Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Drs. Vania

2nd Supervisor

Marco Prado

Joint Supervisor

Abstract

Acetylcholine (ACh) is one of the main neuromodulators in the mammalian central nervous system (CNS). This chemical messenger has been implicated in the underlying physiology of many distinct cognitive functions. However, the exact role that ACh plays in regulating information processing in the brain is still not fully understood. The vesicular acetylcholine transporter (VAChT) is required for the storage of ACh into synaptic vesicles, and therefore it presents a means to modulate release. Diminished VAChT levels cause a decrease in cholinergic tone, whereas increased VAChT expression has been shown to augment ACh release. Previously published data have shown that elimination of VAChT in the basal forebrain in genetically-modified mice impairs learning and memory.

For our studies we have used different mouse lines in which the expression of the VAChT gene is changed, both increased and decreased. We are therefore able to study the consequences of altered cholinergic tone in vivo. Our hypothesis is that changes in cholinergic tone produce specific molecular signatures in target brain areas that underlie alterations in cognitive function. Our studies aimed to elucidate the behavioural and molecular consequences of cholinergic dysfunction. Behavioral testing included classical learning and memory tests as well as sophisticated tasks using novel touch screens chambers to measure attention, learning and memory as well as cognitive flexibility. At the molecular level, the goal was to examine how long-term changes in cholinergic tone impact mechanisms regulating synaptic plasticity and neuronal health. Finally, by aging mouse models of cholinergic dysfunction we were able to elucidate the role that cholinergic tone plays in the classical pathological hallmarks of neurodegenerative disorders.

Ultimately, by establishing the molecular signature of increased and decreased cholinergic tone in targeted brain regions (cortex and hippocampus) it may become possible to find novel targets for therapeutic interventions to improve cognitive deficits due to altered cholinergic tone.

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