Ann E. Stuart - US grants

Photoreceptors can transmit minute changes in voltage to photosynaptic cells over a wide range of background light intensities. Knowledge of the processes and molecule; involved in normal synaptic transmission from these specialized cells is essential if we wish to know how they might be altered in degeneration and disease. We have developed a prepartion, from an invertebrate, consisting-of huge photoreceptors with giant presynaptic terminals and recognizable postsynaptic cells, and have identified the photoreceptors' neurotransmitter as histamine. The particular advantages of this preparation will be exploited to study cellular processes, particularly those of transmitter dynamics, less easily approached in vertebrate photoreceptors. We will follow the fate of transmitter molecules with LM and EM autoradiography control and record the voltage from pre- and postsynaptic cells with electrophysiological methods and follow changes in intracellular calcium concentration using highspeed optical recording. The following questions will be addressed: (1) How does the reuptake of released transmitter contribute to synaptic function, in particular signal transfer? How is uptake into photoreceptors regulated, especially in a cell that releases transmitter continuously as this one does, and what role is played by uptake into glial cells at this synapse? (2) How does the synthesis of transmitter contribute to synaptic function and how is it regulated? (3) Is transmitter released in a quantal fashion from this synapse or by a carrier, and where is it stored? (4) Can we control the internal milieu of these terminals and in this way attempt to dissect out the steps in the release process?

The key to the function of neurons is the voltage across their membranes: changes in the value of this voltage not only control basic neuronal processes but constitute the signals that underlie perception, movement, and thought. An understanding of how these signals are generated and how they travel in neurons is fundamental to any understanding of the nervous system. Yet this area, rooted in concepts of electricity, can be perplexing to students, the more so because the voltages move in the neuron but texts can present the material only as static figures. Two educational improvements are needed to make this subject accessible: first, a new way of visualizing the activity of neurons and, second, an interactive learning tool that allows students to predict what a neuron will do as their understanding grows, with immediate feedback to let them know if their insight is correct or incorrect.
John Moore and Ann Stuart developed the prototype for this project, a CD-ROM-based set of interactive tutorials called Neurons in Action (NIA1), to encourage students to learn how neurons function by experimentation. The student does experiments on the computer, asking "What if?" by choosing parameter values such as the neuron's geometry, its channel types and densities, the degree of myelination of its axon, its synaptic inputs, the ionic environment and temperature. A sophisticated, professional simulator, NEURON, carries out the computations and graphs the resulting voltages, currents, and underlying conductances. The software is unique in having moving graphs that show how voltages spread within the neuron; this feature quickly dispels misconceptions that arise from the static figures of textbooks. Hyperlinks in the tutorials lead the student to a wealth of supporting information: explanations of results, answers to questions asked in the tutorial, background text material, and PDFs of original papers.
The current project, Neurons in Action Version 2 (NIA2), undertakes an improvement in the prototype tutorials (NIA1), based on user feedback, as well as new tutorials and an emphasis on understanding how diseases, toxins, and drugs can affect the neuron. The particular new tutorials are now made possible by advances in the sophistication of NEURON and in the speed and memory of computers. Colleagues who are currently using NEURON or NIA1 are providing assistance for new tutorials developed in their areas of expertise and/or help with evaluation. As in the prototype, the tutorials are written in HTML and hyperlinked to supporting material.
Intellectual merit: The NIA tutorials exploit the power of a professional simulator widely used as a research tool. The experiments suggested for students to carry out reflect accurately the knowledge gained over the past half century. This project is unique in using a browser to launch NEURON from HTML tutorials hyperlinked to a wealth of scholarly information; no equivalent program exists.
Broader impacts: The NIA2 tutorials have been planned with a wide scope to be used at several levels. At the most introductory level, they are appropriate for undergraduates with no previous knowledge of neuroscience. At the same time, they are intended to lure the student more deeply into the material by providing intriguing subjects for the naive student whose knowledge is just beginning to expand or for the more sophisticated student to explore. While promoting understanding of neurophysiology broadly among undergraduate students (and often faculty), NIA also can acquaint and intrigue them with the research field of computational neuroscience. Further, the NIA web site provides a forum where contributions from faculty for the extension of these tutorials and problem sets can be posted. The wide range of these tutorials makes them appropriate for students in undergraduate biology, neuroscience, psychology, or physiology courses, or for students with career aspirations not only in neuroscience but also in biomedical engineering, medical, or other health-related fields. The fact that NIA1 has already sold over 3000 copies to a wide assortment of institutions in the US and other countries bodes well for the broad impact of the final product.