Sex-dependent changes in neuronal morphology and psychosocial behaviors after pediatric brain injury
Introduction
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among children and adolescents worldwide [32], [119]. Children under five years of age have the highest incidence of injuries resulting in emergency department visitations, with falls accounting for a large proportion of these [66], [119]. A significant proportion of brain-injured children develop chronic behavioral problems, which may persist and worsen over time [74], [67]. In particular, children exposed to a TBI during early life are at elevated risk of impairments in social interaction and adjustment, language, non-verbal communication, and adaptive behaviors [95]. Social dysfunction is increasingly recognized as a significant negative contributor to quality of life for survivors of pediatric TBI, having chronic and diverse consequences on mental health, academic and workplace performance, and relationships [25], [92], [67], [129].
Several injury-related and environmental factors have been identified, that contribute to an individual's likelihood of developing social impairments after TBI [see Ref. [95] for review]. Injury severity, for example, is likely to influence the degree of social dysfunction after injury. Severe TBI in young children has been associated with poorer social functioning compared to mild and moderate TBI [16], [30], [17], and animal models of moderate and severe TBI are more likely to present with social deficits than models of mild severity [94]. However, others have found that even a mild TBI during early childhood can disrupt the normal development of social behaviours [54], and children with TBI of all severity levels show deficits in cognitive theory of mind tasks [22], [23].
The potential involvement of biological sex in the manifestation of injury-related social dysfunction has not been well-studied to date. Of note, differential psychosocial and communication problems have recently been identified between male and female patients after TBI [39], [24], [81], [99], even among young children and infants [19], [54]. At adulthood after pediatric TBI, females are more likely to report internalizing problems (e.g. depression and anxiety), whereas males are more likely to report externalizing problems such as aggression [99]. Such differences may be attributed to sexually-dimorphic neuroanatomy, environmental factors, and/or differences in post-injury neuropathology or neuroendocrinology. The potential for sex differences in social outcomes highlights the need to better understand the extent to which psychosocial functioning is affected in both sexes [97]. In the context of early life brain injuries, sex differences in how the developing brain responds to TBI may have important implications for both diagnosis and treatment of persistent symptoms long-term.
The evolution of psychosocial outcomes after early-life TBI, whereby symptoms often emerge over time, remains poorly understood. It has been suggested that vulnerability to neurocognitive deficits (for example, deficits in executive function and social problem-solving) may underlie the manifestation of secondary behavioral problems, particularly as children face greater demands and expectations with increasing age [128], [67]. Secondary neuropathological processes triggered by the initial insult may continue over an extended time course of many years post-injury, contributing to progressive neurodegeneration even remote from the primary injury [73], [31]. These processes, superimposed upon a young brain undergoing considerable maturation and development, may influence the presentation of later-life deficits in cognition and psychosocial function [108]. Social functioning in mammals is mediated by a dispersed, interconnected network of limbic, cortical and sub-cortical brain structures, collectively termed the ‘social brain network’ [51], [8], [5]. The social brain network exhibits a protracted refinement of structure and function throughout childhood and adolescence, coinciding with the development of higher-order social skills with age. This developmental trajectory may contribute to the network's vulnerability to dysfunction when any of its regions or interconnecting pathways are disrupted by insult [77].
The prefrontal cortex is an integral component of the social brain network, with a key role in social cognition and the regulation of behaviors including reward-seeking, social motivation, knowledge of self and others, and behavioral flexibility in social contexts [7]. In animal models, focal lesions to the medial prefrontal cortex (mPFC) yield changes in both adult and juvenile social behaviors, strongly implicating this region in social functioning [63], [87], [61]. Aberrant plasticity in this region has been hypothesized to play a role in social dysfunction associated with psychiatric conditions such as autism spectrum disorders and schizophrenia [7]. Of note, there is some evidence that brain injuries, even remote from the frontal lobes, also have the potential to impact mPFC structure and function. In rats, lesions to the motor cortex [43], sub-thalamic nucleus [13] and hippocampus [35] result in neuroplasticity changes in dendritic morphology in the mPFC, associated with alterations in social behavior [96], [68], [36]. These findings further implicate cortico-limbic connectivity in social functioning and suggest that aberrant development of the mPFC after early life brain damage may be a critical factor in the manifestation of social dysfunction [69]. The hippocampus and associated parahippocampal regions are also implicated in the regulation of social behaviors, as rodents with hippocampal lesions often display impaired social recognition memory [28], [71], [124], [118]. Several intriguing studies have demonstrated that neonatal hippocampal lesions alter the development of normal social interactions in rodents and primate models [6], [3], [78], although both an increase and decrease in social behaviors have been reported.
Impairments in social behaviors after early life TBI can be modeled in experimental animals, typically as a reduction in social investigation, social recognition and/or social communication [see Ref. [95] for review]. However, the majority of rodent studies to date have focused exclusively on male subjects [85], [64], [111], [101], [110], [33], [59], [4]. Using male mice at postnatal day 21, approximating a toddler-aged child [100], we have previously demonstrated that a moderate-to-severe TBI to the unilateral parietal lobe results in social and sociosexual behavior deficits as mice develop to adulthood [101], [103]. Of note, abnormalities in sociability, social memory, and social communication were apparent at adulthood (p70+) but not earlier at adolescence (p35). The temporal emergence of social problems suggests that early life brain injury may influence the maturation and connectivity of the social brain network during subsequent brain development [95].
In the current study, we extend our previous findings to consider the effect of biological sex on social outcomes after pediatric TBI, by comparing psychosocial behaviors in brain-injured male and female mice. Secondly, we hypothesize that post-injury changes in social behavior may be mediated by neuroplasticity in neuroanatomical nodes of the social brain network, and examined the effect of pediatric TBI on neuronal morphology in the hippocampus and mPFC. Our findings suggest that sex-specific changes in neuronal morphology neurons precede the onset of social behaviors deficits after pediatric TBI, providing new insight into the biological mechanisms underlying chronic outcomes following early life brain insults.
Section snippets
Animals
Adult C57Bl/6 mice were purchased from the Animal Resource Centre (Perth, Australia) and bred in-house at the Florey Institute of Neuroscience and Mental Health specific-pathogen-free facility. Timed matings generated litters that were weaned at postnatal day 21 (p21) for surgery. From each litter, a total of 56 mice were randomly allocated to one of four experimental groups: male sham, male TBI, female sham, or female TBI. Group allocation was coded to ensure that investigators were blinded
Growth trajectory is not affected by pediatric TBI
Male and female littermate mice were randomly allocated to receive sham or TBI surgery at age p21. Righting time was quantified as the latency to self-right from a supine to prone position following removal from anesthesia, as an indirect measure of injury (Fig. 1a). 2-way ANOVA revealed a significant effect of injury (F1,50 = 5.57, p = 0.02) but no effect of sex, nor an interaction (F1,50 = 1.27, p = 0.27, and F1,50 = 0.02, p = 0.90, respectively), reflecting a longer time to right post-anesthesia after
Discussion
Acquired brain injuries in young children have been associated with a range of enduring social behavior problems, including decreased social responsiveness, social isolation, difficulties with social problem solving, and problems understanding verbal and non-verbal communication [132], [30]. These deficits often persist chronically into adulthood, or emerge over time as demands for more complex social skills increase with age [29]. Experimental pediatric TBI, modeled by a unilateral controlled
Conclusions
A key finding from this study was that male and female mice exhibit different social behavior deficits at adulthood after early life TBI – a male-specific deficit in social recognition memory with a reduction in the dendritic complexity of ipsilateral hippocampal and mPFC neurons. Together, these results suggest that remote sex-specific neuronal changes, likely due to alterations in synaptic inputs and organization, may contribute to the emergence of sex-specific psychosocial deficits over time
Acknowledgements
BDS was supported by a CJ Martin Overseas Early Career Fellowship (#1052505) from the National Health and Medical Research Council of Australia, and an Early Career Researcher Grant from the University of Melbourne. The authors thank A/Prof. Ann Turnley for providing access to the controlled cortical impactor device, and Victorian State Government Infrastructure Support.
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2023, Neuroscience and Biobehavioral ReviewsHippocampal cognitive impairment in juvenile rats after repeated mild traumatic brain injury
2020, Behavioural Brain ResearchCitation Excerpt :Some clinical studies have found that females incur more severe and longer lasting cognitive deficits following TBI [85,86,88–92]. In contrast, some experimental models have found a neuroprotective effect of estrogens [93], or have reported evidence for sex-dependent outcomes [94–96] in juvenile animals. In the current study, we induced our injuries at a pre-pubertal time-point, and we observed similar effects in both male and female rats.