Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population today; however, there is currently no accurate description of the etiology of this devastating disorder. No single factor theory has been demonstrated as being causative; however, an alternative theory suggests that the interaction of multiple risk factors is responsible for AD. In this thesis I present data suggesting a neuroprotective role for acetylcholine during aging. Using a rat model of cholinergic depletion of the medial septum, I explored the effects of four common risk factors for AD (stress, seizures, stroke and circadian dysfunction) targeted at the hippocampus and examined the effects on measures of hippocampal dependent (water maze) and hippocampal independent (fear conditioning) memory. Here, I propose a role for acetylcholinemediated compensatory mechanisms in the functional recovery observed following sub threshold insults similar to those commonly observed in the elderly. m First and foremost I would like to thank my supervisor, Dr. Robert McDonald. Thank you for your support and encouragement, and for allowing me the independence to pursue my own projects and to learn from my experiences. I would also like to thank Nhung Hong for doing the majority of the cholinergic depletion and stroke surgeries used in this thesis and for teaching me the techniques. I would like to give a huge thank you to Joelle Kopp who was an invaluable asset who assisted in histology and spent many hours on the microscope counting cholinergic neurons. I would also like to thank Dr. Christine Werk for patiently reading and re-reading early drafts of my papers and this thesis and Dr.Hugo Lehmann for all his help in running statistics and interpreting my data. In addition, many thanks go out to Courtney Lamb, Robert Court and Arthur Verhoef for helping me with histology and behavioural testing, to Keri Colwell for running the corticosterone assays, the Metz lab for kindly allowing me the use of their microscope and to Karen Dow-Cazel and the rest of the animal care staff for taking care of my rats and helping me set up the circadian experiements. The cholinergic hypothesis of Alzheimer's disease 6 Acknowledgements IVThe basal forebrain cholinergic system 8The role of the basal forebrain cholinergic system in learning and memory 10The current state of the cholinergic hypothesis of Alzhimer's disease 15Risk factors for Alzheimer's disease 16Multiple combinations of co-factors theory of Alzheimer's disease 22The role of the hippocampus in learning and memory 24Objective of the present thesis 25Chapter 2: A series of pilot studies to determine the threshold for behaviourally sub threshold stroke, seizures and stress 28Abstract 29Experiment la: The effect of a chronic variable stress schedule on performance of the water maze task 32 Materials and Methods 33Results 36Experiment lb: The effects of a variable restraint stress procedure on levels of blood borne CORT 39 Materials and Methods 39Results 40Discussion 41Experiment 2: T...

No abstract

Recent evidence suggests that N-methyl-D-aspartate (NMDA)-receptor mediated plasticity in hippocampus has a more subtle role in memory-based behaviours than originally thought. One idea is that NMDA-based plasticity is essential for the consolidation of post-training memory but not for the initial encoding or for short-term memory. To further test this idea we used a three-phase variant of the hidden goal water maze task. In the first phase, rats were pre-trained to an initial location. Next, intense, massed training was done in a 2-h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) or of vehicle. Finally, under drug-free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N-methyl-D-aspartate (NMDA)-receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA-receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA-receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA-receptors participate in post-training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

No abstract

This series of experiments represents a test of a theory concerning the etiology of age-related cognitive decline, including Alzheimer's disease (AD). The theory suggests that multiple combinations of cofactors produce variants of these disorders. Two factors that have been linked to the etiology of AD, that are of interest to our laboratories, are stress and vascular strokes. The current experiments tested the cofactors theory by evaluating the neuronal and functional effects of localized subthreshold strokes in the hippocampus of different groups of rats. One group experienced episodes of stress prior to stroke induction while the other did not. The results showed that a low dose of endothelin-1 (ET-1) injected into the hippocampus of groups of rats that had previously experienced stressful episodes showed enhanced hippocampal cell death and neurodegeneration that did not occur in the rats that did not experience stress prior to stroke induction. The results also showed that the stressed rats given subthreshold ET-1 injections into the hippocampus showed hippocampal-based learning and memory deficits that were not present in the non-stressed group given the same injections. This pattern of results suggests that individuals that are under stress are more vulnerable to insults to the hippocampus that have little effect on an individual that is not stressed. This vulnerability might be due to the actions of stress hormones, like the glucocorticoids, that have been previously shown to endanger hippocampal neurons.

No abstract

No abstract

Alzheimer's disease is the most common form of dementia in North America today. Though many risk factors have been suggested to increase the likelihood of developing this disease, an accurate etiology has yet to be described. One of these risk factors commonly associated with Alzheimer's disease is the loss of cholinergic neurons of the medial septum that project to the hippocampus, leading to depletion in cholinergic activity. A second risk factor is the presence of seizures, which can increase the risk of excitotoxic cell death. To examine the interaction between these two common risk factors, we gave rats a focal cholinergic lesion of the medial septum using the specific immunotoxin 192-IgG Saporin, followed 2 weeks later by a non-convulsive dose of kainic acid. We then assessed the rats for seizure severity, hippocampal damage and performance on a spatial memory task. The combination of the two factors resulted in a trend towards increased seizure severity in the cholinergic depleted rats, but more importantly, the lesioned rats that had non-convulsive seizures were significantly impaired on a spatial version of the Morris water maze when compared with either the rats with a cholinergic depletion or non-convulsive seizure alone. This result could not be explained by seizure severity or the extent of hippocampal damage, suggesting a more subtle interaction between these two risk factors in the development of a hippocampal based memory impairment.