The overall, long-term goal of these studies is to understand the cellular and synaptic mechanisms of rhythm generation in the adult vertebrate nervous system using the locomotor network of the lamprey, a lower vertebrate fish, as the model system for study. In lamprey and other vertebrates, it is known that the neural networks responsible for generating the signals that rhythmically contract muscles for locomotion (called locomotor central pattern generators) are located in the spinal cord. However, it has been observed recently that the region of the lamprey brain nearest to the spinal cord (i.e., the last hindbrain segment) also exhibits rhythmic motor signals of locomotion and contains a central pattern generator for locomotion. The lamprey hindbrain preparation offers numerous advantages for investigating the underlying mechanisms of rhythm generation, and we will use a combination of electrical recordings of nerve cell activity, pharmacology, and anatomical techniques on the isolated brainstem - spinal cord preparation of the lamprey to 1) identify which nerve cell classes of the hindbrain participate in locomotor activity, 2) determine the synaptic connectivity and synaptic physiology of these nerve cells in the hindbrain, and 3) investigate the contributions of several important ionic currents to the function of the locomotor network at the level of the individual nerve cells composing the network. These studies will provide insight int the structure and function of the rhythm-generating network for locomotion at the level of the component neurons, their cellular electrical properties, and their synaptic interactions. Rhythmic activity of nerve cells is widespread in the vertebrate nervous system, underlying both normal functions and neuropathologies such as epilepsy. Understanding the cellular and synaptic mechanisms of rhythm generation in the nervous system will advance our understanding of normal brain function and aid in the search for treatments of epilepsy. In addition, understanding the mechanisms underlying the generation of locomotion is an important step toward developing rational therapies for injuries or diseases of the central nervous system that affect motor functions. It is likely that the fundamental mechanisms underlying rhythm generation in the brain of the lamprey will be common to many vertebrate rhythm generating networks.
These proposed studies will add to our fundamental knowledge of how the nervous systems of vertebrates generate rhythmic neural activity and in particular, how rhythmic locomotor signals are produced by the nervous system. Understanding the mechanisms of rhythm generation in the adult vertebrate nervous system is relevant to public health because such fundamental knowledge is necessary to guide the development of effective therapies for the treatment of injuries and diseases of the nervous system that affect basic neural functions including movement.