Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Bussey, Tim J.

2nd Supervisor

Saksida, Lisa, M.

Co-Supervisor

Abstract

The lack of treatments targeting the cognitive symptoms of schizophrenia has prompted interest in understanding the neural mechanisms of attention in the context of the disease. Acetylcholine (ACh) and parvalbumin-expressing interneurons (PVIs) are pivotal in controlling top-down attention in the prefrontal cortex, with their dysfunction linked to schizophrenia. Despite evidence hinting at ACh's interaction with PVIs during attention, no prior studies have explored this interaction and its role in attention. This thesis employed pharmacological inhibition of muscarinic and nicotinic ACh receptors, alongside in vivo calcium recordings from prefrontal PVIs in mice engaged in an attention-based task. Muscarinic inhibition impaired behavior and PVI activity. M1-muscarinic receptor inhibition had no effect, while prefrontal nicotinic inhibition did not alter behavior or PVI activity. This indicates that prefrontal muscarinic signalling modulates PVI activity and plays a significant role in attention, while prefrontal nicotinic signalling lacks impact on prefrontal PVIs or a substantial role in attention.

Summary for Lay Audience

Schizophrenia is a severe and widespread psychiatric disorder which does not have adequate treatments targeting the cognitive disabilities associated with the disorder, like attentional dysfunction. A better understanding of the underlying biology of attention, can help guide the development of more effective drug therapies targeting attentional dysfunction. Mounting evidence has implicated acetylcholine, an important neurotransmitter in the brain, having a crucial role in attention. Several studies have also shown that parvalbumin neurons, a subtype of neuron that suppresses neural activity by releasing the inhibitory neurotransmitter GABA, are also crucial for attention. Interestingly, in schizophrenia, acetylcholine signalling, and parvalbumin neuron signalling is dysfunctional. Thus, determining whether acetylcholine signalling modifies parvalbumin neuron signalling and whether this modulation by acetylcholine is crucial for attention may illuminate a new target for drug therapies for the cognitive dysfunction associated with schizophrenia. For my thesis, I used a rodent touchscreen behavioural system to run a behavioural task designed to measure the attention of mice. While mice completed the behavioural task, I used calcium fibre photometry to selectively observe and record the neural activity of parvalbumin neurons in real time, in a brain region important to attention known as the prefrontal cortex. To assess whether acetylcholine signalling impacts the activity of parvalbumin neurons in the prefrontal cortex and whether this interaction impacts attention, I administered drugs specifically blocking either muscarinic receptor-mediated or nicotinic-receptor-mediated acetylcholine signalling. This allowed me to assess the impact removing muscarinic and nicotinic acetylcholine signalling had on parvalbumin neuron activity, and on attention. With the application of the muscarinic subtype-selective acetylcholine antagonist, both parvalbumin neuron activity and performance on the attention-based behavioural tasks were impaired. Contrastingly, application of a more selective antagonist, specifically only targeting the M1-subtype muscarinic acetylcholine receptors, did not alter parvalbumin neuron activity or attention. Application of a nicotinic-subtype selective acetylcholine receptor antagonist did not change parvalbumin neuron activity. However, the nicotinic antagonist did impair attention when the drug blocked nicotinic signalling throughout the body but did not impair attention when administered directly to the prefrontal cortex. These results suggest that muscarinic acetylcholine receptors play a crucial role in controlling parvalbumin neuron activity as well as facilitating attention, while nicotinic acetylcholine receptors do not play a crucial role in in controlling parvalbumin neuron activity or facilitating attention. Further experiments are required to understand the contribution of different subtype-muscarinic receptors. My thesis project shows that certain acetylcholine receptor subtypes play a necessary role in parvalbumin neuron activity and attention.

Creative Commons License

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

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