Richelle M. Mychasiuk

Description:While our understanding of long-term disability after traumatic brain injury (TBI) has habitually focused on cognitive and sensorimotor functioning, it is increasingly appreciated that changes in social function for survivors of a brain injury are common and have a profound impact on one's quality of life. In this chapter, we highlight the consequences of TBI on social behavior, taking into account evidence from studies of patient populations as well as from preclinical animal models. After first considering the protracted nature of the development of social behavior across the lifespan, including the neurobiological networks that underlie social functioning, we discuss how TBI results in social behavior impairments and how these manifest. We focus particularly on how age-at-injury influences TBI-induced social impairments, with most of the evidence suggesting age-dependent vulnerability after injury at a younger age. In addition, we explore how biological sex is a key determinant of social behavior impairments after TBI, while gender in humans may also influence the nature and extent of social outcomes. Finally, we identify key knowledge gaps and emphasize the need for further research in the field.

Description:Adverse childhood experiences (ACEs) alter brain development, leading to vulnerability for chronic pain, mental health disorders, and suicidality. These effects often emerge during adolescence. Importantly, ACEs can occur prenatally, including when exposed to in utero intimate partner violence (IPV) or postnatally as maternal neglect. Maternal social support has demonstrated promise in the mitigation of ACE-related deficits. Oxytocin, which has a role in social-bonding and stress regulation, serves as a suitable surrogate for social support in preclinical studies. Therefore, we aimed to explore the effects of oxytocin on alleviating social deficits, nociception, and epigenetic changes resulting from models that aimed to mimic the stress normally induced following exposure to two ACEs: IPV in utero and maternal neglect. During pregnancy, dams were randomly assigned to experience the model of IPV or a sham insult. Following birth, offspring from the IPV group underwent 10 days of maternal separation. Dams received three days of oxytocin therapy while nursing. In adolescence, half of the offspring underwent a plantar surgery to induce pain. Overall, in adolescence, rats exposed to the ACEs exhibited increased nociceptive sensitivity and aberrant social interactions, particularly among males, further suggesting that ACEs can increase an individual's risk for chronic pain. The ACEs changed gene expression related to social behaviour and neuroplasticity. Maternal oxytocin normalized pain, social, and gene changes, while oxytocin levels in offspring correlated with nociceptive sensitivity. Although ACEs have enduring consequences, the outcomes are modifiable, and oxytocin may be a robust and implementable therapeutic capable of attenuating early adversity.

Description:Abusive head trauma (AHT) resulting from violent shaking and whiplash-induced brain injury by a caregiver, is the leading cause of abusive mortality and morbidity in children. Cerebral oedema is common in survivors of AHT. While many children may initially appear behaviourally asymptomatic or present with non-specific symptoms following the AHT, deficits often emerge later in childhood. Additionally, AHTs are frequently repetitive, with a single child likely to experience multiple AHTs. Despite the prevalence of AHT, the mechanisms that lead to brain pathology and the latent emergence of behavioural deficits are poorly understood, and there is a paucity of preclinical, small animal models to investigate the biology and cumulative effects of repetitive injuries. This study aimed to develop a preclinical model of repetitive AHT and subsequently examine alterations in gene expression, cell types, and early adolescent behaviour. Mice were placed on a 400 rpm shaking device for 60s. This was repeated one, three, or five times throughout the neonatal development period (postnatal days (P)8-12). Injured mice initially displayed no overt behavioural changes compared to uninjured controls; however, in adolescence (P40-45) they later developed deficits in socialisation and thermal nociception. Further, alterations in the expression of genes involved in growth, cell damage, and development were observed in the brains of injured mice, along with an increase in white matter cells and evidence of blood-brain barrier leakage. This novel preclinical model of AHT provides a valuable platform for exploring diagnostic biomarkers and potential therapeutic interventions for children with an AHT.

Description:The primary circadian clock in the brain, the suprachiasmatic nucleus (SCN), drives ∼24-hour circadian rhythms that help regulate physiology and behaviour. To conform to the environment, circadian rhythms are entrained to zeitgebers "time givers", external cues that assist in resetting of the circadian clock and shift the timing of its rhythms. The primary zeitgeber is light, which is considered a photic input. Additional zeitgebers that can modify circadian rhythms independent of light are known as non-photic stimuli, and are innervated by arousal regions of the brain. The mechanisms by which non-photic stimuli contribute to resetting of the circadian clock are currently not clear; however, evidence indicates that activation of arousal regions is necessary. A concept not yet investigated is the involvement of the sensory vestibular system in non-photic clock resetting. Therefore, this review synthesizes current literature and proposes a novel role for the vestibular system in resetting the circadian clock in a non-photic manner. By providing insight into the potential role of vestibular regulation in circadian rhythmicity, we provide valuable evidence that can be used in the future to develop strategies to mitigate circadian misalignment and subsequent dysfunction.

Description:Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.