Anne-Elise Tobin - US grants

Most rhythmic motor patterns such as swimming, walking, chewing, and breathing are coordinated by neural networks called central pattern generators (CPGs). The ability of these networks to produce rhythmic output is determined by the membrane currents of the cells and the synaptic connections among the cells. Studies of a variety of vertebrate and invertebrate systems have shown that endogenous peptide modulators alter the output rhythm by modifying synaptic connections and/or membrane currents of neurons in the network (Dale and Kuenzi, 1997). Characterizing how modulators work aids our understanding of how rhythmic networks function and how they can respond adaptively to the environment by neuromodulation. This knowledge will advance understanding of CPG dysfunction, such as occurs in some respiratory and ambulatory disorders (Feldman and Gray, 2000; Feraboli-Lohnherr et al., 1999). Because of its small size and well-defined anatomy, the 14-interneuron network, controlling the leech heartbeat is a model system for exploring rhythmic network function. Within this network, two pairs of oscillator interneurons create the underlying alternating rhythm of the leech heartbeat. This proposal focuses on understanding how a neuromodulator acts on these oscillator interneurons to accelerate the heartbeat pattern. In addition, this proposal discusses the development of a computer model of these interneurons incorporating information about cell morphology to understand how morphology and ion channel distribution contribute to rhythmic activity. This series of experimental and modeling studies clarifies how neural networks produce rhythmic activity and how neuromodulation of current kinetics affects the rhythmic output.

[unreadable] DESCRIPTION (provided by applicant): Neural networks that drive rhythmic motor patterns (such as chewing, breathing, swimming, locomotion, and heartbeat in some) need to produce stable activity throughout the lifetime of the animal. Neuromodulators that modify these rhythms should also have reliable, predictable responses. The network that drives rhythmic chewing and food filtering in the crab stomach, the stomatogastric network, shows stereotyped activity across animals, and neuromodulators produce somewhat predictable responses in network activity. However, recent studies have demonstrated that identified component neurons in these and other networks vary considerably across animals. Theoretical work has demonstrated that similar cellular and network activity can be produced by very different conductance sets. The question arises, how does a neuromodulator produce a predictable response when its target conductances are variable from animal to animal? This will be addressed by investigating variability at the level of modulator receptors, modulatory action on target conductances, and modulatory effects on isolated neuron and network activity. In humans, it is thought that depression, schizophrenia and other mental illnesses can result from imbalances in neuromodulation, the action of chemicals that affect activity of neurons. This work investigates the mechanisms of stable neuromodulation, helping us understand how instabilities in neuromodulation might occur. We focus our studies on serotonin, whose imbalance in humans is implicated in many mental illnesses. [unreadable] [unreadable] [unreadable]