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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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Burst analyses reveal temporal differences in USV calls after injury at p21.Call burst patterns were calculated from the distribution of inter-call intervals. In Cohort 1, the mean number of calls per burst was higher in mice after injury at p21 compared to sham mice in response to the female stimulus mouse (*p<0.05). Similarly, bursts of USV calls from TBI mice towards female stimuli were of a longer duration (c; **p<0.01), as well as towards a stimulus male (*p<0.05). In contrast, no such injury-related differences were observed in burst patterns produced in the absence of prior social experience (Cohort 2; b, d).
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pone-0103386-g006: Burst analyses reveal temporal differences in USV calls after injury at p21.Call burst patterns were calculated from the distribution of inter-call intervals. In Cohort 1, the mean number of calls per burst was higher in mice after injury at p21 compared to sham mice in response to the female stimulus mouse (*p<0.05). Similarly, bursts of USV calls from TBI mice towards female stimuli were of a longer duration (c; **p<0.01), as well as towards a stimulus male (*p<0.05). In contrast, no such injury-related differences were observed in burst patterns produced in the absence of prior social experience (Cohort 2; b, d).

Mentions: We next examined the burst patterns of USV calls to determine whether TBI altered the temporal organization of calls after addition of the stimulus. Call bursts were calculated from the distribution of inter-call intervals (ICIs). The fraction of calls contained within bursts was not affected by TBI (2-way RM ANOVA effect of injury, F1, 10 = 3.04, p = 0.109), averaging 0.91 (or 91% of total calls) across both groups and all stimuli (Table S1). We next assessed the mean number of calls per burst in Cohort 1 (figure 6a), and found a trend towards an effect of injury (2-way RM ANOVA F1, 8 = 5.244, p = 0.051). This was most evident in response to a female stimulus, where TBI mice produced an average of 9.45±0.72 calls within a burst compared to 6.37±0.62 for sham-operated mice (one-way ANOVA F1, 9 = 10.12, p = 0.013). This difference corresponded to a similar distinction in the mean burst duration in Cohort 1 (figure 6c), whereby TBI mice produced USV bursts of longer duration compared to sham mice in response to a female stimulus (2-way RM ANOVA effect of injury F1, 8 = 5.19, p = 0.052; one-way ANOVA F1, 9 = 13.32, p = 0.006). No trends or statistically significant differences were found in the burst parameters for female bedding or male mouse stimuli.


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)

Burst analyses reveal temporal differences in USV calls after injury at p21.Call burst patterns were calculated from the distribution of inter-call intervals. In Cohort 1, the mean number of calls per burst was higher in mice after injury at p21 compared to sham mice in response to the female stimulus mouse (*p<0.05). Similarly, bursts of USV calls from TBI mice towards female stimuli were of a longer duration (c; **p<0.01), as well as towards a stimulus male (*p<0.05). In contrast, no such injury-related differences were observed in burst patterns produced in the absence of prior social experience (Cohort 2; b, d).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103386-g006: Burst analyses reveal temporal differences in USV calls after injury at p21.Call burst patterns were calculated from the distribution of inter-call intervals. In Cohort 1, the mean number of calls per burst was higher in mice after injury at p21 compared to sham mice in response to the female stimulus mouse (*p<0.05). Similarly, bursts of USV calls from TBI mice towards female stimuli were of a longer duration (c; **p<0.01), as well as towards a stimulus male (*p<0.05). In contrast, no such injury-related differences were observed in burst patterns produced in the absence of prior social experience (Cohort 2; b, d).
Mentions: We next examined the burst patterns of USV calls to determine whether TBI altered the temporal organization of calls after addition of the stimulus. Call bursts were calculated from the distribution of inter-call intervals (ICIs). The fraction of calls contained within bursts was not affected by TBI (2-way RM ANOVA effect of injury, F1, 10 = 3.04, p = 0.109), averaging 0.91 (or 91% of total calls) across both groups and all stimuli (Table S1). We next assessed the mean number of calls per burst in Cohort 1 (figure 6a), and found a trend towards an effect of injury (2-way RM ANOVA F1, 8 = 5.244, p = 0.051). This was most evident in response to a female stimulus, where TBI mice produced an average of 9.45±0.72 calls within a burst compared to 6.37±0.62 for sham-operated mice (one-way ANOVA F1, 9 = 10.12, p = 0.013). This difference corresponded to a similar distinction in the mean burst duration in Cohort 1 (figure 6c), whereby TBI mice produced USV bursts of longer duration compared to sham mice in response to a female stimulus (2-way RM ANOVA effect of injury F1, 8 = 5.19, p = 0.052; one-way ANOVA F1, 9 = 13.32, p = 0.006). No trends or statistically significant differences were found in the burst parameters for female bedding or male mouse stimuli.

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