Morphology-based models and modulation of oscillator interneurons in the leech heartbeat central pattern generator

Rhythmic motor patterns, such as locomotion, swimming, breathing and chewing, are driven by neural networks called central pattern generators (harder and Calabrese 1996). This study focuses on the network controlling the rhythmic heartbeat of the leech, a well characterized and accessible system for studying principles of rhythmic pattern generation. The goal of this thesis was to gain insight, through electrophysiological and modeling techniques, into how rhythmic networks can change through modulatory influences and how ionic conductances contribute to rhythm generation.; At the core of the network pacing the leech heartbeat are two pairs of rhythmically active heart interneurons. Each pair is linked with reciprocally inhibitory synapses to form a half-center oscillator. The alternating bursting of these neurons is shaped by synaptic input, but they are also capable of endogenous bursting when synaptically isolated. The neuropeptide myomodulin speeds the bursting both of synaptically isolated interneurons and of half-center oscillators. As discussed here, myomodulin appears to cause these changes by increasing the hyperpolarization activated cation current, Ih, and by down-regulating the Na/K pump.; To investigate the influence of morphology on single neuron and network activity, we built a detailed morphology Full Model of a leech heart interneuron. We reduced the number of compartments, preserving passive and active properties, and maintaining the general morphology such that it could be directly mapped to the Full Model. We used this computationally-efficient Reduced Model in an automated parameter optimization routine and found multiple parameter sets that produced endogenous and half-center bursting in the Reduced Model, most of which produced similar activity in the Full Model. Two parameter sets best met our criteria for sustained, regular bursting, and we used them to assess whether the modulatory targets of myomodulin could account for the modulated burst properties. When the effects of myomodulin were mimicked, one of the two models showed a decrease in endogenous burst period, and both models showed an increase in the spike frequency of endogenous bursting. Additionally, when configured as half-center oscillators, the effects of myomodulin decreased period and increased spike frequency in both models, as seen in experiments.; These studies provide a multi-faceted approach to understanding how membrane conductances generate and regulate rhythmic bursting in oscillator interneurons of the leech heartbeat central pattern generator. The principles uncovered here of how rhythmic activity is modulated and how to build and utilize models for exploring rhythm generation, may be applicable to studies of rhythmic motor patter generation in other systems.