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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 scent marking indicates impaired sociosexual communication after pediatric TBI.Scent marking by sham and TBI mice was assessed in an open field arena lined with absorbent paper, in the presence and absence of a cage-enclosed novel female mouse (a). Representative examples from sham mice and after injury at p21 are shown in panels (b) and (c), respectively. All mice produced more scent marks in the presence of a stimulus female compared to an empty arena (d). However, despite comparable production of scent marks at baseline (empty open field), TBI mice deposited significantly fewer scent marks in response to a novel female, compared to sham-operated mice (*p<0.05). This reduction was unlikely due to potential changes in mobility, anxiety or gross bladder dysfunction, as measures of anxiety (e) and bladder capacity (f) were comparable.
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pone-0103386-g004: Reduced scent marking indicates impaired sociosexual communication after pediatric TBI.Scent marking by sham and TBI mice was assessed in an open field arena lined with absorbent paper, in the presence and absence of a cage-enclosed novel female mouse (a). Representative examples from sham mice and after injury at p21 are shown in panels (b) and (c), respectively. All mice produced more scent marks in the presence of a stimulus female compared to an empty arena (d). However, despite comparable production of scent marks at baseline (empty open field), TBI mice deposited significantly fewer scent marks in response to a novel female, compared to sham-operated mice (*p<0.05). This reduction was unlikely due to potential changes in mobility, anxiety or gross bladder dysfunction, as measures of anxiety (e) and bladder capacity (f) were comparable.

Mentions: Scent marking in response to a novel female stimulus was assessed as an assay for sociosexual communication and recognition (figure 4a) [22]. In line with the use of this test in mouse models of autism, and based upon preliminary experiments, we restricted our analyses to the area surrounding the female stimulus as a better representation of communication and sociosexual motivation, as compared to the total number of scent marks deposited throughout the entire open field arena [26], [29]. After injury at p21, both sham and TBI mice deposited few scent marks in the arena in the absence of a stimulus female (figure 4d). Addition of a stimulus female to the arena dramatically stimulated scent marking behavior (2-way RM ANOVA effect of stimulus, F1, 18 = 100.40, p<0.0001), increasing the number of urine-containing grid squares 13-fold in sham-operated mice compared to when the arena was empty. Brain-injured mice also showed an increase in scent marking in the presence of a stimulus female compared to the empty arena; however, this response was ∼35% lower compared to sham-operated mice (2-way RM ANOVA effect of injury F1, 18 = 6.86 p = 0.017; stimulus×injury interaction F1, 18 = 3.93, p = 0.063; Bonferroni's post-hoc, p<0.05), indicating a reduced response towards a novel female mouse after injury (figure 4b, c). Defecation was also increased in the presence of the female stimulus compared to the empty arena (2-way RM ANOVA effect of stimulus F1, 18 = 7.03, p = 0.008). Defecation is thought to reflect emotionality in response to a stressful or novel environment [58], [59]. A non-significant trend towards reduced defecation was seen in brain-injured mice compared to sham (2-way RM ANOVA effect of injury F1, 18 = 3.99, p = 0.069).


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 scent marking indicates impaired sociosexual communication after pediatric TBI.Scent marking by sham and TBI mice was assessed in an open field arena lined with absorbent paper, in the presence and absence of a cage-enclosed novel female mouse (a). Representative examples from sham mice and after injury at p21 are shown in panels (b) and (c), respectively. All mice produced more scent marks in the presence of a stimulus female compared to an empty arena (d). However, despite comparable production of scent marks at baseline (empty open field), TBI mice deposited significantly fewer scent marks in response to a novel female, compared to sham-operated mice (*p<0.05). This reduction was unlikely due to potential changes in mobility, anxiety or gross bladder dysfunction, as measures of anxiety (e) and bladder capacity (f) were comparable.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0103386-g004: Reduced scent marking indicates impaired sociosexual communication after pediatric TBI.Scent marking by sham and TBI mice was assessed in an open field arena lined with absorbent paper, in the presence and absence of a cage-enclosed novel female mouse (a). Representative examples from sham mice and after injury at p21 are shown in panels (b) and (c), respectively. All mice produced more scent marks in the presence of a stimulus female compared to an empty arena (d). However, despite comparable production of scent marks at baseline (empty open field), TBI mice deposited significantly fewer scent marks in response to a novel female, compared to sham-operated mice (*p<0.05). This reduction was unlikely due to potential changes in mobility, anxiety or gross bladder dysfunction, as measures of anxiety (e) and bladder capacity (f) were comparable.
Mentions: Scent marking in response to a novel female stimulus was assessed as an assay for sociosexual communication and recognition (figure 4a) [22]. In line with the use of this test in mouse models of autism, and based upon preliminary experiments, we restricted our analyses to the area surrounding the female stimulus as a better representation of communication and sociosexual motivation, as compared to the total number of scent marks deposited throughout the entire open field arena [26], [29]. After injury at p21, both sham and TBI mice deposited few scent marks in the arena in the absence of a stimulus female (figure 4d). Addition of a stimulus female to the arena dramatically stimulated scent marking behavior (2-way RM ANOVA effect of stimulus, F1, 18 = 100.40, p<0.0001), increasing the number of urine-containing grid squares 13-fold in sham-operated mice compared to when the arena was empty. Brain-injured mice also showed an increase in scent marking in the presence of a stimulus female compared to the empty arena; however, this response was ∼35% lower compared to sham-operated mice (2-way RM ANOVA effect of injury F1, 18 = 6.86 p = 0.017; stimulus×injury interaction F1, 18 = 3.93, p = 0.063; Bonferroni's post-hoc, p<0.05), indicating a reduced response towards a novel female mouse after injury (figure 4b, c). Defecation was also increased in the presence of the female stimulus compared to the empty arena (2-way RM ANOVA effect of stimulus F1, 18 = 7.03, p = 0.008). Defecation is thought to reflect emotionality in response to a stressful or novel environment [58], [59]. A non-significant trend towards reduced defecation was seen in brain-injured mice compared to sham (2-way RM ANOVA effect of injury F1, 18 = 3.99, p = 0.069).

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