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