State-dependent neuromodulation of mammalian spinal networks

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It has been known for centuries that the brain is not necessary for the generation of movements that allow for animals to walk. For many farmers, the sight of a chicken running around the farm yard following decapitation was fairly common. At the turn of the 20th century Charles Sherrington and Thomas Graham Brown proposed that circuits located within the spinal cord are responsible for the generation of rhythmic movements of the limbs for walking. With over a century of scientific investigation of rhythmically active circuits of vertebrates and invertebrate species, we have learned that rhythmic movements for locomotion, breathing and chewing are controlled by neuronal circuits called central pattern generators. Large emphasis has been directed toward dissecting the central pattern generator circuits for walking. Locomotor movements are remarkably adaptable and respond to not only external demands imposed by the environment but also internal needs of the animal. Thus, the underlying circuits that generate these diverse movements also need to be flexible to readily adjust in response to imposed demands. Nevertheless, the mutability of these rhythm generating circuits is not well understood. Neuromodulation endows spinal circuits with flexible properties that allow motor outputs to be adaptable to modify ongoing movement. I initially started to study how one neuromodulator, dopamine, controls rhythmic network activities of the spinal cord for walking in in the neonatal mouse in vitro (Sharples et al., 2015). My preliminary studies demonstrated that modulation of rhythmic circuits might have state-dependent effects on locomotor rhythms which is consistent with work conducted in invertebrates (Marder et a., 2014). In this thesis, I explored the diverse actions of modulators on spinal networks across varying states of excitability. This is important because changes in behavioural state or pathology result in alterations in network excitability. In general, I demonstrated that neural networks of the spinal cord are degenerate in their ability to generate locomotor rhythms and that neuromodulators can tune this ability through both degenerate and redundant mechanisms.
movement, spinal cord, locomotion, neuromodulation, Dopamine, state-dependency
Sharples, S. A. (2018). State-dependent neuromodulation of mammalian spinal networks (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from doi:10.11575/PRISM/32870