Cholinergic Modulation of Behaviour
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.