Browsing by Author "Dyck, Richard H."
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- ItemOpen AccessAdministering 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.
- ItemOpen AccessBehavioural characterization of mice following medial frontal cortex lesions(2006) Keller, Avril Jeanel; Dyck, Richard H.
- ItemOpen AccessBehavioural outcomes of mice perinatally exposed to fluoxetine(2011) Kiryanova, Veronika; Dyck, Richard H.
- ItemOpen AccessCellular and molecular responses in the postnatal brain after medial frontal cortex injury induced by stroke or aspiration(2007) Maxwell, Kimberley; Dyck, Richard H.
- ItemOpen AccessCharacterization of the experience-dependent regulation of vesicular zinc in the cerebral cortex(2011) Nakashima, Amy S.; Dyck, Richard H.
- ItemOpen AccessCharacterizing 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.
- ItemOpen AccessThe 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.
- ItemOpen AccessAn 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.
- ItemOpen AccessExploring 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.
- ItemOpen AccessMechanisms of Neurogenesis-Mediated Forgetting in the Hippocampus(2020-12-18) Evans, Alexandria; Epp, Jonathan Richard; Dyck, Richard H.; Teskey, Gordon CampbellThe mammalian hippocampus is an area of the brain responsible for learning and memory, and one of the few regions where neurogenesis continues throughout life (Altman, 1962). Neurogenesis in the dentate gyrus (DG) of the hippocampus has a role in many essential learning and memory processes, including forgetting (Akers et al., 2014). This forgetting process is important because it prevents proactive interference between old and new memories (Epp et al., 2016). However, the DG is not typically thought of as the place where new memories are stored; therefore, this process is likely occurring downstream of the DG. While several studies have examined the modulation of neurogenesis in forgetting behaviour, little research has investigated how this process is occurring within the hippocampus. Thus, the main goal of my thesis was to identify subregions of the hippocampus that play a role in this forgetting mechanism by (1) quantifying c-Fos expression in hippocampal subregions and the entorhinal cortex (EC) following a contextual conditioning task in mice and (2) monitoring real-time neuronal activity during the contextual task using fiber photometry. We replicated previous findings by others, confirming that increasing neurogenesis enhances forgetting. We found that voluntary running, to the extent that neurogenesis is increased, results in decreased context memory and decreased activity in CA1 and the supragranular and infragranular layers of the EC.
- 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 AccessParent and family impact of raising a child with perinatal stroke(BioMed Central, 2014-07-14) Bemister, Taryn B.; Brooks, Brian L.; Dyck, Richard H.; Kirton, Adam
- ItemOpen AccessPlasticity of zincergic synapses: an ultrastructural analysis(2008) Ross, Dana; Dyck, Richard H.
- ItemOpen AccessPredictors of caregiver depression and family functioning after perinatal stroke(BioMed Central Pediatrics, 2015-07-15) Bemister, Taryn B.; Brooks, Brian L.; Dyck, Richard H.; Kirton, AdamBACKGROUND: Perinatal stroke is a leading cause of cerebral palsy and lifelong neurological morbidity. Studies on perinatal stroke outcomes are increasing, although examinations of its broader impact on parents and families have been limited. A recent study found that parents of children with moderate and severe outcomes have increased risk for psychosocial concerns, including depressive symptoms and poor family functioning. Other parents adapt remarkably well, but how this occurs is unknown. The primary aim of this study was to examine predictors of parent and family outcomes, namely caregiver depression and family functioning. The secondary aim was to explore potential mediators and moderators of the relationship between condition severity and parent and family outcomes. METHODS: Parents were recruited from a large, population-based perinatal stroke research cohort, and they completed measures assessing their demographics, social supports, stress levels, marital quality, feelings of guilt and blame, psychological well-being, and family functioning. Bivariate analyses compared these variables. Predictor variables, mediators, and moderators were chosen according to the strength of their relationship with the outcome variables (i.e., caregiver depression and family functioning) and theory. Hierarchical regression, mediator, and moderator analyses were conducted accordingly. RESULTS: A total of 103 parents participated in this study (76 mothers, 27 fathers; mean age of 39.2 years; mean child age of 7.46 years). Condition severity, anxiety, social support, and blame independently predicted caregiver depression while condition severity, stress levels, and marital quality independently predicted family functioning. Blame regarding the cause of their child's condition also mediated the relationship between condition severity and caregiver depression. CONCLUSIONS: Adverse parental outcomes can be predicted in perinatal stroke populations. Moreover, anxiety and stress management techniques, marital support, and psychoeducation regarding the unpreventable nature of perinatal stroke may be utilized in the future to enhance family outcomes.
- ItemOpen AccessThe Role of Postictal Hypoxia in Seizure-Induced Neurogenesis, Dentate Gyrus Area and Ectopic Migration of Granule Cells(2020-01-24) Addo-Osafo, Kwaku; Teskey, G. Campbell; Epp, Jonathan Richard; Gordon, Grant Robert J.; Dyck, Richard H.Background: Adult neurogenesis is influenced by several external factors such as exercise, enrichment, and seizures. The mechanism behind seizure-induced neurogenesis, however, is unknown. Following seizures, a phenomenon known as postictal severe hypoxia occurs in areas localized to seizure activity. Hippocampal oxygen levels drop from the normoxic range of 18-30mmHg below the severe hypoxic threshold of 10mmHg. This can be prevented with the pre-administration of a COX inhibitor (ibuprofen) or L-type calcium blocker (nifedipine). We hypothesized that the postictal hypoxia phenomenon would result in increased neurogenesis and alter the migration pattern of newborn granule cells causing them to ectopically migrate into the hilus. Methods: Electrical kindling was utilized to elicit hippocampal seizures in rats. An oxygen sensing probe and a bipolar electrode to elicit and record seizures were implanted ipsilaterally into the dorsal and ventral hippocampus, respectively. Rats were separated into a no seizure and seizure group. Rats undergoing kindling were administered DMSO, 20mg/kg ibuprofen, or 15mg/kg nifedipine 30 minutes prior to each session while rats without seizures were handled identically. All rats were perfused following 30 kindling or control sessions. Cryostat sections of 40μm were taken and labelled for doublecortin (DCX). DCX expressing cells were analyzed using confocal microscopy. Results: Seizures with hypoxia increased the total number of DCX expressing cells by 90%. Seizures with attenuated hypoxia via ibuprofen or nifedipine did not prevent the increase in neurogenesis following kindled seizures. Dentate gyrus area was significantly increased with seizures except when treated with nifedipine. The density of DCX cells was increased with seizure activity and was unaffected by hypoxia, though nifedipine treated rats had a higher increase in density following seizures. Lastly, the ectopic migration of cells into the hilus was also increased with seizure activity independent of hypoxia. Conclusion: Postictal hypoxia is not the underlying mechanism in seizure-induced neurogenesis, the increase in dentate gyrus area and the ectopic migration of cells into the hilus. It is the seizure activity driving these phenomena.
- ItemOpen AccessRole of synaptic zinc in neocortical development and plasticity(2001) Brown, Craig E.; Dyck, Richard H.
- ItemOpen AccessThe 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.
- ItemOpen AccessThe 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.
- ItemOpen AccessRole of zincergic neurons in cortical function and plasticity(2004) Brown, Craig E.; Dyck, Richard H.Zinc ions are essential for life as they regulate the function of numerous structural, transcriptional and enzymatic proteins. In addition to its role in basic cellular functioning, zinc is contained within and released from the nerve terminals of a subset of glutamatergic neurons in the central nervous system. Physiological studies have shown that synaptically-released zinc can powerfully modulate synaptic transmission by regulating the activation of numerous voltage and ligand gated ion channels and intracellular signaling proteins. Consequently, the goal of this thesis was elucidate the anatomical organization and functional significance of zinc-releasing (ie. zincergic) neurons in the mammalian forebrain, particularly within the cerebral cortex. To do this, we first describe a novel procedure for staining the cell bodies of zincergic neurons that eliminates background staining of zinc within synaptic terminals, thereby enabling a clear and accurate description of these neurons. Using this method, we found that zincergic neurons were typically pyramidal in shape and densely populated telencephalic structures such as the cerebral cortex, hippocampus and amygdala. In addition, labeled neurons were found in the lateral ventricle, lateral septum, zona incerta, as well as select regions of the hypothalamus, a region previously thought to be devoid of neurons with a zincergic phenotype. In order to implicate zincergic neurons in cerebral cortical plasticity, we characterized zincergic innervation of the mouse barrel cortex, our model system. Utilizing a zinc-specific retrograde labeling method, we found that the majority of zincergic projections to the barrel cortex originated from ipsilateral and callosal neurons situated within layers 2/3 and 6 of the cerebral cortex. Given that zinc is potent modulator of synaptic transmission, and that intracortical circuits drive experience-dependent reorganizations in the adult cortex, we then examined the effect of tactile stimulation or deprivation on the homeostatic regulation of zinc within barrel cortex synapses. Our data indicate that levels of synaptic zinc in layer 4 were rapidly and bi-directionally regulated by tactile experience. Furthermore, we found that the experience-dependent regulation of synaptic zinc was highly dependent on age, with aged animals no longer showing this capability. In summary, these results suggest that zincergic circuits comprise a chemospecific associative network that reciprocally interconnects telencephalic structures. Furthermore, our data implicate zincergic circuits in rapid, experience-dependent plasticity in the adult cerebral cortex, as well decrements in this plasticity that accompany senescence.