Younger is Better but Only for Males: Social Behavioral Development Following Juvenile Traumatic Brain Injury to the Prefrontal Cortex

Author

Sophie Shonka, Southern Illinois University CarbondaleFollow

Date of Award

12-1-2024

Degree Name

Doctor of Philosophy

Department

Psychology

First Advisor

Hylin, Michael

Abstract

Juvenile traumatic brain injuries (jTBIs) lead to significant social impairments, with injuries sustained earlier on in development resulting in more significant deficits than when comparable injuries occur later in life. The prefrontal cortex is most susceptible to injury due to its position within the skull and the prevalence of falls as a cause for jTBIs. As neural growth is an ongoing process during the early years, the behavioral deficits observed are shaped by the various stages of development. Injuries during phases with high levels of synaptic pruning or myelination can lead to maladaptive changes resulting in increased synaptic pruning and decreased myelination, causing myriad of deficits that will sometimes appear after the end of these stages. Developing brains also respond differently to injury than adult brains with secondary injury cascades resulting in more cell death than an adult brain, and with unmyelinated fibers demonstrating an increased sensitivity to excitotoxic cell death. Finally, the development of social behaviors are fine-tuned early on and utilize behaviors, such as play, to aid in the appropriate development of adult social behaviors. Disruptions to normal social development are especially apparent when damage involves the prefrontal cortex, resulting in social deficits that impair function in adulthood. While the network for social behavior and cognition involves numerous regions throughout the brain, the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC) and amygdala are three regions consistently affected by jTBI damage resulting in deficits in social behavior. Disturbance to these regions appear to play principal roles in social behavior as indicated by the observed deficits following a jTBI. These deficits lead to diminished social relationships at the time of injury and continue across development into adulthood. For this study, animals received a single midline cortical contusion injury which resulted in bilateral damage to the mPFC. To evaluate the premise that the development age at injury impacts the resulting social behavioral outcome, the injury occurred on either post-natal day 17 (PND 17) or 28 (PND 28), which in humans approximates toddlerhood and middle childhood, respectively. Following injury, social behavioral development of play behavior and social preference/memory was assessed at each of three time points: prepuberty (post-natal days [PNDs] 35-41), puberty (PNDs 42-48), and young adulthood (PNDs 56-63), while social dominance and aggression were only assessed during young adulthood. Following completion of the study, the animals’ brains were harvested and the dendritic complexity in the orbitofrontal and remaining medial prefrontal regions were assessed using Golgi-Cox staining. The integrity of myelin on axons between the medial prefrontal region, orbitofrontal region, and amygdala were examined using Luxol-Fast Blue staining. Based upon prior research, it was hypothesized that injury at PND 17 would result in a greater degree of social deficits and increased aggression when compared to injury at PND 28 and sham animals. We additionally hypothesized that male jTBI animals would display increased social deficits and aggression relative to their corresponding female jTBI group. It was also predicted that the development of social behavior, including the presence of deficits, would serve as a predictive factor for social dysfunction in young adulthood. Furthermore, as these injuries would be occurring at times when there are ongoing changes in synaptogenesis and myelination, the social deficits observed would be reflected in the histopathology with PND 17 injured animals demonstrating an overall decrease in dendritic complexity and PND 28 injured animals would display less myelin when compared to sham animals. Finally, it was predicted that these histological changes would be more apparent in male subjects when compared to their respective age-at-injury female jTBI groups. The results of our studies supported some of our predictions. With respect to social behaviors, results showed that the initiation of play behaviors were affected but play engagement behaviors were not impacted by jTBI. More specifically, PND 28 injury increased play initiation behavior in both male and female animals in adulthood while a PND 17 injury delayed the normal developmental pattern in females but had no impact on male animals. Surprisingly, injury had no effect on sociability patterns or social memory abilities across development regardless of when the injury occurred. Furthermore, injury at PND 28 increased social dominance behavior in young adulthood, whereas injury on PND 17 did not. This impact of age at injury was also mirrored in the social aggression results with injuries at PND 28 resulting in an increase in aggressive behaviors. Though it is worth noting that sex moderated this relationship for PND 17 TBI animals. Unexpectedly, an injury at this age decreased aggression in male animals and increased aggression in female animals. However, it was specific to the circumstances in the test, as there was no effect on violent social behavior for either the resident or intruder. Lastly, regarding the predictability of play behavior in social outcome, childhood play attacks predicted resident and intruder offensive behaviors and was moderated by sex and injury. For intruder aggression, PND 28 TBI animals displayed higher intruder aggression levels if they displayed several play attacks in childhood at or above the mean level, but not if they display play attacks rates lower than the mean. For resident aggression, a younger injury in female animals but not male animals decreased aggression behavior across development. Finally, our histological results showed no effect of injury or age of injury on dendritic complexity or myelination. However, effect sizes suggested decreased basal and apical complexity and length in both the OFC and mPFC for jTBI animals, as well as decreases in myelin in the mPFC in PND 28 TBI animals. In conclusion, there was a sex- and age at injury-dependent effects of TBI on the development of social behaviors. Injury at an earlier age resulted in more social deficits in female animals while a similar injury at a later juvenile age was more detrimental to male animals. While these observations were not exactly as predicted, these effects are potentially due to sex-dependent developmental trajectories and social interactions, reflecting the need to examine male and female animal subjects both individually and concurrently.