Browsing by Author "Borgland, Stephanie Laureen"

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    Dietary Protein and Prebiotic Fiber Improve Energy Balance and Metabolic Health
    (2018-08-28) Singh, Arashdeep; Chelikani, Prasanth K.; Borgland, Stephanie Laureen; Banse, Heidi E.; Knight, Cameron; Thompson, Jennifer A.; Moran, Timothy
    Background: Obesity and metabolic syndrome are highly complex disease states and still needs effective treatment and prevention strategies. Growing evidence suggests that dietary milk proteins and prebiotics plays a role in preventing metabolic disorders; however, the underlying mechanisms are unknown. Objective: This dissertation examines how dietary milk proteins and prebiotics (inulin fiber) affect energy balance, host physiology, and gut microbiota to affect metabolic health. The overall objectives of this thesis include: 1) assess the effects of milk protein components on energy balance and stroke onset in stroke-prone rats; 2) determine the role of prebiotics and gut microbiota in regulation of energy balance in obesity-prone and obesity-resistant rats; 3) assess the combined effects of milk protein components and prebiotic on energy balance in obese rats. Methods: Animal studies were conducted using male wistar-kyoto, spontaneously hypertensive stroke-prone, sprague-dawley (SD), obesity-prone (OP) and obesity-resistant(OR) rats. Energy intake, meal patterns, respiratory quotient, and energy expenditure were measured using CLAMS metabolic chambers. Body composition was measured with magnetic resonance imaging. Intraperitoneal glucose and meal tolerance tests were conducted to measure glucose and plasma hormone concentrations. Gut microbiota was assessed using qPCR and 16S rRNA gene sequencing. Gene mRNA abundance was measured using real-time RT-PCR. Results: The primary findings from our study objectives were: 1) supplementation of dietary casein, whey, or its components lactalbumin and lactoferrin, improved energy balance, prevented neurological deficits, morbidity and renal damage and delayed the onset of stroke in stroke-prone rats; 2) gut microbiota play an indispensable role in mediating prebiotic fiber-induced satiety via its effects on cholecystokinin-A and peptide YY Y-2 receptor signaling in high-fat-fed SD, OP, and OR rats; 3) combination of lactoferrin and inulin additively improved energy balance and decreased body weight and adiposity in diet-induced obese rats. Conclusion: Our results provide evidence for the role of milk protein components and prebiotics in improving metabolic dysfunctions in obesity and metabolic syndrome. The findings from our preclinical studies provide a rationale for clinical trials assessing the effects of milk protein components and prebiotics in the prevention and treatment of obesity and its related metabolic abnormalities.
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    The effects of µ-opioid receptor activation on GABAergic synaptic transmission within the orbital frontal cortex
    (2019-01-09) Ambrose, Brittany Pauline; Borgland, Stephanie Laureen; Bains, Jaideep; Wilson, Richard J. A.
    The orbital frontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Several studies have demonstrated that administering opioids can alter reward valuation and action selection. More specifically, µ-opioid activation within the OFC has been shown to enhance both consumption of food rewards and the hedonic reaction to them. Mechanistically, there is ample evidence confirming that µ-opioid agonists act pre-synaptically to disinhibit the output of other cortical regions; however, the precise cellular mechanism of µ-opioid signalling across the OFC remains unknown. Thus, we investigated the cellular actions of µ-opioids within the medial and lateral OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, I found a dose-dependant effect of µ-opioid receptor (MOR) activation on GABAergic synaptic transmission within the medial, but not lateral, OFC. Furthermore, this effect occurred via decreased pre-synaptic release probability of GABA onto pyramidal neurons, consistent with actions of µ-opioids in other cortical regions. Preliminary data also suggest µ-opioid agonists are acting on parvalbumin-positive subpopulations of interneurons. The findings of this study further elucidate the effects of MOR activity on synaptic transmission within the OFC, which remains largely understudied. Importantly, understanding the interaction between the OFC and the opioid system may reveal new mechanisms of action in disorders of aberrantly motivated behaviours.
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    Microglial pannexin-1 is a cellular determinant of opioid withdrawal
    (2018-06-28) Burma, Nicole Elizabeth; Trang, Tuan; Teskey, G. Campbell; Borgland, Stephanie Laureen; Finn, David P.; Dyck, Richard Henry
    Opioid analgesics are indispensable for treating acute post-operative pain, and a variety of chronic pain conditions. However, an over-reliance on opioids can put individuals at risk of developing severe side effects. For chronic opioid users, stopping or decreasing opioid use is difficult as many individuals experience a severe withdrawal syndrome. Opioid withdrawal is characterized by a host of debilitating signs and symptoms, including somatic and autonomic physical symptoms and an aversive affective component. The adverse effects associated with opioid use have become increasingly linked to the activity of microglia, which are immune cells in the central nervous system. Yet, the cellular mechanisms mediating this microglial response remain poorly understood. This thesis investigates the core cellular mechanisms by which microglial pannexin-1 (Panx1) channels underlie opioid withdrawal and other adverse effects associated with chronic opioid use. My over-arching hypothesis is that microglial Panx1 critically contributes to opioid withdrawal. Here, I show that morphine produces a preferential increase in Panx1 expression and function on microglia, and that genetic ablation of microglial Panx1 is sufficient to attenuate the physical signs and aversive component of morphine withdrawal. I provide novel evidence for direct microglia-neuron signaling in opioid withdrawal, and identify that Panx1-mediated ATP release is a key spinal substrate of physical withdrawal signs. I also demonstrate that morphine analgesia, opioid-induced hyperalgesia, analgesic tolerance, and reward behaviours are notably intact in microglial Panx1-deficient mice. This suggests that the side effects of repeated opioid use may be mechanistically separable, and that microglial Panx1 preferentially underlies the expression of opioid withdrawal. Finally, I show the potent amelioration of opioid withdrawal using the clinically utilized broad-spectrum Panx1 blocker, probenecid, indicating that Panx1 may represent a feasible therapeutic target for combating withdrawal in the clinic. In conclusion, this thesis identifies microglial Panx1 as a novel cellular determinant and unexpected target for combating opioid withdrawal, and as a result, represents a paradigm shift in understanding how opioid withdrawal occurs.
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    Microglial Panx1 as a therapeutic target for opioid withdrawal
    (2020-03-31) Komarek, Kristina; Trang, Tuan; Teskey, Gordon Campbell; Borgland, Stephanie Laureen
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    Neuromodulatory Effect of Kappa Opioid Receptor Activation on Spinal Network Activity
    (2018-06-21) Ozogbuda, Prince Nyekazi; Whelan, Patrick J.; Borgland, Stephanie Laureen; Gosgnach, Simon
    Dynorphin is a potent anti-nociceptive neuropeptide ubiquitously expressed throughout the peripheral and central nervous system. Previous studies have shown that dynorphin is co-packaged and co-released with orexin, a pro-locomotory neuropeptide known to be involved in goal-directed movement. Why then is an inhibitory neuropeptide co-released with an excitatory pro-locomotory neuropeptide orexin, and what is its role? In this thesis, the expression of kappa opioid receptors (KOR) on motoneurons was demonstrated using RNAscope Assay. Consistent with the observation of other studies, my results show that KOR activation significantly reduced spontaneous network activity, increased motoneuron excitability, and increased presynaptic inhibition. These results suggest that dynorphin modulates the spinal motor network rather than inhibits it. This also explains why the co-release of orexin and dynorphin does not have an antagonistic effect. My work suggests that perinatally dynorphin can have potent effects on spinal cord networks. This raises the possibility that dynorphin release may contribute to the development and correct function of spinal cord motor networks.
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    Reward Neurocircuitry in Autism Spectrum Disorder
    (2018-09-14) Schuetze, Manuela; Bray, Signe L.; Kennedy, Dan; Graham, Susan A.; Borgland, Stephanie Laureen; Goodyear, Bradley G.; Dewey, Deborah
    Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with social impairments and restricted interests. Early behavioural interventions often focus on reinforcing desired behaviours (e.g., eye contact) and reducing atypical behaviours (e.g., echoing others' phrases). A recent framework suggests reward system dysfunction to be at the core of ASD symptoms. However, if the reward system is impaired in ASD, it is paradoxical that reward-based strategies are commonly used during interventions. The goal of this thesis was to investigate the reward neurocircuitry to explore whether reward system dysfunction contributes to the ASD phenotype. We conducted a literature review on physiological, behavioural, and neural responses to reinforcers to look for common atypical patterns across all domains. We then investigated structural changes in basal ganglia and the thalamus using advanced surface-based methodology. For this, we modelled effects of diagnosis, age, and their interaction on volume, shape, and surface area on T1-weighted anatomical images of 373 male participants with ASD and 384 typically developing (TD). Finally, we investigated neural responses in the context of learning using rewards that were tailored to participants’ unique interests. 27 adolescents with ASD and 31 TD adolescents performed a reinforcement learning task while we collected fMRI data. Participants had to learn which of two doors showed images of their personal interests. The literature review revealed no consistent pattern of atypical reward responses in ASD. Further, we found that subcortical regions did not differ in volume between individuals with and without ASD. However, we found localized structural changes in shape and surface area of the putamen, globus pallidus and thalamus. Some changes were modulated by age, IQ and symptom severity. Interestingly, when using personal interests as reinforcers during a learning task, we found intact learning performance and similar neural responses in the reward system between ASD and TD groups. Taken together, mixed findings from the literature review and subtle structural changes in subcortical regions of the reward system suggest a role of this neurocircuitry in the ASD phenotype. However, intact learning and typical neural responses towards individual interests suggest that the reward system is not generally impaired in ASD.
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    The role of the mesocortical dopaminergic pathway in the processing of chronic pain signals
    (2020-04-27) Huang, Shuo; Zamponi, Gerald W.; Borgland, Stephanie Laureen; Bains, Jaideep Singh; Trang, Tuan; Gordon, Grant Robert J.; Smith, Peter A.
    Chronic pain is a debilitating condition which is prevalent in terminal diseases and aged populations. Pain medications are frequently ineffective for chronic use due to resistance to treatment. This is because the pathophysiology, especially cerebral mechanisms of chronic pain is not fully understood. The processing of chronic pain signals is mainly through the cortical areas, the limbic system, and the nucleus accumbens in the brain, which outputs affect downstream targets exerting top-down control. These brain areas mediate emotional and salience-related processing of pain signals, forming the ‘pain matrix’. The ‘pain matrix’ refers to the brain regions mediating different functions such as valance, salience, emotion, and memory that are able to interact with each other to allow pain perception to emerge. The ‘pain matrix’ also process reward information. Signals from pain and reward converge in the ‘pain matrix’and dopamine modulates the emotional and salience aspects of both. The medial prefrontal cortex (mPFC) is a cortical region that controls many executive functions such as attention, working memory, and learning. The mPFC is involved in pain perception, and undergoes plasticity during development of chronic pain. The PFC receives dopaminergic inputs from the ventral tegmental area (VTA), forming the mecoscortical pathway. The mesocortical circuit modulates neuronal plasticity in the mPFC. This modulation has been shown to affect working memory and aversion; however, whether and how the VTA-mPFC dopaminergic inputs are involved in chronic pain remains incompletely understood. This PhD dissertation examines the hypothesis that VTA dopaminergic neurons undergo plasticity during chronic pain states, and projections from these neurons to the mPFC modulate chronic pain-associated behaviours. Dopaminergic subpopulations of both the lateral and medial VTA were defined by action potential firing patterns. However, plasticity induced by neuropathic chronic pain only resides in specific dopaminergic subpopulations. In addition, dopaminergic subpopulations of lateral and medial VTA are differentially altered after induction of neuropathic pain. Using optogenetic approaches to selectively target dopaminergic inputs to the mPFC, we found that phasic activation of VTA-mPFC dopaminergic inputs reduced mechanical hypersensitivity during neuropathic pain states. Photostimulation of dopamine input to the mPFC also induced a preference for photostimulation-paired context only in mice with neuropathic pain. Fiber photometry imaging of calcium signals demonstrated that dopamine enhances the activity of mPFC neurons projecting to the ventrolateral periaquductal gray, a crucial downstream target for top-down regulation of pain states. Altogether, this study indicates an important modulatory role of mesocortical dopamine in cerebral chronic pain signaling.
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    The Role of Vesicular Zinc in Instrumental Conditioning and Drug-Evoked Plasticity
    (2020-09-03) Thackray, Sarah Elizabeth; Dyck, Richard H.; Antle, Michael C.; Sargin, Derya; Borgland, Stephanie Laureen; Tzounopoulos, Thanos
    Zinc is critical for the functioning of all cells. A subset of the zinc in the brain (vesicular zinc) acts as a neurotransmitter and is capable of modulating a variety of receptors. Not all areas of the brain contain vesicular zinc; however, there are high amounts found in the striatum, neocortex, and limbic regions. Some regions have received more attention than others concerning the function of vesicular zinc. Those that have been studied have found that vesicular zinc is important for synaptic plasticity. Less studied regions include areas involved in instrumental conditioning, motivation and reward. A commonly used model to study the role of vesicular zinc is the zinc transporter 3 (ZnT3) knockout (KO) mouse which lack the protein solely responsible for loading zinc into vesicles and thus shows a complete absence of vesicular zinc. The purpose of this thesis was to examine the behaviour of ZnT3 KO mice (compared to wildtype mice) on instrumental conditioning tasks as well as on their response to cocaine. Drugs of abuse, including cocaine, can be used to probe the functioning of the reward pathways. Results found no difference in instrumental conditioning in ZnT3 KO mice. There were, however, differences in response to cocaine which, for the most part, were restricted to one sex or the other. In general, ZnT3 KO mice had reduced locomotor response to cocaine, particularly at higher doses and in females. They also showed differences in “memory” of cocaine experience, with male KO mice more affected. Overall, findings suggest that vesicular zinc is involved in both acute response to cocaine and in the long-term memory of drug-associated cues.
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    State-dependent neuromodulation of mammalian spinal networks
    (2018-08-28) Sharples, Simon Arthur; Whelan, Patrick J.; Teskey, Gordon C.; Borgland, Stephanie Laureen; Turner, Ray W.
    It has been known for centuries that the brain is not necessary for the generation of movements that allow for animals to walk. For many farmers, the sight of a chicken running around the farm yard following decapitation was fairly common. At the turn of the 20th century Charles Sherrington and Thomas Graham Brown proposed that circuits located within the spinal cord are responsible for the generation of rhythmic movements of the limbs for walking. With over a century of scientific investigation of rhythmically active circuits of vertebrates and invertebrate species, we have learned that rhythmic movements for locomotion, breathing and chewing are controlled by neuronal circuits called central pattern generators. Large emphasis has been directed toward dissecting the central pattern generator circuits for walking. Locomotor movements are remarkably adaptable and respond to not only external demands imposed by the environment but also internal needs of the animal. Thus, the underlying circuits that generate these diverse movements also need to be flexible to readily adjust in response to imposed demands. Nevertheless, the mutability of these rhythm generating circuits is not well understood. Neuromodulation endows spinal circuits with flexible properties that allow motor outputs to be adaptable to modify ongoing movement. I initially started to study how one neuromodulator, dopamine, controls rhythmic network activities of the spinal cord for walking in in the neonatal mouse in vitro (Sharples et al., 2015). My preliminary studies demonstrated that modulation of rhythmic circuits might have state-dependent effects on locomotor rhythms which is consistent with work conducted in invertebrates (Marder et a., 2014). In this thesis, I explored the diverse actions of modulators on spinal networks across varying states of excitability. This is important because changes in behavioural state or pathology result in alterations in network excitability. In general, I demonstrated that neural networks of the spinal cord are degenerate in their ability to generate locomotor rhythms and that neuromodulators can tune this ability through both degenerate and redundant mechanisms.