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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Prado, Vania F.

2nd Supervisor

Prado, Marco A.M.

Joint Supervisor

Abstract

The cholinergic system is one of the most influential and essential signalling systems in the body. In the brain, cholinergic neurons innervate many brain regions where they influence a wide variety of behaviours. However, the precise role of each cholinergic region on distinct types of behaviour is not well known. Furthermore, in recent years there has been evidence that many cholinergic neurons in the brain have a capacity for co-transmission. Yet the functional significance of secreting two classical neurotransmitters from the same neuron is still largely unidentified. In this thesis, we investigated how different cholinergic nuclei modulate behavioural functions. To do that we selectively eliminated acetylcholine (ACh) release from cholinergic neurons of the striatum, brainstem and basal forebrain in mice. We then evaluated cognitive and non-cognitive behaviours using classical behavioural tests as well as sophisticated automated touchscreens tasks. In the striatum cholinergic interneurons are known to co-release ACh and glutamate (Glu), so we focused our investigation on how the individual neurotransmitters modulate striatal-dependent behaviours. We demonstrated that ACh modulates cognitive behaviours such as cognitive flexibility, extinction and cue detection. Glu released from striatal cholinergic interneurons also affects striatal-dependent behaviours but usually in an opposing manner to ACh, so, a balance between ACh and Glu is critical to regulating behaviours. As dopaminergic signalling in the striatum is widely influenced by ACh and Glu released by cholinergic interneurons, we also investigated how dopaminergic signalling changes while animals are performing a striatal-dependent cognitive task. In the brainstem, we showed that ACh influences motor functions and stress but does not have a major impact on cognition. However, stress induced by brainstem ACh-deficiency can interfere with results from cognitive tasks. In the forebrain, we find that ACh signalling is essential for maintaining social memory. Decreased cholinergic signalling in the hippocampus and cortex lead to deficits in social recognition. In conclusion, we demonstrate the complexity that ACh brings into behavioural regulation and how changes in its release can contribute to the pathophysiology of diseases such as Parkinson’s disease and Alzheimer’s disease. Ultimately, this data helps define novel pharmacological mechanisms tailored to improve specific cholinergic-mediated symptoms.

Summary for Lay Audience

One of the most influential and essential signalling systems in the body is the cholinergic system. This system is composed of organized nerve cells, called cholinergic neurons which use the chemical messenger acetylcholine (ACh) as a signalling molecule. Cholinergic neurons are widespread, which allows them to influence a variety of behaviours and organ systems. In the brain, there are four distinct populations of cholinergic neurons which together provide the entire brain with ACh. Notably, some cholinergic populations not only secrete ACh but also secrete a second chemical messenger which increases the complexity of how behaviours are regulated. Due to technical hurdles, it has been difficult to clearly establish the exact role of ACh in different behaviours. In this thesis, we used selective approaches to eliminate ACh release from cholinergic populations in three different brain areas of mice: the striatum, brainstem and basal forebrain. We then evaluated cognitive and non-cognitive behaviours. In the striatum, an important information processing center, we found that ACh modulates cognitive behaviours such as reversal learning, extinction and cue detection. Cholinergic neurons in the striatum also release the chemical messenger glutamate, however the two often affect behaviours in opposing manners. In the brainstem we find that ACh regulates motor functions, leading to behaviours that mimic symptoms of Parkinson’s disease. Brainstem ACh also appears to modulate susceptibility to stress which can affect performance in cognitive tasks. In the basal forebrain, we find that ACh is essential for remembering familiar individuals (social memory). Results from this thesis help us to understand how different brain circuits that control behavioural functions are modulated by cholinergic signalling and highlight how dysfunctional cholinergic populations can contribute to behavioural/cognitive deficits.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Monday, May 01, 2023

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