Browsing by Author "Kurrasch, Deborah M."

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    Development and Validation of an Animal Model of Gestational Cannabis Exposure: Prenatal and Postnatal Outcomes
    (2024-09-13) Baglot, Samantha Lorraine; Hill, Matthew N.; Kurrasch, Deborah M.; Borgland, Stephanie L.
    Cannabis is one of the most widely used drugs, even during pregnancy. Clinical and preclinical research have shown important but variable effects of prenatal cannabis exposure (PCE) on cognitive, social, emotional, and metabolic domains. Preclinical studies allow for precise control and mechanistic exploration; however, studies utilizing translational routes of administration (such as inhalation) are limited. The overall aim of this thesis was to validate a preclinical model of cannabis inhalation and then use that model during pregnancy to examine maternal-fetal transmission and both pre- and post-natal outcomes across several domains. In chapter 2, we characterized and validated a preclinical model of cannabis inhalation and compared pharmacokinetics with injection exposure. Despite comparable dosages and similar peak blood THC levels following inhalation and injection, we found drastically different metabolism and pharmacokinetics of THC and metabolites. In chapter 3, we validated a preclinical model of inhaled PCE and compared maternal-fetal transmission to a common PCE injection model. We found that inhalation exposure resulted in a transmission rate (from maternal blood to fetal brain) of about 30%, whereas injection resulted in roughly 100%. These studies were the first to directly compare THC and metabolite levels following inhalation or injection in adulthood and during pregnancy, and taken together our results suggest that animal models need to consider route of administration when discussing translational implications. In chapter 4 and 5, we aimed to examine the effects of inhaled PCE on several pre- and postnatal outcome domains. In general, we found that PCE resulted in altered early-life immune profile, reduced social investigation, elevated stress-response in adult males, altered glucose metabolism that was sex and diet dependent, modified food choice, and reduced sucrose preference in adulthood. However, we also found that PCE did not alter maternal outcomes, litter size or birthweight, embryonic endocannabinoid or stress system functioning, adolescent structural brain development or social play behaviour, and adult anxiety-like behaviour, bodyweight, or adiposity. Collectively, these studies provide a large overview of the effects of PCE utilizing a moderate inhalation dosage and may help promote more accurate public health messaging around the risk of cannabis use during pregnancy.
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    Elucidating the role of cystatin c in astrocytes in multiple sclerosis
    (2020-08-20) Palmer, Alexandra L.; Ousman, Shalina S.; Yong, Voon Wee; Antel, Jack P.; Kurrasch, Deborah M.; Kuipers, Hedwich F.; Jirik, Frank Robert
    Multiple sclerosis (MS) is one of the most common neurological disabilities of young adults. During the disease course there are a variety of molecules that become dysregulated, one of them being cystatin C (CysC). CysC is a small molecule inhibitor of cysteine cathepsins and is implicated in a variety of biological processes. The role of CysC in MS remains undetermined. Astrocyte reactivity is well noted in the MS literature and contributes to pathological processes during disease development and progression. This thesis set out to 1) characterize the expression of CysC in MS and the animal model, experimental autoimmune encephalomyelitis (EAE), 2) clarify the role of CysC in astrocytes and, 3) determine whether CysC can be therapeutically targeted. CysC expression was characterized in both MS and EAE central nervous system (CNS) samples. The expression of CysC was found to be increased in both MS and EAE brain and spinal cord samples, its expression overlapped with astrocytes, and a loss of CysC (CysCKO) in EAE ameliorated disease. This attenuation of clinical disability in CysCKO EAE mice was associated with a CNS intrinsic effect. A mixed glial culture system was then used to explore the effect of CysC on the response of astrocytes to pro-inflammatory stimuli. From this, it was found that CysCKO glia reduced cytokine and chemokine production in response to lipopolysaccharide (LPS) and increased cytokine and chemokine production upon activation by Interleukin-1beta + interferon-gamma, however CysC may not mediate this effect through the astrocyte signalling pathways STAT1, STAT3, or NF-kappaB. Lastly, Valsartan, a generic medication with the ability to reduce serum CysC levels in humans, was examined to see if it could therapeutically decrease CysC levels in vivo during EAE. Valsartan decreased CysC levels and delayed disease onset, however its effect did not appear to be mediated through astrocytes. Finally, an astrocyte-specific CysC conditional KO mouse was developed to more directly interrogate the role of CysC in astrocytes in vivo during EAE. This thesis provides novel evidence that CysC may influence astrocyte cytokine and chemokine secretion and may be a potential therapeutic target in MS.
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    Hippocampal Oxygen Dynamics During and Following Febrile Seizures
    (2021-01-22) Harris, Sydney; Teskey, Gordon Campbell; Scantlebury, Morris H.; Kurrasch, Deborah M.; Trang, Tuan
    Objective: Febrile seizures are the most common convulsive event, with anywhere from 2-14% of the population having at least one between 6 months and 5 years of age. Febrile seizures are linked to memory impairments and increased seizure susceptibility. In adults, prolonged seizures resulting from a brain damaging event such as status epilepticus result in hyperoxia. Conversely, brief self-terminating seizures lead to postictal hypoxia. It is currently unknown the dynamic changes in oxygen levels and the mechanisms involved in febrile seizures. Methods: Eight-day-old rat pups were implanted with a hippocampal electrode and oxygen sensing optode. Following surgery rat pups received an immune challenge through 4, once daily injections of lipopolysaccharide. Febrile seizures were then induced using a modified heated dry air model. Before, during and after seizure induction hippocampal local field potentials and oxygen levels were recorded. Separate groups of pups received injections of drugs targeting COX-1, COX-2, L-type calcium channels, CB1 receptors, TRPV1 receptors and adenosine receptors prior to febrile seizure induction. Following febrile seizures, a subset of pups were raised to young adulthood then tested in a novel object recognition paradigm to test learning deficits Seizure thresholds following pentylenetetrazol administration were also tested in adulthood. Results: Febrile seizures result in oxygen dynamics that are related to epileptiform activity. Oxygen following seizures are the same in both male and female rat pups. Oxygen dynamics appear to be linked to seizure length and severity. When a seizure starts there is an initial increase in oxygen, followed by a local oxygen minimum. While oxygen is at the lowest rat pups behaviourally recovery from the seizure, but epileptiform activity in the brain persists. Oxygen then climbs for a second time and does not begin to fall until the epileptiform activity terminates. Calcium channels are involved in seizure behavioural termination with inhibition prolonging recovery while activation decreases time to behavioural recovery without altering epileptiform activity termination. Additionally, inhibiting calcium channels decreases hyperoxia during and following the seizure. Inhibiting COX-1, CB1 and TRPV1 receptors all lead to less hyperoxia postictally. Caffeine had a proconvulsant effect and resulted in less oxygen fluctuations in the hippocampus. A single febrile seizure leads to decreased memory formation but did not alter seizure thresholds in adulthood. Significance: Febrile seizure postictal brain oxygenation does not follow the same pattern or have the same mechanisms as a brief focal seizure or status epilepticus in adults. A single febrile seizure can lead to lasting consequences in memory formation. Brain oxygen dynamics may be an important consideration in the development of treatments for febrile seizures.
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    Mitochondria, Inflammation, and T-Cell Metabolism in a Rat Model of Pediatric Mild Traumatic Brain Injury
    (2020-07-24) Fraunberger, Erik Albert; Esser, Michael J.; Shutt, Timothy E.; Gallagher, Clare N.; Yeates, Keith Owen; Kurrasch, Deborah M.; Noble-Haeusslein, Linda J.
    Representing approximately 20,000 emergency department visits in Canada every year, pediatric traumatic brain injury (TBI) can be an intractable medical problem with limited treatment options. While most research has been directed towards the devastating, moderate-severe end of the TBI spectrum, most clinical injuries present as mild with minimal duration of loss of consciousness and lack of macroscopic damage to neural tissue. The pediatric population is especially vulnerable to the consequences of these milder injuries as developmental processes and long-term functioning can be impacted by negative cognitive and emotional changes persisting for up to and beyond one month after injury. Although we have some understanding of TBI pathophysiology including diffuse axonal injury, mitochondrial dysfunction, and cerebral blood flow dysregulation, there is still no clear understanding as to how the developing brains responds and adapts to injury. This thesis takes up the challenge of studying a mild, heterogeneous injury using a juvenile rat TBI model. It begins to unravel some of the complex pathophysiological patterns after pediatric mTBI from the perspectives of mitochondrial function, inflammation, and T-cell metabolism. First, we documented females having greater mitochondrial oxygen consumption in brain cells 21 days after a single mTBI, offering insight into one mechanism for persistent impairments in females following pediatric mTBI. Second, we highlight inflammatory changes to the understudied cerebellum, show cytokines as poor biomarkers of mTBI, and illustrate dynamic changes in inflammation after pediatric mTBI using network analysis. Third, we found preliminary evidence of metabolic changes in CD4+ T-cells starting at 24h post-mTBI, revealing possible upstream changes to observed inflammation previously shown only at 4-7 days after injury. Seeing changes in substrate oxidation patterns presaging inflammation may reveal nascent benefits to targeting metabolism to alter inflammation for therapeutic intervention. Collectively, the work in this thesis significantly advances our knowledge of pediatric mTBI pathophysiology, introduces new ways to interpret inflammation data, and paves the way for the investigation of novel pathways for therapeutic intervention.
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    Molecular mapping of rax+ lineages
    (2012) Kar, Deepon; Kurrasch, Deborah M.
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    Rnd2 and Rnd3 expression in the ventromedial hypothalamus is compromised during embryonic development in absence of proneural genes Neurog2 and Ascl1
    (University of Calgary, 2018-09-24) Zhang, Cindy HaiQin; Kurrasch, Deborah M.
    The ventromedial hypothalamus (VMH) is a hypothalamic nucleus with essential roles in homeostatic functions such as satiety signaling and reproductive behaviors. Despite the functional importance of the VMH, mechanisms driving VMH development are just starting to be explored. Among the most important unanswered questions regarding to VMH development is: what are the mechanisms responsible for VMH neurons migrate from their birthplace to their final positions? Here, we investigated whether the absence of the proneural genes Neurogenin-2 (Neurog2) and Achaete-scute homolog 1 (Ascl1) compromises the expression of downstream Rho family GTPase 2 and 3 (Rnd2 and Rnd3), respectively, in migrating VMH neurons. In migrating cortical neurons, Neurog2 has been shown to directly induce Rnd2 expression, and Rnd3 expression is likewise induced by Ascl1. When expressed normally, Rnd2 and Rnd3 both facilitate critical aspects of radial migration, and Rnd3 further maintains the correct timing and direction of migration. We used Ascl1GFP/KI and Neurog2GFP/KI mouse embryos as model organisms. Rnd2 and Rnd3 expression throughout critical development periods was examined by individually immunostaining for anti-Rnd2 and anti-Rnd3 at E12.5, E15.5, and E19.5 slices and imaging slices using compound fluorescence microscopy. VMH neurons expressing Rnd2 and Rnd3 were visually counted and compared with counts of control slices. Up until now, we have found that Ascl1 null embryos had fewer cells expressing Rnd3 at E15.5 and E19.5, and Neurog2 null embryos had fewer cells expressing Rnd2 at E19.5. Preliminary immunostaining results shows a reduction in transcription of both Ascl1 and Neurog 2. Results from this work will shed important insight into the mechanisms employed by hypothalamic neurons during migration. Abnormalities in neuronal migration to the VMH may result in obesity disorders and early puberty; thus, understanding migration mechanisms is an essential first step in developing tools to treat and prevent potentially debilitating conditions.