Cognitive Impairment in a Prefrontal Cortex Model of Ischaemia
|dc.contributor.advisor||Clarkson, Andrew N|
|dc.contributor.advisor||Young, Sarah L|
|dc.contributor.author||Zhou, Lisa Ying Yi|
|dc.identifier.citation||Zhou, L. Y. Y. (2019). Cognitive Impairment in a Prefrontal Cortex Model of Ischaemia (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/8991||en|
|dc.description.abstract||Every year, millions of people worldwide will have a stroke. For those that survive, many will live with long lasting disabilities, including cognitive impairment. Unfortunately, there are a limited number of preclinical stroke models available to assess cognitive impairments without also having deficits in gross motor movement. Recently, we have established a new mouse model of stroke targeting the prefrontal cortex (PFC), which results in a delay in the development of spatial memory impairment between weeks 1- and 4- after stroke. The overall aim of this thesis was to further characterise this model of PFC stroke by investigating cognitive behavioural deficits and cellular mechanisms underlying these impairments which occur in the sub-acute period of stroke recovery (Days – weeks post-stroke). Animals were given a bilateral photothrombotic stroke to the PFC and cognitive behaviour assessed using the following tests: the reaching task; novel object recognition (NOR); object-location recognition (OLR); reversal; re-reversal; and five-choice serial reaction time task (5-CSRTT). We aimed to firstly determine whether age-matched animals with PFC stroke were impaired in behavioural flexibility in the reversal and re-reversal tasks. We found younger animals learned the reversal task faster than aged when assessed between 2–3 weeks post-stroke, suggesting an age-related cognitive decline in behavioural flexibility. Animals were also examined in the reaching task starting at either 7- and 28-days post-stroke. This resulted in PFC stroke animals demonstrating a progressive impairment in motor learning. Additionally, immunohistochemical (IHC) staining showed no differences in acetylcholinesterase (AChE) and choline acetyltransferease (ChAT) in the reaching task animals, indicating that neither of these cholinergic enzymes are involved in this motor learning impairment. The attention of animals given PFC stroke was measured in the 5-CSRTT and resulted in attentional deficits when the inter-trial interval (ITI) was varied. Stroke animals also demonstrated a decreased percentage of correct responses and an increased number of omissions at specific ITI durations. When the stimulus duration was varied, stroke animals exhibited fewer correct responses at specific stimulus duration time points. These deficits in the 5-CSRTT were unaffected by motivational or motor impairment from examining reward latency times. Cholinergic cognitive enhancing compounds starting treatment at either 3-days or 3-weeks after stroke, PHA568487 (nicotinic receptor agonist selective for the alpha7 subunit) and donepezil (acetylcholinesterase inhibitor), failed to improve attentional performance in animals following PFC stroke in the 5-CSRTT probe tasks. Lastly, the GABAergic system was examined after stroke to the PFC. Using quantitative polymerase chain reaction (qPCR) and IHC techniques, we found alterations in the GABAergic activity after stroke between young and aged animals. We also identified that GABAergic cognitive enhancing drugs, zolpidem and L-655,708 (targets gamma-aminobutyric acid subunit type A [GABAA] receptors on alpha1 and alpha5 subunits respectively), did not improve spatial memory deficits in young animals with PFC stroke when assessed in the OLR at 4-weeks post-stroke. Overall, this thesis has further characterised this novel model of PFC stroke, demonstrating cognitive impairment similar to what we observe in human stroke patients, which has the potential to aid testing of future stroke pharmacotherapies.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.subject||Touchscreen cognitive testing|
|dc.title||Cognitive Impairment in a Prefrontal Cortex Model of Ischaemia|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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