Acetylcholine and cerebellar dependent motor learning

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Motor learning is fundamental to all new behaviours and includes the improvement of voluntary motor skills with practice and adapting reflex responses to sensory experience (conditioning). Whilst motor learning involves a network of brain regions, the cerebellum is critically involved in both types of motor learning - when the cerebellum is damaged our capacity to learn new voluntary movements and adapt reflex responses is severely impaired. The importance of the cerebellum to brain and behaviour is further emphasized by the fact that it contains over 80% of all neurons in the brain. Text book descriptions of the cerebellum tell us there are two types of input to the cerebellum: mossy fibres and climbing fibres. However, there is an additional class of inputs that have been largely overlooked, which have important modulatory effects on cerebellar circuits and cerebellar-mediated function. These include fibres that use acetylcholine (ACh) as a neurotransmitter and have widespread connections throughout the cerebellum. The primary source of these cholinergic fibres is a brainstem structure called the pedunculopontine nucleus (PPN). Whilst ACh is vital for learning and memory, almost nothing is known about the behavioural significance of cholinergic projections to the cerebellum. This is an important gap in our understanding given the critical role of the cerebellum in motor learning.The current study tests the hypothesis that cholinergic projections from the PPN to the cerebellum regulate neuronal function to control motor learning. An important organizational principle of the cerebellum for understanding its contributions to motor learning is a division into a series of functional units called modules. How individual modules contribute to motor learning remains far from clear, especially those involved in the control of limb movements. The current project uses the modular organization of the cerebellum as a framework to study cholinergic effects on cerebellar circuits during two different types of forelimb-related motor learning: a forelimb reaching task, and a reflex forelimb-flexion conditioning task. The use of these two distinct types of task allows a comprehensive investigation of the roles of the cholinergic projections to the cerebellum during motor learning, in relation to well-defined behavioural outputs. The project is timely because a strong physiological connection between the PPN and cerebellum has only recently been identified, and genetically modified rats to selectively interrogate cholinergic circuits are now available. We will use the combined power of whole animal behavioural and brain slice approaches. At the systems level we will use multichannel electrophysiological recording methods to examine neuronal population activity and spike trains of individual neurons, and interventionist methods (pharmacological/optogenetic) to understand how PPN and cerebellum orchestrate their activity during motor learning. At the cellular level we will use genetic approaches to selectively stimulate PPN release of ACh to determine how this neuromodulator controls neuronal and synaptic function at the cellular level. Collectively these approaches will provide novel insights into the cellular mechanisms and circuit basis of motor learning. Choice of experimental model: cerebellar network architecture and patterns of connectivity are highly conserved across mammalian species, including human. However, rats are the experimental animal of choice because our understanding of the basic neuroanatomy and physiology is most complete in this species. Importantly, our experiments will include study of neural network interactions during behavioural situations that have been well characterized in rats and that correlate to human motor learning. Overall, the results of our study aim to provide a mechanistic understanding of how neural circuits within the brain give rise to our ability to learn new movements.