Browsing by Author "Antle, Michael C."
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Item Open Access Administering Ketamine to Rickrolled Mice Lacking Vesicular Zinc(2023-09-22) Le, Linda Thu; Dyck, Richard H.; Antle, Michael C.; Sargin, Derya; Teskey, G. CampbellDepression is a highly prevalent mood disorder, especially during adolescence and early adulthood. It is commonly treated with antidepressants; however, one-third of patients with depression do not respond to current therapies. Interestingly, it has been found that depression severity is correlated with zinc deficiency, and zinc supplements can improve individuals’ depressive symptoms, potentially through its actions as a neurotransmitter. This phenomenon is facilitated by zinc transporter 3 (ZnT3), which packages zinc into synaptic vesicles. Using a ZnT3 knockout (KO) mouse model that lacks vesicular zinc, we sought to investigate the interplay between vesicular zinc and chronic stress, as well as ketamine, a novel therapeutic for treatment-resistant depression, which has been shown to display rapid and sustained antidepressant-like effects. Wildtype (WT) and ZnT3 KO mice were subjected to multiple simultaneous acute stress (MAS) or kept under standard housing conditions during late adolescence, and subsequently administered ketamine (10 mg/kg) or 0.9% saline. The lack of vesicular zinc in ZnT3 KO mice differentially altered the effects of MAS in behaviours related to anxiety, motivation/apathy, and passive coping, but not anhedonia, in a sex-dependent manner. These data suggest that vesicular zinc modulates stress response. Vesicular zinc, however, did not impact the effects of MAS on neuronal morphology. Moreover, we found limited effects of ketamine in depressive-like behaviours and neuronal structure, but intriguingly, ketamine appeared to compensate for the lack of vesicular zinc in ZnT3 KO mice. Collectively, these findings support that chronic stress impacts behaviour differently in WT and ZnT3 KO mice. However, the single subanaesthetic dose of ketamine administered was not sufficient to alter responses to stress. Further inquiry is warranted to elucidate the combined effect of vesicular zinc and ketamine in stress response.Item Open Access An examination of the functional role of gastrin-releasing neuropeptide within the circadian clock(2011) Sterniczuk, Roxanne; Antle, Michael C.Item Open Access Characterizing circadian behaviour in the BTBR mouse model(2019-08-15) Vijaya Shankara, Jhenkruthi; Antle, Michael C.; Colwell, Christopher S.; Dyck, Richard H.; Kurrasch-Orbaugh, Deborah M.; Spanswick, Simon C.Circadian rhythms span across species and temporally co-ordinate behaviour and physiological processes to not only maintain a rhythm in the absence of cues but to also effectively coincide with external time giving cycles. A disruption in circadian rhythms causes a variety of psychological and physiological health impacts and can worsen already present disease states. Sleep and circadian issues are also comorbid with many disease and disorder states. Finding ways to alleviate the impact of circadian disruption is thus crucial. We characterized circadian behaviour in BTBR mice, that are used to model aspects of ASD. We found that BTBR mice differ drastically from C57BL/6J mice on many measures of circadian behaviour including, their free running period, their duration of activity, their total activity, their response to dark pulses in LL their entrainment patterns to shifted light dark cycle, their food anticipatory activity to schedules feeding and in the number of VIP and AVP cells in the SCN. Despite their short FRP BTBR mice entrained to ambient light cycles with stability and precision, a property that is not commonly observed. Additionally, they had more drastic changes in constant light conditions when compared to C57 controls. Despite this they maintained normal responses to light pulses, suggesting a conservation light input pathway, instead a possible dysregulation of arousal pathways, which aligns with what is known about BTBR physiology. We also found differences in VIP and AVP expressing cells in the BTBR SCN. Both these peptides have been implicated in the circadian entrainment to light cycle. Therefore, the BTBR mouse model provides not only the novel opportunity to study the mechanisms of circadian rhythms in a mouse with a drastically altered phenotype, but also can be used to study circadian rhythms when they are dysregulated. Finally, their precise entrainment might provide clues of how to better deal with circadian disruption and how to optimize entrainment to changing light cycles.Item Open Access The effects of maternal immune activation on the behaviour of mice lacking vesicular zinc(2020-09-15) Sandoval, Katy Celina; Dyck, Richard H.; Antle, Michael C.; Sargin, Derya; Guo, JiamiZinc is an important part of the structure and functioning of the brain. It helps in the development of neurons and synaptic connections as well as neural transmission. Within the brain, zinc transporter 3 (ZnT3) is important for the uptake of zinc into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder-like behaviour, such as decreased social interaction, and increased anxiety- and repetitive-like behaviour. We were interested in assessing the effects of maternal immune activation (MIA) on the behaviour of mice lacking vesicular zinc. MIA has been identified as an environmental factor for neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. To evaluate the interaction effect of a genetic factor (ZnT3 knockout (KO) mice) and environmental factor (MIA induced polyI:C), we expected to observe an increased susceptibility of developing ASD- and SZ-like phenotype in ZnT3 KO MIA-offspring. We hypothesized that this phenotype would be more severe in ZnT3 KO, and more severe in male ZnT3 KO MIA-offspring than female mice. MIA induction during gestation showed ASD- and SZ-like phenotype only in certain behavioural tests. ZnT3 KO mice did not show enhanced ASD- and SZ-like phenotype compared to WT mice. The behavioural phenotype was more significant in male mice than female offspring. These results suggest that loss of vesicular zinc does not increase susceptibility to develop ASD- and SZ-like features in the behaviours examined here.Item Open Access Enhancement of photic shifts with 5HT1A partial antagonist NAN-190: intra SCN pathway(2007) Sterniczuk, Roxanne; Antle, Michael C.Item Open Access Experience-dependent regulation of vesicular zinc in conditions of altered cortical plasticity(2007) Nakashima, Amy S.; Antle, Michael C.Item Open Access An Exploration into the Non-Photic Influence of Acetylcholinesterase Inhibitors on Circadian Rhythms(2020-09-24) Jamani, Naila Feroz; Antle, Michael C.; Dyck, Richard H.; Sargin, Derya; Epp, Jonathan RichardWhile light is the dominant zeitgeber (“time giver”) for the circadian system, nonphotic cues, such as exercise and arousal, also affect circadian rhythmicity. Our lab has reported that cholinergic innervation of the suprachiasmatic nucleus arising from the basal forebrain is both necessary and sufficient for phase shifting circadian rhythms in a nonphotic manner. Therefore, the present study investigated a new avenue for modulating cholinergic activity in a less invasive manner by testing whether enhancing acetylcholine neurotransmission with acetylcholinesterase (AChE) inhibitors will cause nonphotic-like phase shifts of the circadian system. Three different AChE inhibitors were explored (Donepezil, Rivastigmine, and Tacrine) at varying doses. First, Syrian hamsters were housed in constant darkness (DD), and were administered an intraperitoneal (IP) injection of one of the AChE inhibitors or vehicle control in counterbalanced order six hours before their activity onset, a phase when nonphotic treatments elicit phase advances. The second hypothesis was that nonphotic phase shifts elicited by AChE inhibitor administration requires acetylcholine activity at the SCN. Hamsters were given a microinjection of either saline or the acetylcholine antagonist Atropine to the SCN 10 minutes prior to a CT6 injection of donepezil (10mg/kg). In experiment one, Donepezil at 10mg/kg had the most robust phase advances relative to the controls. In experiment two, the results were mixed with no significant differences were found between conditions, including the baseline measurement of Donepezil/control.Item Open Access Exploring the Antidepressant-like Effects of Ketamine and Synaptic Zinc in a Mouse Model of Depression(2021-01-27) Markovina, Mariya; Dyck, Richard H.; Antle, Michael C.; Sargin, Derya; McGirr, AlexanderZinc is critical for proper cellular function due to its role in protein synthesis, brain development, and neural transmission. In the brain, zinc is found at glutamatergic synapses in many regions implicated in regulating emotions. Due to its inhibitory action on glutamatergic receptors and involvement in downstream signalling pathways, zinc is thought to be an important factor in depression. Evidence has shown that in animals and humans, zinc deficiency can lead to depressive-like behaviours and zinc on its own provides antidepressant-like effects. Ketamine, a novel and effective antidepressant, also exerts inhibitory action on the same receptor as zinc and produces rapid and sustained antidepressant effects in both animals and humans. Due to their comparable effects, we aimed to see how zinc and ketamine are involved in depression pathways when examined together. Zinc is transported into synaptic vesicles by zinc transporter 3 (ZnT3). Therefore, to understand the action of synaptic zinc, we used ZnT3 KO mice, mice that lack synaptic zinc, to explore the antidepressant effects of zinc and ketamine in the brain. We compared data found in these mice to ZnT3 HT mice, mice that have approximately half the amount of zinc, and ZnT3 WT mice. The first experiment in this thesis was designed to assess the effects of ketamine treatment on synaptic zinc levels in mood-related structures. No changes in synaptic zinc levels were observed 24h or 7 days after ketamine injection, however sex differences were seen 3 days after ketamine injection. No evidence was found that ketamine causes increases in synaptic zinc levels across all mood-related brain structures. The second experiment aimed to understand the ability of ketamine to reduce depressive-like symptoms in ZnT3 animals subjected to chronic mild stress (CMS), a method of modeling depressive-like symptoms in animals. Overall, CMS was unable to induce depressive-like symptoms in mice and therefore ketamine only had a significant effect in one behavioural test. Animals subjected to stress displayed stress resilience in some tests. ZnT3 KO mice also showed greater resilience to stress than WT mice in some behavioural tests.Item Open Access Exploring 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.Item Open Access Investigating the neural basis of multiphasic respiratory rhythm generation in the American Bullfrog(2019-04-05) Baghdadwala, Mufaddal Imran; Wilson, Richard J. A.; Antle, Michael C.; Whelan, Patrick J.We breathe from the day we are born to the day we die; admittedly a cliché, but true nonetheless. Breathing is in fact so vital that it has historically been associated with a mythical life force; the very term ‘spirit’ is derived from the Latin word for a breath – ‘spiritus’ (Vanhove, 2008). This breathing ‘force’, as ancient medical practitioners serendipitously guessed, underscores nearly all of the physiological functions of the body. From something as (relatively) simple as oxygenating the blood to the control of something as elusive as one's mood and general health – all appears to be rooted in breathing. The centuries-old curiosity to decipher this rhythmic activity is, therefore, understandable. Thankfully, we have come a long way from describing breathing as a force. The mechanism of breathing has been thoroughly investigated, and over the last century of effort, we have discovered the neural underpinnings of the breath, but I suspect our work in deciphering breathing has just begun – the neural controller of breathing in vertebrates is still unresolved. My efforts, through this thesis, attempt to add to this growing body of knowledge. I utilized the central nervous system of the American Bullfrog (Rana catesbeiana) because it is arguably one of the champion organisms to study the neural control of breathing (Krogh's principle). In very general terms, I first confirm that the neural controller of breathing in bullfrogs is comprised of two independent respiratory oscillators (rhythm generating components) which couple over the course of metamorphosis. Second, I demonstrate that the bullfrog brain-stem hosts a third, previously undiscovered, respiratory oscillator. Finally, I show that the necessity of discrete respiratory oscillators can only be demonstrated under some conditions indicating that oscillators are labile and state-dependent entities.Item Open Access Mild 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.Item Open Access Mitochondria and Fatty Acid Homeostasis in the Aging Nervous System(2019-08-22) Lee, Jonathon R.; Wildering, Willem C.; Treberg, Jason R.; Wilson, Richard J. A.; Antle, Michael C.; Syme, Douglas A.Impairments of learning and memory are among the most salient outcomes of the natural aging process. Particularly among humans who have experienced dramatic increases in lifespan over the last century, age-associated cognitive decline has become especially problematic in our increasingly elderly population. To mitigate the impact of these demographic changes, understanding of the fundamental biology that underlies the aging process is essential. The aim of the research presented in this thesis is to provide a new perspective on the foundational biological processes that contribute to age-related declines in cognitive function. In this regard, mitochondrial dysfunction and resulting oxidative stress have been widely implicated in the cellular and molecular deterioration of aging cells including neurons. Yet, how these phenomena arise and translate to the neuronal and behavioural dysfunction observed in aging animals remains an open question. The research conducted here integrates existing knowledge of biological aging with the novel idea that mechanisms surrounding lipid (dys)homeostasis play a prominent role in cognitive outcomes of aging. Using the gastropod model system Lymnaea stagnalis, the general hypothesis that deregulation of lipid homeostasis contributes to neuronal and behavioural impairment is investigated. Briefly, evidence is provided for the following ideas. 1) Neurons do not generally rely on lipids to meet energy requirements, yet mitochondrial fatty acid metabolism (β-oxidation) is important for the maintenance of metabolic reserve capacity and excess lipid management. In aging neurons, this is compromised as β-oxidation capacity declines. 2) Mitochondria are often considered the “seat of senescence”; however, plasma membrane lipid peroxidation and associated phospholipase A2 activity is involved with producing characteristics of age-related mitochondrial dysfunction, suggesting an extra-mitochondrial origin of biological aging. These changes may arise due to ailing β-oxidation capabilities in old neurons, and subsequent uncoupling of oxidative phosphorylation in a fatty acid-dependent manner. 3) β-oxidation dysfunction has wide-ranging implications for fatty acid-sensitive biological functions, such as ion channel function. The KATP potassium channels are particularly sensitive to activation by fatty acids, and directly translate β-oxidation failures to age-associated declines in neuronal excitability and long-term memory formation.Item Open Access Modulation 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.Item Open Access Raphe modulation of circadian phase(2009) Yamakawa, Glenn; Antle, Michael C.Item Open Access 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, ThanosZinc 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.Item Open Access The Role of Vesicular Zinc in Modulating Cell Proliferation and Survival in the Developing Hippocampus(2022-09) Fu, Selena; Dyck, Richard H.; Antle, Michael C.; Spanswick, Simon C.; Epp, Jonathan R.In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects in neuronal signaling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. To assess whether vesicular zinc plays a role in early developmental hippocampal neurogenesis, we used ZnT3 knockout (KO) mice, which lack ZnT3 and thus vesicular zinc, to evaluate cell proliferation at three different developmental age points, and the survival of these cells into adulthood. Our primary finding was that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but higher numbers of these cells were retained to P60. Additionally, male and female ZnT3 KO mice retained a greater number of cells labelled on P6. These findings suggest that loss of vesicular zinc affects normal cell proliferation and cell survival at different age points during postnatal development. Additionally, we found sex-dependent differences whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell retention for P14-labelled cells, compared to female mice. There were also significant effects of age on cell proliferation and survival. Collectively, our findings offer novel insights into a unique role for vesicular zinc in the modulation of neurogenesis and cell survival during early postnatal development and highlight prominent sex- and age-dependent differences.Item Open Access The Behavioural, Neuroanatomical, and Molecular Effects of Chronic Social Stress on Mice That Lack Zinc Transporter 3 and Vesicular Zinc(2018-12-04) McAllister, Brendan Barrymore; Dyck, Richard H.; Antle, Michael C.; Trang, Tuan; Pittman, Quentin J.; Tzounopoulos, ThanosIn certain neurons, zinc ions are stored in synaptic vesicles by a dedicated vesicular zinc transporter, called zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically, in an activity-dependent fashion, to transmit signals by modulating a plethora of targets. To understand the function of vesicular zinc in the central nervous system, a useful tool is the ZnT3 knockout (KO) mouse, which lacks ZnT3 and, as a result, lacks vesicular zinc. Behavioural characterization of these mice has revealed subtle abnormalities in cognition and sensory processing. In addition, a pattern is becoming apparent, wherein ZnT3 KO mice behave normally under standard laboratory conditions but fail to exhibit neural plasticity and behavioural adaptation in response to certain treatments or experiences. The experiments described in this thesis were designed to assess how ZnT3 KO mice would respond to the experience of repeated social defeat (RSD) stress, a method of modelling depression-like behaviour in rodents, and to test the hypothesis that ZnT3 KO mice would fail to exhibit stress-induced neural plasticity, resulting in an altered behavioural response to stress. The primary finding was that, compared to wild type (WT) mice, ZnT3 KO mice exhibited reduced social avoidance of a novel conspecific following RSD, suggesting reduced susceptibility to the depression-like behaviour of social withdrawal. Both genotypes were equally susceptible to anxiety-like behaviour following RSD, however. To investigate the mechanisms behind the seemingly protective effect of eliminating vesicular zinc on stress-induced social avoidance, several neuroanatomical parameters were examined. No evidence was found that microglial activation, hippocampal neurogenesis, or hippocampal brain-derived neurotrophic factor (BDNF) levels could account for the difference in behavioural outcome. However, some evidence was found that altered structure of the corpus callosum or reduced BDNF levels in the nucleus accumbens may contribute to the protection against social avoidance in ZnT3 KO mice. Further work will be required to validate and extend these findings, in order to more fully understand the mechanisms behind the altered behavioural response to chronic stress – and the altered capacity for experience-dependent neuroplasticity – in mice that lack vesicular zinc.Item Open Access The role of the 5-ht1a receptor in normal and enhanced responses of the mouse circadian clock to light(2008) Smith, Victoria M.; Antle, Michael C.