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Following sudden failure of the Na+/K+ATPase pump, the acute neuronal swelling and dendritic damage that occurs within minutes of stroke onset are consequences of anoxic depolarization (AD). The AD front in our protocol is imaged as an increase in tissue light transmittance (LT) propagating across gray matter of the hippocampal slice preparation. Under current clamp in the single neuron, AD is recorded as a sharp depolarization within 6 min of O2/glucose deprivation (OGD). Simultaneous imaging and current clamp recordings show that the increased LT front and sudden depolarization are coincident. AD onset in CA1 hippocampal neurons is delayed in slices pretreated with 10 μM dibucaine (dib), a local anaesthetic understood to block voltage-gated sodium channels, and 10 to 100 µM carbetapentane (CP), a sigma1 receptor agonist. We examined if changes to single cell excitability could explain how dibucaine and CP work to inhibit AD. Pretreatment of slices with dibucaine for 30 min had no effect upon resting membrane potential, or whole cell input resistance (n=11). However dib pretreatment consistently raised spike threshold, decreased AP frequency and increased the fast afterhyperpolarization (fAHP). Orthodromic and antidromic APs were also eliminated within 15 min. Intracellular dibucaine application in addition to similar effects upon intrinsic electophysiological properties reduced the peak potential of the fast AD while extending the time until the persistent depolarization of AD reached zero. In contrast, 30 -100 μM CP had no effect upon orthodromic or antidromic responses, probably because unlike dibucaine it did not markedly raise spike threshold. Also unlike dibucaine, the fAHP was eliminated while the slow AHP was accentuated, resulting in a lowering of the AP frequency during steady depolarization. Both drugs appear to inhibit AD onset by reducing cortical excitability at the level of the single pyramidal neuron, but through strikingly different mechanisms. Our simultaneous imaging and single cell recording under current clamp allowed for further examination of potential cell recovery after AD in CA1 neurons and astrocytes, as well as confirmation of AD generation in the CA3 region. Indirect evidence for a more robust AD generation and propagation was evident in the transverse slices of dorsal hippocampal CA3 region compared to coronal slices. AD in astrocytes was lower in amplitude and more prolonged, as well as often displaying recovery to near resting potential. This supported our previous imaging experiments showing that astrocytes quickly recover their volume post-AD. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2008-09-25 15:44:07.114

Post-stroke seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here I combined behavioral, electrophysiological and histological assessments to examine acute seizures in adult mice following hypoxia-ischemia (HI). C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and were then exposed to systemic hypoxia (8% O2, ~30 minutes). The HI episode resulted in decreases in cerebral blood flow, suppression of EEG activities and extensive brain injury in the hemisphere ipsilateral to the carotid artery occlusion. Generalized motor seizures were observed within 72 hours following HI. These seizures occurred nearly exclusively in animals with the extensive ipsilateral brain injury, but their generation was not associated with EEG discharges in bilateral hippocampal and cortical areas. Animals exhibiting these seizures had a high rate of mortality. Post-HI treatments with diazepam and phenytoin suppressed these motor seizures and improved post-HI animal survival. Based on these data, I conclude that these seizures are a consequence of HI brain injury, contribute to mortality following HI, and that they may originate from deep subcortical structures.

Post-stroke seizures are associated with worsened outcome following stroke, but the underlying pathophysiology is poorly understood. Here I combined behavioral, electrophysiological and histological assessments to examine acute seizures in adult mice following hypoxia-ischemia (HI). C57BL/6 mice aged 4-9 months received a permanent occlusion of the right common carotid artery and were then exposed to systemic hypoxia (8% O2, ~30 minutes). The HI episode resulted in decreases in cerebral blood flow, suppression of EEG activities and extensive brain injury in the hemisphere ipsilateral to the carotid artery occlusion. Generalized motor seizures were observed within 72 hours following HI. These seizures occurred nearly exclusively in animals with the extensive ipsilateral brain injury, but their generation was not associated with EEG discharges in bilateral hippocampal and cortical areas. Animals exhibiting these seizures had a high rate of mortality. Post-HI treatments with diazepam and phenytoin suppressed these motor seizures and improved post-HI animal survival. Based on these data, I conclude that these seizures are a consequence of HI brain injury, contribute to mortality following HI, and that they may originate from deep subcortical structures.

Diss. (sammanfattning) Umeå : Umeå universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph.D.) in Biochemistry and Molecular Biology--University of Maine, 2008. / Includes vita. Includes bibliographical references (leaves 103-123).

Thesis (M.S.)--University of Wisconsin--Madison. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-75).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 304-333).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1984. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 205-225).

No description available.