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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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The number and duration of USV calls after injury at p21 are both stimulus and experience-dependent.USVs were recorded at adulthood after injury at p21, in response to three different stimuli; addition of a novel male mouse, novel female mouse, or bedding from a cage of novel female mice. In Cohort 1, which had previously encountered conspecifics of both genders during the resident-intruder test, TBI mice emitted significantly more total calls (a), particularly in response to a female stimulus mouse (*p<0.05). Histograms of the mean median call frequency revealed a distribution of calls above and below 75 kHz (c; dotted line). Application of a frequency filter to restrict analysis to calls greater than 75 kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse (***p<0.001) and female bedding (**p<0.01). In contrast, a lack of prior social encounters as experienced by Cohort 2 (b, d, f) resulted in sham and TBI mice emitting a similar number of calls (both total and restricted to >75 kHz kHz). Call duration was not affected by injury in Cohort 1 (g), although in Cohort 2 (h) there was a trend towards TBI mice producing calls of shorter duration compared to sham mice overall (p = 0.069).
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pone-0103386-g005: The number and duration of USV calls after injury at p21 are both stimulus and experience-dependent.USVs were recorded at adulthood after injury at p21, in response to three different stimuli; addition of a novel male mouse, novel female mouse, or bedding from a cage of novel female mice. In Cohort 1, which had previously encountered conspecifics of both genders during the resident-intruder test, TBI mice emitted significantly more total calls (a), particularly in response to a female stimulus mouse (*p<0.05). Histograms of the mean median call frequency revealed a distribution of calls above and below 75 kHz (c; dotted line). Application of a frequency filter to restrict analysis to calls greater than 75 kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse (***p<0.001) and female bedding (**p<0.01). In contrast, a lack of prior social encounters as experienced by Cohort 2 (b, d, f) resulted in sham and TBI mice emitting a similar number of calls (both total and restricted to >75 kHz kHz). Call duration was not affected by injury in Cohort 1 (g), although in Cohort 2 (h) there was a trend towards TBI mice producing calls of shorter duration compared to sham mice overall (p = 0.069).

Mentions: We first examined the total number of calls produced. For Cohort 1, sham-operated mice showed a high response to either a female mouse or female bedding, emitting an average of 476.17 and 575.83 calls respectively during the post-stimulus recording period (figure 5a). The number of calls was lower in response to a male stimulus mouse, averaging 240.17 total calls (2-way RM ANOVA effect of stimulus F1, 9 = 31.09, p<0.001). Brain-injured mice produced a greater total number of USV calls compared to sham mice (effect of injury F1, 9 = 6.15, p = 0.035). This difference was dependent upon the stimulus, with TBI showing a higher number of calls in response to a female mouse (F1, 17 = 8.23, p = 0.011) and a trend towards higher numbers of calls in response to female bedding (F1, 19 = 3.48, p = 0.078), but not in response to a male mouse (F1, 11 = 0.57, p = 0.468). The presentation of a male stimulus mouse elicited USVs from only a subset of mice (n = 6 sham and n = 5 TBI), and fewer calls from those that did vocalize. In contrast, presence of a female stimulus induced USVs in 90% of mice, and 100% of mice vocalized in response to female bedding.


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)

The number and duration of USV calls after injury at p21 are both stimulus and experience-dependent.USVs were recorded at adulthood after injury at p21, in response to three different stimuli; addition of a novel male mouse, novel female mouse, or bedding from a cage of novel female mice. In Cohort 1, which had previously encountered conspecifics of both genders during the resident-intruder test, TBI mice emitted significantly more total calls (a), particularly in response to a female stimulus mouse (*p<0.05). Histograms of the mean median call frequency revealed a distribution of calls above and below 75 kHz (c; dotted line). Application of a frequency filter to restrict analysis to calls greater than 75 kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse (***p<0.001) and female bedding (**p<0.01). In contrast, a lack of prior social encounters as experienced by Cohort 2 (b, d, f) resulted in sham and TBI mice emitting a similar number of calls (both total and restricted to >75 kHz kHz). Call duration was not affected by injury in Cohort 1 (g), although in Cohort 2 (h) there was a trend towards TBI mice producing calls of shorter duration compared to sham mice overall (p = 0.069).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4126664&req=5

pone-0103386-g005: The number and duration of USV calls after injury at p21 are both stimulus and experience-dependent.USVs were recorded at adulthood after injury at p21, in response to three different stimuli; addition of a novel male mouse, novel female mouse, or bedding from a cage of novel female mice. In Cohort 1, which had previously encountered conspecifics of both genders during the resident-intruder test, TBI mice emitted significantly more total calls (a), particularly in response to a female stimulus mouse (*p<0.05). Histograms of the mean median call frequency revealed a distribution of calls above and below 75 kHz (c; dotted line). Application of a frequency filter to restrict analysis to calls greater than 75 kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse kHz found that TBI mice produced more high frequency calls compared to sham mice in response to both a female mouse (***p<0.001) and female bedding (**p<0.01). In contrast, a lack of prior social encounters as experienced by Cohort 2 (b, d, f) resulted in sham and TBI mice emitting a similar number of calls (both total and restricted to >75 kHz kHz). Call duration was not affected by injury in Cohort 1 (g), although in Cohort 2 (h) there was a trend towards TBI mice producing calls of shorter duration compared to sham mice overall (p = 0.069).
Mentions: We first examined the total number of calls produced. For Cohort 1, sham-operated mice showed a high response to either a female mouse or female bedding, emitting an average of 476.17 and 575.83 calls respectively during the post-stimulus recording period (figure 5a). The number of calls was lower in response to a male stimulus mouse, averaging 240.17 total calls (2-way RM ANOVA effect of stimulus F1, 9 = 31.09, p<0.001). Brain-injured mice produced a greater total number of USV calls compared to sham mice (effect of injury F1, 9 = 6.15, p = 0.035). This difference was dependent upon the stimulus, with TBI showing a higher number of calls in response to a female mouse (F1, 17 = 8.23, p = 0.011) and a trend towards higher numbers of calls in response to female bedding (F1, 19 = 3.48, p = 0.078), but not in response to a male mouse (F1, 11 = 0.57, p = 0.468). The presentation of a male stimulus mouse elicited USVs from only a subset of mice (n = 6 sham and n = 5 TBI), and fewer calls from those that did vocalize. In contrast, presence of a female stimulus induced USVs in 90% of mice, and 100% of mice vocalized in response to female bedding.

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