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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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Reduced social investigation at adulthood after pediatric but not adolescent TBI.Experimental timelines illustrate the timing of behavioral assessments; Cohort 1 (a) consisted of n = 10/group after TBI or sham-operation at p21; Cohort 2 (b) was n = 7–8/group, also after TBI or sham at p21; Cohort 3 (c) consisted of mice that received TBI or sham-operation at p35 (adolescence; n = 9/group). Investigative and interactive behaviors by sham and TBI mice, at adulthood after p21 or p35 injury, were quantified after addition of a novel male mouse in the resident-intruder (RI) paradigm (d). Brain-injured mice that received TBI at p21 (e) spent less time engaged in social investigative behaviors including ano-genital sniffing and following (**p<0.01, *p<0.05). Antagonistic behaviors (f), quantified as the number of fighting bouts and latency to first fight, were not different between the injury groups. After injury at p35 (g, h), sham and TBI mice also showed similar investigative behaviors towards a novel male mouse.
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pone-0103386-g001: Reduced social investigation at adulthood after pediatric but not adolescent TBI.Experimental timelines illustrate the timing of behavioral assessments; Cohort 1 (a) consisted of n = 10/group after TBI or sham-operation at p21; Cohort 2 (b) was n = 7–8/group, also after TBI or sham at p21; Cohort 3 (c) consisted of mice that received TBI or sham-operation at p35 (adolescence; n = 9/group). Investigative and interactive behaviors by sham and TBI mice, at adulthood after p21 or p35 injury, were quantified after addition of a novel male mouse in the resident-intruder (RI) paradigm (d). Brain-injured mice that received TBI at p21 (e) spent less time engaged in social investigative behaviors including ano-genital sniffing and following (**p<0.01, *p<0.05). Antagonistic behaviors (f), quantified as the number of fighting bouts and latency to first fight, were not different between the injury groups. After injury at p35 (g, h), sham and TBI mice also showed similar investigative behaviors towards a novel male mouse.

Mentions: Male C57Bl/6J pups at post-natal day 17 with an accompanying lactating mother were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the Laboratory Animal Resource Center at UCSF. Mice were weaned at p21 and group-housed (4–5/cage) with littermates unless otherwise stated. Standard rodent chow and tap water were available ad libitum, and the room was maintained on a 12 hour light/dark cycle at approximately 20°C. A total of 53 mice were used in this study, in three experimental cohorts: cohort 1 (n = 10 sham and n = 10 TBI at p21; Figure 1a), cohort 2 (n = 7 sham and n = 8 TBI at p21; Figure 1b) and cohort 3 (n = 9 sham and n = 9 TBI at p35; Figure 1c).


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)

Reduced social investigation at adulthood after pediatric but not adolescent TBI.Experimental timelines illustrate the timing of behavioral assessments; Cohort 1 (a) consisted of n = 10/group after TBI or sham-operation at p21; Cohort 2 (b) was n = 7–8/group, also after TBI or sham at p21; Cohort 3 (c) consisted of mice that received TBI or sham-operation at p35 (adolescence; n = 9/group). Investigative and interactive behaviors by sham and TBI mice, at adulthood after p21 or p35 injury, were quantified after addition of a novel male mouse in the resident-intruder (RI) paradigm (d). Brain-injured mice that received TBI at p21 (e) spent less time engaged in social investigative behaviors including ano-genital sniffing and following (**p<0.01, *p<0.05). Antagonistic behaviors (f), quantified as the number of fighting bouts and latency to first fight, were not different between the injury groups. After injury at p35 (g, h), sham and TBI mice also showed similar investigative behaviors towards a novel male mouse.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103386-g001: Reduced social investigation at adulthood after pediatric but not adolescent TBI.Experimental timelines illustrate the timing of behavioral assessments; Cohort 1 (a) consisted of n = 10/group after TBI or sham-operation at p21; Cohort 2 (b) was n = 7–8/group, also after TBI or sham at p21; Cohort 3 (c) consisted of mice that received TBI or sham-operation at p35 (adolescence; n = 9/group). Investigative and interactive behaviors by sham and TBI mice, at adulthood after p21 or p35 injury, were quantified after addition of a novel male mouse in the resident-intruder (RI) paradigm (d). Brain-injured mice that received TBI at p21 (e) spent less time engaged in social investigative behaviors including ano-genital sniffing and following (**p<0.01, *p<0.05). Antagonistic behaviors (f), quantified as the number of fighting bouts and latency to first fight, were not different between the injury groups. After injury at p35 (g, h), sham and TBI mice also showed similar investigative behaviors towards a novel male mouse.
Mentions: Male C57Bl/6J pups at post-natal day 17 with an accompanying lactating mother were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in the Laboratory Animal Resource Center at UCSF. Mice were weaned at p21 and group-housed (4–5/cage) with littermates unless otherwise stated. Standard rodent chow and tap water were available ad libitum, and the room was maintained on a 12 hour light/dark cycle at approximately 20°C. A total of 53 mice were used in this study, in three experimental cohorts: cohort 1 (n = 10 sham and n = 10 TBI at p21; Figure 1a), cohort 2 (n = 7 sham and n = 8 TBI at p21; Figure 1b) and cohort 3 (n = 9 sham and n = 9 TBI at p35; Figure 1c).

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