When expressed as tissue loss relative to age-matched sham controls (h), greater tissue ipsilateral hippocampus loss was evident after injury at p21 compared to injury at adolescence.
Mentions: As social dysfunction after TBI in patients has been associated with white matter damage, we examined volumetric changes in the corpus callosum/external capsule as a measure of long-term white matter integrity (figure 7). At adulthood after injury at p21 (figure 7c), an overall reduction in the volume of the corpus callosum was evident (2-way RM ANOVA effect of injury F1, 8 = 29.75, p<0.0001), which was dependent upon proximity to the impact site (effect of region F1, 8 = 219.10, p = 0.0006; injury×region interaction F1, 8 = 85.76, p<0.0001). Of note, atrophy of the corpus callosum was observed both ipsilateral to the impact site (Sidak's post-hoc, p<0.0001), as well as contralaterally (p<0.01).

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