Browsing by Author "Wildering, Willem C."
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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 Novel role of integrin ligands in neuromodulation(2004) Diep, Chi Que; Bulloch, Andrew G. M.; Wildering, Willem C.Integrins, a family of cell adhesion receptors, and their ligands, the extracellular matrix proteins, have been implicated as neuromodulators in the adult CNS. Previous studies from our laboratory on neurons isolated from the CNS of the gastropod snail Lymnaea stagnalis show that integrin peptides increase HVA Ca2+ concentrations and other active intrinsic membrane properties. The current study extends this line of investigation to the intact CNS. Extracellular electrophysiological recording from the trunk of one of the nerves (right internal parietal or RIP nerve) originating from the Lymnaea CNS shows that integrin peptide with the consensus integrin binding motif RDG increases the electrical discharge of some projecting neurons. Further investigations, involving the intracellular recording from 2 synaptic partners that have axonal projections in the RIP nerve, provide evidence that in the Lymnaea CNS integrins play a role in synaptic modulation since they modulate the kinetics of the postsynaptic potentials through synaptic remodeling.Item Open Access Oxidative-stress induced increase in circulating fatty acids does not contribute to phospholipase A2-dependent appetitive long-term memory failure in the pond snail Lymnaea stagnalis(BioMed Central, 2014-05-01) Beaulieu, Emily; Ioffe, Julie; Watson, Shawn N.; Hermann, Petra M.; Wildering, Willem C.Item Open Access Rapid Non-genomic Actions of Cortisol in Fish(2019-12-20) Das, Chinmayee; Vijayan, Mathilakath M.; Prenner, Elmar J.; Wildering, Willem C.; Thundathil, Jacob C.; Lee, Lucila E. J.Cortisol, the primary glucocorticoid (GC) in teleosts signals through either the genomic pathway, by activating the intracellular glucocorticoid receptor (GR) and/or the mineralocorticoid receptor (MR), or through non-genomic pathways. However, the mechanism of action of non-genomic cortisol signalling is far from clear, and there is a complete lack of consensus as to the physiological significance of this rapid action. The major goal of this thesis was to determine the mode of action of cortisol in bringing about rapid changes in intracellular Ca2+ levels [iCa2+] as a non-genomic response, and to assess the physiological consequences of this rapid effect at the cellular and organismal level. This was tested using rainbow trout (Oncorhynchus mykiss) hepatocytes (non-excitable) and zebrafish (Danio rerio) muscle (excitable) explant as in vitro and ex vivo models, respectively. The results indicate that a direct interaction of cortisol with the calcium release-activated (CRAC) channel may be responsible for the rapid increase in [iCa2+] due to cortisol. This increase in [iCa2+] with cortisol played a key role in the translocation of intracellular GR to the plasma membrane. This was evident because inhibition of the CRAC channel abolished the colocalization of GR to the caveolin-1 on the plasma membrane of hepatocytes. Cortisol also stimulated a rapid increase in [iCa2+] in zebrafish muscle explants, underscoring a conserved non-genomic role for cortisol in rapidly increasing [iCa2+] in excitable and non-excitable cells. A zebrafish tail-fin amputation model was used to investigate the physiological role of non-genomic and genomic cortisol signalling in regulating epimorphic regeneration. Cortisol rapidly increased [iCa2+] at the amputated site, and this corresponded with an increased ORAI1 (protein subunit of CRAC) expression at the site. Also, an increase in cell proliferation of ORAI1 expressing cells and blastema formation was evident at 24 h in response to cortisol stimulation, but absent in the GR knockout and MR knockout larvae, suggesting that this CRAC channel protein may be both non-genomically and genomically regulated by cortisol. Taken together, this thesis represents a significant contribution to the mechanism of action of rapid non-genomic effects of cortisol, which is essential to our understanding of the role of cortisol in stress adaptation in vertebrates.Item Open Access Redox modulation of neuronal excitability as a factor in age-related memory impairment(2008) Risling, Tara; Wildering, Willem C.Item Open Access The roles of rgd-integrin interactions in peripheral nerve regeneration(2008) Liu, Wei-Qiao; Zochodne, Douglas; Wildering, Willem C.