Stroke is the leading cause of long-term disability in the developed world and can have
devastating effects on the health and everyday functioning of individuals. In most cases
stroke is ischemic and is caused by the obstruction of blood flow due to a clot in the brain
blood vessels. This initiates a cascade of events that result in tissue death and loss of
behavioural function associated with the damaged region. The peri-infarct cortex is a
region surrounding the infarct core that survives the ischemic event and is most
susceptible to pharmacological treatments and rehabilitation. α4ß2 nicotinic acetylcholine
receptor (nAChR) signalling has been implicated as a mechanism that affects cell
survival and cell death in the acute response after stroke. Nicotinic receptor signalling is
also involved in modulating brain excitability, which can affect neural plasticity and
restoration of cortical circuits and lead to recovery of lost function after stroke. In order
to elucidate the role of α4ß2 nAChRs on acute and chronic recovery after stroke, we
tested two hypotheses: (1) blocking α4ß2 nAChRs triggers acute neuroprotection and (2)
α4ß2 nAChRs play a role in regulating plasticity and long-term functional recovery. In
the first set of experiments a new model of targeted photothrombotic stroke was induced
in a distal branch of the middle cerebral artery (MCA) in awake and anaesthetized mice.
Mice treated with the α4ß2 nAChR antagonist dihydro-ß-erythroidine (DHßE) showed
smaller lesion sizes relative to vehicle controls and this effect was greater in mice that
were awake during stroke induction. To determine the mechanism of α4ß2 nAChRmediated
neuroprotection, changes in collateral flow were measured using Evans bluestained
surface angiograms and laser Doppler flowmetry. Contrary to what was expected,
DHßE did not appear to induce neuroprotection by altering collateral flow. In the second
set of experiments, we first used confocal imaging to quantify and characterize the
expression of α4ß2 nAChRs after stroke. Next, mice were induced with a targeted
photothrombotic stroke in the forelimb somatosensory cortex. Mice were then chronically
treated with DHßE to determine if α4ß2 nAChR antagonism could improve recovery of
function. Behavioural tests showed that blocking α4ß2 nAChRs chronically had no effect
on forelimb function after stroke. Voltage-sensitive dye imaging was used to measure
forelimb-evoked responses in the somatosensory cortex and revealed no differences in
cortical responsiveness between treated and non-treated groups. Altogether, these results
show that changes in α4ß2 nAChR signalling that occur after stroke mediate ischemic
cell death but do not have an effect on long-term recovery and plasticity. Moreover, they
present a novel pathway for investigating stroke pathophysiology and the development of
acute neuroprotective treatments. / Graduate / 0317 / aseto@uvic.ca
| Identifer | oai:union.ndltd.org:uvic.ca/oai:dspace.library.uvic.ca:1828/4666 |
| Date | 27 June 2013 |
| Creators | Seto, Angela |
| Contributors | Brown, Craig E. |
| Source Sets | University of Victoria |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | Available to the World Wide Web |
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