Wolfgang Otto Friesen, Ph.D. - US grants

Control of rhythmic movements in animals is mediated by specific neuronal interactions that occur in the spinal cord and brain of vertebrates and in the segmental ganglia and cephalic ganglia of invertebrates. The research proposed here is designed to elucidate mechanisms underlying the control of such movements through the investigation of swimming activity in an invertebrate model, the medicinal leech. The specific aims are to: 1) discover mechanisms by which brief stimulation of "trigger" neurons in the subesophageal ganglion elicits prolonged rhythmic motor output in midbody neurons; 2) describe the mechanisms by which inhibitory neurons in the subesophageal ganglion inhibit such motor output; and 3) determine the roles of the cephalic neurons for the initiation of locomotion in nearly intact animals. Experiments will be carried out on the ventral nerve cord and cephalic ganglia of the leech, Hirudo medicinalis. Standard physiological and morphological techniques will be employed to identify neurons, to describe neuronal circuits, and to evaluate the role of these circuits during the initiation of leech swimming movements. The long-range objective for this research project is to explain the physiological mechanisms by which the nervous system generates and controls movements in animals. The approach taken here is to study intensively the relatively simple movements of one favorable invertebrate model system. Our present models for the mechanism underlying neuronal interactions in all animals are derived largely from research on invertebrate system. The discoveries made during this investigation should likewise contribute importantly to an understanding of the neuronal control of animal movements and, by extension, to the treatment of neurological diseases.

9410779 Friesen Many animal movements result from precise coordination between body parts. The two wings of a flying bird, the four limbs of a trotting mammal, and the undulations of a swimming fish are all common examples of the elegance of organized rhythmical movements. Coordination of limb movements and body musculature results from internal coordination between sets of neuronal oscillators that control individual appendages or segments. Neuronal oscillators are sets of nerve cells that interact with each other to generate rhythmic changes in the electrical signals of these nerve cells. Neurobiologists have learned a lot about how these individual neuronal oscillators work, but know little about how the oscillators work together to produce rhythmic movements. This proposal is to study how the interconnections between neuronal oscillators in the leech produce intersegmental coordination during swimming. Mathematical and computer models of intersegmental coordination of this well-characterized swim neural network will be developed. Because of the fundamental similarity of rhythmic movements in all animals, insights gained from this study on a complex, yet tractable, nervous system of a lower animal should be applicable to the more complex and less tractable nervous systems that produce rhythmic movements in higher animals.

Lay Abstract PI: Friesen, Otto; and Mellon, DeForest Proposal Number: IBN-9723320 Much is known about the complex neuronal circuits that control rhythmic movements such as walking, flying in insects, and swimming in different species. A major source of neuronal complexity arises from tight coupling between neuronal oscillators that are integral components of larger brain circuits. These larger circuits then generate purposeful, coordinated movement patterns. Another source of complexity is sensory input, which can alter the activity of the oscillators. The experiments funded by this award are designed to advance the understanding of coordination and sensory modulation of neural circuits underlying movement patterns. The specific functions of sensory feedback in setting the patterns of rhythmic activity in nervous system circuits are determined. This information is then combined with the results of experiments investigating the way different circuits interact to generate larger, more complex rhythmic movements. Computer models of nervous system function are developed and tested based on the experimental data. Because of the functional unity of rhythmic movements in all animals, analytical tools developed by, and insights gained from, this research will be widely applicable to the understanding of the control of movement in all organisms, including humans, and will contribute to the base of information important for the development of artificial movement control systems.

Lay Abstract

Animal locomotion results from the intricate interplay between connections within the nervous system and sense organs that monitor the execution of commands from the central nervous system. For animals that swim by undulating the whole body, sensory receptors detect body bending and transmit that information to the central nervous system, where the 'commanded' and realized movements are compared and compensatory actions are orchestrated. Much is already known about the neuronal wiring diagrams for some behaviors and about relevant sensory structures, but the nature of the connections between the two is largely unknown. The experiments funded by this grant are designed to advance the understanding of interactions between stretch receptors in the body wall, their connections with the central nervous system, and the importance of these interactions in generating an optimal body shape during locomotion.

Experiments are conducted on animal preparations and on isolated central nervous systems with two approaches. One approach is electrophysiological, with the aim of describing stretch-sensitive receptors in greater detail and to map their interactions with neurons in the central nervous system. The other is a 'systems' approach, with experiments designed to test the functional importance of the stretch receptors for swimming movements. Electrophysiological experiments to map neuronal interactions are conducted with standard extracellular and intracellular recording techniques. Systems experiments, employing similar techniques, include tests of whether stretch receptors form oscillatory circuits with the central nervous system and of the nature of intersegmental mechanical interactions. Because there is significant functional similarity between swimming and related locomotory movements in all animals, insights gained from this research will be widely applicable throughout the animal kingdom.

Animals initiate movements either in response to specific stimuli (such as touch, sound or light signals), or as a result of an internal change in state (such as hunger). One important aspect of such voluntary animal movements that has received relatively little attention is their episodic nature, with distinct beginnings and endings. Much is already known about the networks of nerve cells that control rhythmic movements like flying and swimming, but the nervous system components that control the initiation and termination of rhythmic behavior are largely unknown. The experiments funded by this grant are designed to significantly advance the understanding of how nervous systems process information generated by brief sensory stimuli and how they thereby produce episodic locomotion.
Experiments will be conducted on isolated central nervous systems of the medicinal leech using two different approaches. One approach is electrophysiological, with experiments to investigate connections among nerve cells that control the initiation and maintenance of swimming movements. The second approach is pharmacological, with studies on the neurohormone serotonin and on other messenger molecules to learn how these substances are involved in converting the quiescent motor system into one that is functionally active. Because there is significant functional similarity between swimming and related locomotory movements in all animals and because the transformation of a system from quiescence to activity and back to quiescence is a feature of all episodic animal movements, insights gained from this research will have a major impact on our understanding of how the nervous system controls animal movements generally.
The activities funded by this grant have a broader impact on science by increasing the opportunities for undergraduates, primarily women, to conduct scientific research at Bryn Mawr and at the University of Virginia. Also, experiments conducted in the research laboratory are subsequently incorporated into laboratory exercises for advanced neurobiology courses at both institutions. Finally, training is provided to graduate students in modern electrophysiological recording techniques, data acquisition, and analysis. Results from these experiments are widely disseminated through posters at scientific meetings, including student presentations at local science fairs and scientific meetings; publication in scientific journals; lectures open to the public; and demonstrations on animal behavior at K-12 schools.