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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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Changes in sociosexual investigation at adulthood after pediatric but not adolescent TBI.Investigative behaviors were quantified at adulthood after addition of a novel female mouse, after injury or sham-operation at p21 or p35. Sham and TBI mice injured at p21 showed similar investigative behaviors overall (a). However, sexual behavior was markedly reduced (b), with TBI mice initiating fewer mounting attempts, and a delayed latency to the first attempt (*p<0.05). After injury at p35 (c), both sham and TBI mice showed similar investigative behaviors towards a novel female mouse. Sexual behavior, quantified as the number of mounting attempts and latency to first attempt, were also comparable in sham and TBI mice after injury at adolescence (d).
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pone-0103386-g002: Changes in sociosexual investigation at adulthood after pediatric but not adolescent TBI.Investigative behaviors were quantified at adulthood after addition of a novel female mouse, after injury or sham-operation at p21 or p35. Sham and TBI mice injured at p21 showed similar investigative behaviors overall (a). However, sexual behavior was markedly reduced (b), with TBI mice initiating fewer mounting attempts, and a delayed latency to the first attempt (*p<0.05). After injury at p35 (c), both sham and TBI mice showed similar investigative behaviors towards a novel female mouse. Sexual behavior, quantified as the number of mounting attempts and latency to first attempt, were also comparable in sham and TBI mice after injury at adolescence (d).

Mentions: The resident-intruder paradigm was also employed to examine social investigation in a sociosexual context, by introducing a female stimulus mouse into the home cage of the test male mouse (sham or TBI; figure 2). At adulthood after surgery at p21, in contrast to male-to-male interactions, both sham-operated and brain-injured mice spent a remarkably similar amount of time engaged in social investigation of the intruding female, averaging a cumulative time of 241.7±13.7 and 247.6±20.2 sec, respectively (unpaired t-test, t18 = 0.24, p = 0.810). When analyzed by specific behaviors (figure 2a), a preference for sniffing the ano-genital region was again evident independent of injury (2-way RM ANOVA effect of behavior F2, 36 = 55.14, p<0.0001). Consistent with similar total investigative times, both sham and TBI mice spent comparable time participating in different social behaviors including sniffing head-torso, sniffing ano-genital, and following (no effect of injury F1, 18 = 0.06, p = 0.810). In contrast, mounting behavior was strikingly suppressed after brain injury (figure 1b). Compared to sham-operated mice, TBI mice showed a significant reduction in the number of mounting attempts towards the female stimulus (t18 = 2.85, p = 0.011). Ninety percent of sham-operated mice made at least one mounting attempt during the 5 minute test period, compared to only 70% of brain-injured mice. Further, latency from the initiation of the encounter until the first mounting attempt was delayed in TBI mice (t18 = 2.51, p = 0.021). Thus, TBI to the developing brain resulted in reduced sexual approach behavior despite normal social investigation towards a stimulus female.


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)

Changes in sociosexual investigation at adulthood after pediatric but not adolescent TBI.Investigative behaviors were quantified at adulthood after addition of a novel female mouse, after injury or sham-operation at p21 or p35. Sham and TBI mice injured at p21 showed similar investigative behaviors overall (a). However, sexual behavior was markedly reduced (b), with TBI mice initiating fewer mounting attempts, and a delayed latency to the first attempt (*p<0.05). After injury at p35 (c), both sham and TBI mice showed similar investigative behaviors towards a novel female mouse. Sexual behavior, quantified as the number of mounting attempts and latency to first attempt, were also comparable in sham and TBI mice after injury at adolescence (d).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103386-g002: Changes in sociosexual investigation at adulthood after pediatric but not adolescent TBI.Investigative behaviors were quantified at adulthood after addition of a novel female mouse, after injury or sham-operation at p21 or p35. Sham and TBI mice injured at p21 showed similar investigative behaviors overall (a). However, sexual behavior was markedly reduced (b), with TBI mice initiating fewer mounting attempts, and a delayed latency to the first attempt (*p<0.05). After injury at p35 (c), both sham and TBI mice showed similar investigative behaviors towards a novel female mouse. Sexual behavior, quantified as the number of mounting attempts and latency to first attempt, were also comparable in sham and TBI mice after injury at adolescence (d).
Mentions: The resident-intruder paradigm was also employed to examine social investigation in a sociosexual context, by introducing a female stimulus mouse into the home cage of the test male mouse (sham or TBI; figure 2). At adulthood after surgery at p21, in contrast to male-to-male interactions, both sham-operated and brain-injured mice spent a remarkably similar amount of time engaged in social investigation of the intruding female, averaging a cumulative time of 241.7±13.7 and 247.6±20.2 sec, respectively (unpaired t-test, t18 = 0.24, p = 0.810). When analyzed by specific behaviors (figure 2a), a preference for sniffing the ano-genital region was again evident independent of injury (2-way RM ANOVA effect of behavior F2, 36 = 55.14, p<0.0001). Consistent with similar total investigative times, both sham and TBI mice spent comparable time participating in different social behaviors including sniffing head-torso, sniffing ano-genital, and following (no effect of injury F1, 18 = 0.06, p = 0.810). In contrast, mounting behavior was strikingly suppressed after brain injury (figure 1b). Compared to sham-operated mice, TBI mice showed a significant reduction in the number of mounting attempts towards the female stimulus (t18 = 2.85, p = 0.011). Ninety percent of sham-operated mice made at least one mounting attempt during the 5 minute test period, compared to only 70% of brain-injured mice. Further, latency from the initiation of the encounter until the first mounting attempt was delayed in TBI mice (t18 = 2.51, p = 0.021). Thus, TBI to the developing brain resulted in reduced sexual approach behavior despite normal social investigation towards a stimulus female.

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