This project aims to elucidate the cellular mechanisms that allow a neural network to produce stable output while retaining the flexibility to respond to perturbations, such as those that occur during growth, learning, sensory input and injury. Ionic currents produce the electrical changes that characterize neuronal activity, and individual neurons and neural networks are responsible for the generation of behavior. In so doing, the nervous system and its parts are often capable of homeostatically restoring their properties after a perturbation or damage. Several mechanisms allow this process of stabilization or restoration of activity to be expressed, the best studied of which is perhaps synaptic plasticity. However, a different mechanism is emerging as a powerful candidate to underlie the expression of these two seemingly paradoxical aspects of neuronal activity of flexibility and stability. This mechanism is activity-dependent regulation of voltage-sensitive ionic currents. In this proposal a series of experiments is described to study the properties of this poorly understood mechanism of neuronal activity regulation. This mechanism is potentially of great importance as it may underlie a new form of learning and memory via its stabilizing effect on neural network activity. The regulation of activity in a small and well-characterized neural network, as well as the role of long-term activity-dependent regulation of ionic currents in this process will be investigated. Previous work has shown some evidence of long-term interactions and mutual regulation between different ionic currents. I will investigate in depth these mutual regulatory interactions and their possible role in the process of stabilization of neuronal activity. The experimental methodology will include several modes of electrophysiological recording of neurons in the intact network in vitro, in the intact network in the living a freely moving animal, in dissociated cells in culture, and in long-term culture of the whole network. Pharmacological manipulations, as well as RNA injections of recently cloned ionic channels, will be used to modify the expression of endogenous ionic currents.
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