Browsing by Author "Mychasiuk, Richelle"
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- ItemOpen AccessCaffeine Exacerbates Postictal Hypoxia(2019-01-07) Phillips, Thomas James; Teskey, G. Campbell; Mychasiuk, Richelle; Federico, PaoloBackground: Postictal hypoxia (PIH) is a stroke-like event that follows seizures and may be responsible for the postictal state. PIH may also be a contributing factor to the development of seizure-induced brain abnormalities and behavioral dysfunction associated with epilepsy. Caffeine is the world’s most popular drug with ~85% of people in the US consuming it daily. Thus, persons with epilepsy are likely to have caffeine in their system during seizures. This pre-clinical study investigated the acute and chronic effects of caffeine on tissue oxygenation pre- and post-seizure. Methods: We utilized the electrical kindling model in rats. A stimulating/recording electrode was placed into the rat ventral hippocampus (CA3), and an oxygen measuring optrode in dorsal hippocampus (CA1). Rats were administered vehicle (saline) or caffeine (5.0, 10.0, or 15.0 mg/kg) intraperitoneally, 30 minutes prior to an elicited seizure. Hippocampal oxygen levels were continually measured post-injection, and post-seizure, until returning to the normoxic range. Further, rats were administered various agonists and antagonists to determine adenosine receptors role in PIH. Lastly, rats were administered a chronic regime of caffeine to determine the long-term effects of caffeine in relation to PIH. Results: Caffeine at high (15. 0mg/kg) doses, caused a significant drop in pre-seizure hippocampal pO2. Following a seizure, caffeine at 10.0mg/kg and 15.0mg/kg, increased the time below the severe hypoxic threshold (10mmHg). Caffeine’s metabolites, paraxanthine, theobromine, and theophylline also increased the time below the severe hypoxic threshold. Adenosine A1 receptor agonist n6-Cyclopentyladenosine caused a significant drop in pre-seizure mean pO2 and increased the area below severe hypoxic threshold. A2A receptor antagonist SCH-58261 caused a significant drop in pre-seizure mean pO2. The A2B receptor, appeared to have no effect on hippocampal pO2 or PIH. Chronic caffeine consumption resulted in an increase in the area below the severe hypoxic threshold on day 15. Rats became tolerant to the drop-in pre-seizure pO2 via chronic consumption but became sensitized to the postictal severe hypoxia effects. Conclusions: Caffeine exacerbates postictal hypoxia; thus, this research hopes to guide future clinical investigations into the effect of caffeine on postictal blood flow and postictal symptomology in persons with epilepsy.
- ItemOpen AccessChronic BMY7378 treatment alters behavioral circadian rhythms(Wiley, 2017-10-17) Vijaya Shankara, Jhenkruthie; Orr, Angélique; Mychasiuk, Richelle; Antle, Michael CThe mammalian circadian clock is synchronized to the day:night cycle by light. Serotonin modulates the circadian effects of light, with agonists inhibiting response to light and antagonists enhancing responses to light. A special class of serotonergic compounds, the mixed 5-HT1A agonist/antagonists, potentiate light-induced phase advances by up to 400% when administered acutely. In this study, we examine the effects of one of these mixed 5-HT1A agonist/antagonists, BMY7378, when administered chronically. Thirty adult male hamsters were administered either vehicle or BMY7378 via surgically implanted osmotic minipumps over a period of 28 days. In a light:dark cycle, chronic BMY7378 advanced the phase angle of entrainment, prolonged the duration of the active phase, and attenuated the amplitude of the wheel running rhythm during the early night. In constant darkness, chronic treatment with BMY7378 significantly attenuated light-induced phase advances, but had no significant effect on light-induced phase delays. Non-photic phase shifts to daytime administration of a 5-HT1A/7 agonist were also attenuated by chronic BMY7378 treatment. qRT-PCR analysis revealed that chronic BMY7378 treatment upregulated mRNA for 5-HT1A and 5-HT1B receptors in the hypothalamus, and downregulated mRNA for 5-HT1A and monoamine oxidase-A in the brainstem. These results highlight adaptive changes of serotonin receptors in the brain to chronic treatment with BMY7378, and link such up- and down-regulation to changes in important circadian parameters. Such long-term changes to the circadian system should be considered when patients are treated chronically with drugs that alter serotonergic function.
- ItemOpen AccessEarly Life Adversity, Traits and Opioid Addiction(2018-08-14) Zumbusch, Alicia Solange; Teskey, G. Campbell; Mychasiuk, Richelle; Hill, Matthew; Bray, Signe L.Addiction has a negative impact on addicted individuals, their relationships and society at large. Though most adults have sampled addictive substances such as alcohol or prescription painkillers, only a small subset of them exhibit the chronic and relapsing drug use that characterizes addiction. Prior to compulsive and relapsing drug use, individuals will escalate their intake through increase dose or dose frequency. Given that escalation is the first hallmark of addiction to emerge, it is critical to the early detection of addiction. The increasing prevalence of synthetic and semi-synthetic opioids such as fentanyl is of critical concern as current treatments for opioid addiction are largely ineffective. Increasing focus on predisposing factors and early detection are essential to the prevention of opioid addiction. It is unknown what renders certain individuals more liable to develop addiction. Correlational research done in humans shows that there is a strong positive relationship between early life adversity and addiction prevalence in adulthood. The mechanism by which early life adversity impacts addiction vulnerability has not been well characterized. One way that early life adversity may increase the propensity to develop addiction is through the alteration of addiction-related behavioural traits. Several traits have been linked to addiction, namely impulsivity, novelty preference, anxiety and cue attraction. Human and rodent literature suggests that these traits are malleable and that stress during development can alter their expression. To date, no studies have experimentally examined the effects of early life adversity on the expression of addiction-related traits and self-administration behaviours in the same population. This thesis shows the first experimental evidence that early life adversity increases the prevalence of individuals expressing of multiple addiction risk traits as well as the number of individuals that escalate their opioid seeking and taking in a self-administration paradigm. Understanding the etiology of addiction and how early life stress augments the expression of addiction-related traits paves the way for the development of preventative interventions and knowing how early life adversity and addiction-related traits relate to the increased prevalence of opioid escalators will be beneficial to developing treatments for opioid addiction.
- ItemOpen AccessThe Effects of Anabolic-Androgenic Steroids on Repetitive Mild Traumatic Brain Injury Outcomes(2019-08-16) Tabor, Jason Benjamin; Mychasiuk, Richelle; Yeates, Keith Owen; Spanswick, Simon C.; Shultz, Sandy R.; Debert, Chantel Teresa; Pittman, Quentin J.Given the considerable prevalence of AAS abuse and RmTBI incidence in adolescents and their overlapping symptomology, the goal of this research was to characterize any cumulative behavioural and neuropathological outcomes of AAS on the concussed brain in adolescent Sprague Dawley rats. Although there were minimal effects of AAS on RmTBI outcomes, we identified cumulative effects of RmTBI and abrupt AAS and exercise cessation on measures of anxiety, working memory, in addition to altered gene expression in the neural circuitry involved in the innate stress response. Additionally, we identified alarming effects of AAS on the developing brain; prefrontal cortex atrophy, amygdala hypertrophy, and damaged white matter in the corpus callosum were identified which were associated with changes in gene expression and subsequent behavioural impairments. The findings from this investigation provide valuable insight into the effects of AAS exposure on the developing brain in the context of RmTBI.
- ItemOpen AccessExploring the Role of ATF4 in Circadian Photic Phase Shifting(2018-07-23) Chan, Ryan K.; Antle, Michael C.; Spanswick, Simon C.; Mychasiuk, Richelle; Epp, Jonathan RichardThe phenotypic role of activation transcription factor 4 (ATF4) in the mammalian circadian system has yet to be characterized. Previous research has provided evidence that ATF4 may play a key role in modulating molecular circadian activity, and it has been hypothesized that it may also be important for modulating photic resetting of the clock as a repressor of CREB. The main objectives of this investigation were to characterize the circadian expression of ATF4 protein in different lighting conditions, and to examine if downregulation of ATF4 using small interfering RNA (siRNA) technology would significantly potentiate photic phase shifts. In the Syrian hamster, ATF4 appeared to have a circadian expression in a light/dark cycle, but not when animals were in constant darkness. Light sufficiently increased ATF4 protein expression 2-3hrs following light exposure suggesting light plays an important role in regulating ATF4 expression. However, downregulation of ATF4 via siATF4 did not significantly potentiate phase advances to light as hypothesized. Rather, injections of siATF4 appeared to significantly alter an animal’s phase angle of entrainment. In summary, ATF4 plays an important role in the rhythmicity of the clock as light appears to be important in driving ATF4 circadian expression and its downregulation resulted in increased phase angle. However, the function of light-induced ATF4 expression remains to be determined.
- ItemOpen AccessImpact of Alterations to Early Life Microbiota (Antibiotics, Prebiotics, and C-Section) on Body Weight and Brain Development(2021-09-21) Cho, Nicole A; Reimer, Raylene A.; Mychasiuk, Richelle; Sharkey, Keith A; Giesbrecht, GeraldBackground: Communication between the gut microbiota, gut, and brain is now known to influence behavior, metabolic health, and immunity. Foods that improve the composition of the gut microbiota as well as factors that can disrupt it during early development are of interest to investigate the origins of and possible therapeutics for chronic diseases like obesity and mood and neurodevelopmental disorders. Objective: This dissertation examines how early life perturbations to gut microbiota, such as maternal antibiotic use, prebiotic consumption, maternal obesity, and C-section (CS) alter microbial, metabolic, behavioral, and brain outcomes. Specifically, the objectives of this thesis were to: 1) assess the impact of CS in offspring of lean and obese dams on offspring obesity risk; 2) examine the impact of CS and maternal prebiotic intake on offspring microglia and neuron morphology; 3) determine the effects of maternal antibiotic/prebiotic intake on offspring behavior and microglia reactivity; 4) investigate the effects of maternal and child antibiotic use on BMI z-score and temperament in 3-year-old children in a clinical cohort.Methods: Animal studies were conducted in Sprague-Dawley rats or NIH Swiss mice. Clinical participant data was accessed from the Alberta Pregnancy and Nutrition Outcomes (APrON) study. Body composition was measured with dual x-ray absorptiometry (DXA). Elevated Plus Maze (EPM), Novel Context Mismatch (NCM), and Sucrose Preference Tests (SPT) were used to assess behavior. Microglia were analyzed using the expression of IBA-1. Gut microbiota was assessed using 16S rRNA gene sequencing, and tissue gene expression was measured using RT-PCR. Temperament data was assessed using the Child Behavior Questionnaire (CBQ).Results: The primary findings from our study objectives were: 1) CS-associated obesity risk in offspring is dependent on maternal obesity status; 2) Maternal prebiotic intake reverses CS-induced alterations to microglia; 3) Antibiotic-induced alterations to microglia are reversed by maternal prebiotic intake; 4) Maternal and child antibiotic use is associated with increased BMI z-score in children. Conclusion: Our results provide evidence that early-life microbial perturbations alter obesity risk and microglia activation. We also demonstrated the potential for prebiotics to reduce the neuroinflammation that could modulate the risk for mood and neuropsychiatric disorders.
- ItemOpen AccessImpact of an Early Life Immune Challenge on Outcomes in a Rat Model of Pediatric Mild Traumatic Brain Injury(2016) Candy, Sydney Alexandra; Esser, Michael; Pittman, Quentin; Mychasiuk, RichelleThe focus of this thesis was to determine if neonatal exposure to lipopolysaccharide (LPS) on postnatal day (P) 10 would affect the behavioural and molecular outcomes after mild traumatic brain injury (mTBI) on P30. It appears that female LPS + mTBI rats show alterations in measures of anxiety, working memory and depressive-like behaviour - different from those not previously exposed to LPS. In addition to behavioural changes, the mRNA expression profiles of LPS + mTBI rats showed a differential cytokine response at P45 in comparison to rats that received LPS, mTBI, or saline injury controls (SAL + mTBI). Cytokine mRNA levels were followed up by analyzing two microglia/macrophage phenotype markers; the markers also showed an altered profile for LPS + mTBI animals. The findings of the work highlight the importance of sex differences and suggest that an early life immune challenge could confer selective susceptibility to outcomes after mTBI.
- ItemOpen AccessThe Importance of Sex and Age in Repetitive Mild Traumatic Brain Injury(2022-05) Eyolfson, Eric; Mychasiuk, Richelle; Lohman, Alexander; Antle, Michael; Kuipers, HedwichAdolescence is the age group who experience the highest rates of mild traumatic brain injuries (mTBI). In part due to high risk-taking situations and sensation seeking behaviours adolescents are also at high risk for repetitive mTBIs (RmTBI). As a field, we know shockingly little about the risk factors to receive mTBI, immediate, and long-term outcomes following mTBI in this age group. Although sex appears to exert the greatest influence on these outcomes, even less is known about mTBI and RmTBI in female adolescents. Previous research has focused on adult males, but it is becoming ever clearer that understanding the pathophysiology of underrepresented groups (females and adolescents) may help us fully appreciate the sequelae of mTBI and RmTBI. The review article in chapter two highlights what is currently known about mTBI in adolescence, the role of microglia, and generates hypotheses about the potential long-term consequences of injuries during this critical window of development. The research article in chapter three translates an ecologically valid model of RmTBI from rats to mice and probes the dynamics of the neuroinflammatory response in adolescents, specifically focusing on time- and region-dependent dynamics of microglia. The research article in chapter four directly compares the adolescent and adult behavioural, microglial, and neuronal response to RmTBI. Chapter five probes the influence of epigenetics by manipulating paternal preconception environment and transfer of these experiences to adolescent offspring responses to RmTBI. My current research provides new research directions for future experiments, particularly highlighting the need to include underrepresented groups; emphasizing that females are not small males and adolescents are not small adults. Understanding the age- and sex-specific pathophysiological mechanisms at play following RmTBI will allow us to identify new targeted avenues to treat diverse populations who experience these recurring injuries.
- ItemOpen AccessMicroglia dynamics in adolescent traumatic brain injury(2020-10-29) Eyolfson, Eric; Khan, Asher; Mychasiuk, Richelle; Lohman, Alexander WAbstract Repetitive, mild traumatic brain injuries (RmTBIs) are increasingly common in adolescents and encompass one of the largest neurological health concerns in the world. Adolescence is a critical period for brain development where RmTBIs can substantially impact neurodevelopmental trajectories and life-long neurological health. Our current understanding of RmTBI pathophysiology suggests key roles for neuroinflammation in negatively regulating neural health and function. Microglia, the brain’s resident immune population, play important roles in brain development by regulating neuronal number, and synapse formation and elimination. In response to injury, microglia activate to inflammatory phenotypes that may detract from these normal homeostatic, physiological, and developmental roles. To date, however, little is known regarding the impact of RmTBIs on microglia function during adolescent brain development. This review details key concepts surrounding RmTBI pathophysiology, adolescent brain development, and microglia dynamics in the developing brain and in response to injury, in an effort to formulate a hypothesis on how the intersection of these processes may modify long-term trajectories.
- ItemOpen AccessMild Traumatic Brain Injury, Sleep, and Pain in Adolescence(2018-11-14) Christensen, Jennaya; Mychasiuk, Richelle; Antle, Michael C.; Noel, Melanie; Lebel, Catherine A.The child and adolescent age group exhibit the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) and repetitive mild TBI (RmTBI) accounting for a large proportion of these injuries. Adolescents represent a particularly high risk cohort for experiencing long-term post-traumatic deficits. During this critical development phase, dramatic changes in brain structure and organization coincide with important shifts in the sleep cycle, which predispose adolescents to sleep deprivation. Similarly, mTBI often leads to reports of varying levels of sleep problems, yet the role of post-traumatic sleep in post-concussive symptomology remains unclear. Therefore, it is possible that sleep deprivation in the post-traumatic period could be further exacerbating the deleterious effects of mTBI. The glymphatic system is the central nervous system’s (CNS) macroscopic waste clearance system. Importantly, this system removes neurotoxic waste, such as Tau and β-amyloid, from the CNS. Recent developments have determined that the glymphatic system is 90% more active during sleep states while being dramatically suppressed during wakefulness. Given that Tau and β-amyloid protein aggregates are pathological trademarks of the neurodegenerative disorders that are associated with RmTBI and that mTBI patients commonly report sleep problems, one would reason that a reduced glymphatic clearance function may play an imperative role in the development of the neurological deficits related to RmTBI. Chronic pain and sleep deprivation represent major health issues that plague adolescence. A bidirectional relationship exists between sleep and pain; however, emerging evidence suggests that sleep disturbances have a stronger influence on subsequent pain than vice versa. The neurobiological underpinnings of this relationship, particularly during adolescence, are poorly understood. Given the high prevalence of these health issues during adolescence and the debilitating effects they inflict on nearly every domain of development, it is crucial that we determine the neurobiological mechanisms fundamental to this relationship and identify potential therapeutic strategies.
- ItemOpen AccessModulation of Adult Hippocampal Neurogenesis in ZnT3 Knockout Mice(2019-01-07) Bihelek, Nicoline; Dyck, Richard H.; Antle, Michael C.; Mychasiuk, Richelle; Epp, Jonathan RichardThe adult hippocampus is unique in its ability to generate new neurons and presents an enticing target for developing our understanding of learning, memory and disease. While adult hippocampal neurogenesis appears to be regulated by extrinsic factors such as environmental enrichment and exercise, the mechanisms regulating the proliferation, differentiation and survival of adult-born neurons are unclear. Synaptic zinc, which is packaged into vesicles by zinc transporter 3 (ZnT3), is a neurotransmitter capable of modulating a variety of receptors. Previously, our lab observed that ZnT3 knock-out mice exposed to environmental enrichment do not show increases in neurogenesis and, moreover, that these mice did not show increases in brain-derived neurotrophic factor (BDNF), a neurotrophin whose signalling through its receptor, TrkB, is essential in neurogenesis. We examined whether a TrkB agonist, 7,8-dihydroxyflavone (DHF), was sufficient to recover neurogenesis in ZnT3 knock-out mice, as well as how neurogenesis was affected by exercise and DHF treatment in ZnT3 knock-out and wild-type mice. The results of our study suggest that the loss of synaptic zinc in ZnT3 knock-out mice has a profound effect on proliferation, but not differentiation, and highlights the importance of studying each stage of neurogenesis in order to understand the specific effects of an intervention.
- ItemOpen AccessTwo-generation preschool programme: immediate and 7-year-old outcomes for low-income children and their parents(John Wiley & Sons, 2014-05) Benzies, Karen; Mychasiuk, Richelle; Kurilova, Jana; Tough, Suzanne; Edwards, Nancy; Donnelly, Carlene