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Non-mammalian models for studying neural development and function Eve Marder Volen Center, MS 013, Brandeis University, Waltham, Massachusetts 02454-9110, USA (e-mail:
[email protected])
Early neuroscientists scoured the animal kingdom for the ideal preparation with which to study specific problems of interest. Today, non-mammalian nervous systems continue to provide ideal platforms for the study of fundamental problems in neuroscience. Indeed, the peculiarities of body plan and nervous systems that have evolved to carry out precise tasks in unique ecological niches enable investigators not only to pose specific scientific questions, but also to uncover principles that are general to all nervous systems.
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ot that long ago, neuroscience graduate students were expected to wander the woods, explore tide pools, take ocean voyages, or pore over tomes of zoological texts with wonderful old drawings in search of the perfect preparation with which to study an important problem. In this they were following the lead of their elders. Many of the heroic figures among early neuroscientists avidly sought through the animal kingdom for the ideal preparation with which to study the problem that interested them, and some, like Ted Bulloch and Steve Kuffler, studied many different preparations during their careers. Furshpan and Potter1 first studied electrical coupling in crayfish, Kuffler, Nicholls and Orkand first recorded intracellularly from Necturus (an amphibian) glial cells2,3, Hodgkin and Huxley used the squid giant axon to understand the mechanism of the action potential4, Dudel and Kuffler5 first used quantal analysis to demonstrate presynaptic inhibition at the crustacean neuromuscular junction, and Ratliff and Hartline first described lateral inhibition in photoreceptors of the horseshoe crab Limulus6. Levi-Montalcini and Viktor Hamburger did seminal work on the development of the nervous system using chick embryos7–9, and frogs and fish were the early preparations of choice for the study of the specificity of retinal–tectal projections in development10–12. Retinal structure and function was studied in fish, salamander and turtle retinas13–16, and birds, bats and electric fish were favoured for studies of other sensory modalities17–21.
Journey’s end Today it is almost inconceivable that many neuroscientists would venture back to the ocean, river, field or forest in search of a new preparation. This is for several reasons — practical, philosophical and political. First, and perhaps most important, we now have developed large collections of data on a number of systems upon which new studies build. Initiating studies on the nervous system of an animal on which there is no literature would require a forbidding 318
amount of groundwork to bring it to the level of one of the more established preparations. Second, the pressure for direct medical relevance has pushed neuroscience towards studies of animals thought to be good models of human function and dysfunction. Third, the availability of genetic tools in some organisms has significantly enhanced their power, and thus attractiveness. And fourth, scientists, like other humans, are too often conformists. That said, there are some who have even recently developed new nonmammalian preparations or turned to existing preparations to address questions not previously studied with these animals. For example, Ron Hoy and colleagues have continued to go to the field to find organisms with fascinating attributes, focusing on relatively unstudied insects and jumping spiders for their unusual sensory organs and astonishing behaviour22–26. This work reminds us that the study of neurobiological mechanisms in the context of their natural setting, as is the goal of neuroethology, brings us closest to the fundamental lessons of evolution and natural species diversity. One of the most exciting areas in systems neuroscience is the cellular and circuit mechanisms underlying sustained neural activity and its role in working memory. Much of the work that has defined these issues has been done in awake and behaving monkeys27,28. David Tank and Sebastian Seung have recently started studying these issues using the vestibular ocular reflex of fish29–32. The fish learn, it is relatively easy to combine behavioural and electrophysiological measurements in them, and they allow a variety of mechanistic experiments not possible or practical with primates. Of course, there are many who continue to exploit nonmammalian preparations to study a raft of important problems in neuroscience, only a few of which could be highlighted in this collection of reviews. Although the era that saw the proliferation of preparations has ended, scores of animals, from worms to birds, continue to instruct us. Of these, several have been selected that illustrate how nonmammalian preparations are today catalysing discovery in neuroscience. It would have been just as easy to select
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Tremendous progress has been made in identifying the cellular and molecular mechanisms that underlie simple forms of behavioural learning in the sea slug Aplysia californica.
wonderful work on bat echolocation33,34, zebrafish development and behaviour35,36, electric-field sensing and generation in electric fish and eels37,38, insect sensory processing22–26,39–41, leech, tadpole and lamprey swimming42,43, behaviour of the nematode worm Caenorhabditis elegans44,45 or sexual dimorphism in the frog nervous system associated with courtship behaviours46, to name only a few. In all of these preparations, the peculiarities of these animals have allowed investigators to pose specific scientific questions into basic mechanisms of sensory–motor integration and their relation to behaviour. In each of the articles that follow, the authors have attempted to bring the reader a sense of how each preparation has led to better understanding of a basic question in neuroscience.
problems — sensory map formation and song production. Barn owls localize sound exceptionally well, and use this ability to hunt for their prey even in limited light. Knudsen (pages 322–328) discusses the structure of the owl’s auditory space map, how it develops and how it is modified by experience. The auditory space map is adjusted by visual experience, and the problem of how different sensory maps are brought into register by experience is one that is beautifully posed and studied in owls. Recent work described by Knudsen seeks to define the loci for change in the brain responsible for behavioural change and then to bring these changes down to cellular and molecular mechanisms. Brainard and Doupe (pages 351–358) focus on learning in the birdsong system, an area that provides one of the richest sets of questions in neuroscience and neuroethology. Here it is possible to directly address questions such as how a complex motor behaviour is learned, how complex auditory sequences are decoded, how sexually dimorphic brain structures are controlled by hormones during development, and what cellular and molecular changes underlie ‘critical periods’, the times at which critical experiences are crucial for the appropriate development of the nervous system to occur. As in the barn owl system, work in the songbird system is anchored in behavioural studies showing the animal’s capacity for sensory and motor performance and learning. These observations have then been
Nervous systems, learning and behaviour Learning is required for animals to adapt successfully both to their environment and to changes in their own body. We recently saw the Nobel prize awarded to Eric Kandel47 for his work on the cellular basis of learning using the sea slug, Aplysia californica. Kandel’s choice of this mollusc, with its orange-coloured ‘simple’ nervous system, was crucial in the early attempts to tackle the formidable task of uncovering the cellular and molecular mechanisms underlying simple forms of learning. The small size of the animal’s nervous system, the simplicity of its behaviours, and the ability to easily identify Aplysia neurons facilitated attempts aimed at determining the sites at which changes during learning might occur. Kandel and his colleagues have made extraordinary progress identifying the cellular and molecular mechanisms by which alterations in synaptic strength are produced by a variety of stimulus paradigms at some of the loci in the animal that are likely to be responsible for stable changes in behaviour. Certainly, much remains to be understood about how learning in Aplysia takes place. But in this system one can imagine ultimately discovering answers to questions such as does behavioural learning involve changes at most of the synapses in a set of pathways, how distributed are the changes in the nervous system underlying behavioural modifications, and how do all the changes that occur during learning work together to produce an altered or modified behaviour? These are questions that are crucial for understanding learning in all nervous systems, but are difficult to study in mammalian brains because of the large number of neurons and connections. Learning is studied in organisms throughout the animal kingdom from C. elegans to humans. ‘Birdbrain’ might be a common colloquialism used to insult a person’s intelligence, but bird brains provide outstanding opportunities to study higher cognitive function in remarkable ways. Two articles in this issue discuss learning in auditory processes of birds in the context of two very different NATURE | VOL 417 | 16 MAY 2002 | www.nature.com
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The peculiarities of body plan and nervous system that have evolved as animals colonized strange ecological niches offer huge potential for deducing general principles that will be applicable to all nervous systems.
Seminal work by Viktor Hamburger and co-workers established the chick embryo as an animal model for experimental embryology and marked the beginning of the new discipline of developmental neuroscience.
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mechanisms that can be used to tune the same network to produce a variety of circuit dynamics. There is today an uneasy flirtation between the fields of neuroscience and artificial intelligence and robotics. A growing number of investigators look to invertebrate nervous systems for design principles in the construction of robots that can sense their environment and navigate intelligently through it. Webb (pages 359–363) describes much of this work, and also argues that the construction of robots based in what is known about some ‘simple’ invertebrates can also help neuroscientists understand the limitations of their knowledge about these preparations.
General principles from the arcane
Few students of the biological sciences will have graduated without encountering the classical studies of Hodgkin and Huxley, who investigated the mechanism of the action potential using the squid giant axon.
complemented by forays into the brain to discover the neural circuits and cellular processes that produce the behaviours and their plasticity. It is precisely this solid neuroethological anchor that has made these preparations so instructive for understanding how brains produce complex behaviours.
Conservation in construction Olfaction is central to many animals as they find food and mates. To the surprise of many, the organization of the olfactory system both at the molecular and circuit level is remarkably conserved across species from worms, molluscs, insects, salamanders and rodents48–52. Common themes have emerged from the study of the roles of oscillations in odour processing, and this is a field in which invertebrate, non-mammalian vertebrate (see review by Kauer, pages 336–342) and rodent work continues to inform. The commonality of mechanism across phylogenetic boundaries is illustrated in the review by Panda et al. (pages 329–335) on circadian rhythms. Although the existence of circadian rhythms has been long known, it was the discovery of rhythm mutants in the fruitfly Drosophila melanogaster53,54 that ushered in the modern era of circadian rhythm research. Using Drosophila, a several laboratories have isolated a number of genes that are part of the circadian clock55, and these have led to models of molecular and biochemical feedback loops that can account for circadian rhythmicity. Many of the molecular components of the clock that were first described in flies have since been found in mammals. This is a prime example of a discovery process that depends heavily on the ease of doing genetics and behaviour in an organism that develops quickly and in which thousands of lines can be rapidly screened. Almost twenty years ago, the analysis of small invertebrate motor systems triggered a paradigm shift in our thinking of how networks generate behaviour56–58. Before that time, it was generally believed that networks were static, and that it would be sufficient to work out the ‘wiring diagram’ or ‘connectivity diagram’ to understand how a given network operates. But work on small motor systems showed that networks can be reconfigured to produce multiple outputs, as the synaptic strengths and intrinsic properties of network neurons are modified by synaptic inputs and neuromodulatory substances59. Nusbaum and Beenhakker (pages 343–350) describe work on one of the canonical small motor systems, the stomatogastric ganglion of lobsters and crabs. This work illustrates that networks are modulated by multiple inputs, and provides direct examples of the kinds of 320
For good or ill, some of the preparations that in the past were exploited for significant scientific gain have fallen by the wayside, and have become historical oddities. But to concentrate all resources into the collective study of a very few nervous systems would be a pity on both practical and philosophical grounds. Those who sit on government advisory panels and urge that all funding for neuroscience be used to support mouse, monkey and human work forget the interdependence of species in the survival of our planet. They forget our wonder as we spot an unusual bird in the mangroves of Florida or the jungles of Malaysia. As we revel in the sometimes outrageous forms that species take, we remember that species diversity was an outcome of survival in disparate environments. The peculiarities of body plan and nervous systems that allowed animals to live in strange ecological niches remind me that the most important findings in science often result from individual scientists’ foibles, genius, insight and personal taste. Although brute-force science has its place, we risk an incalculable loss of individual creativity and imagination if we work only on consensus problems and consensus preparations. We should value and protect those who dare to be fascinated by animals that have evolved nervous systems to best carry out a specific task. New technologies are expanding the range of approaches available in the study of all nervous systems. By studying the neural mechanisms underlying the processes in the animals ideally suited for their analysis we stand the best chance of finding the principles that will be general to all nervous systems, including our own. ■ 1. Furshpan, E. J. & Potter, D. D. Transmission at the giant motor synapses of the crayfish. J. Physiol. 145, 289–325 (1959). 2. Kuffler, S. W., Nicholls, J. G. & Orkand, R. K. Physiological properties of glial cells in the central nervous system of amphibia. J. Neurophysiol. 29, 768–787 (1966). 3. Kuffler, S. W. Neuroglial cells: physiological properties and a potassium mediated effect of neuronal activity on the glial membrane potential. Proc. R. Soc. Lond. B 168, 1–21 (1967). 4. Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952). 5. Dudel, J. & Kuffler, S. W. Presynaptic inhibition at the crayfish neuromuscular junction. J. Physiol. 155, 543–562 (1961). 6. Lange, D., Hartline, H. K. & Ratliff, F. Inhibitory interaction in the retina: techniques of experimental and theoretical analysis. Ann. NY Acad. Sci. 128, 955–971 (1966). 7. Hamburger, V. Ontogeny of neuroembryology. J. Neurosci. 8, 3535–3540 (1988). 8. Hamburger, V. History of the discovery of neuronal death in embryos. J. Neurobiol. 23, 1116–1123 (1992). 9. Hamburger, V. The history of the discovery of the nerve growth factor. J. Neurobiol. 24, 893–897 (1993). 10. Gaze, R. M. & Keating, M. J. The depth distribution of visual units in the tectum of the frog following regeneration of the optic nerve. J. Physiol. 200, 128P–129P (1969). 11. Gaze, R. M. & Sharma, S. C. Axial differences in the reinnervation of the goldfish optic tectum by regenerating optic nerve fibres. Exp. Brain Res. 10, 171–181 (1970). 12. Jacobson, M. & Gaze, R. M. Selection of appropriate tectal connections by regenerating optic nerve fibers in adult goldfish. Exp. Neurol. 13, 418–430 (1965). 13. Baylor, D. A. & Fuortes, M. G. Electrical responses of single cones in the retina of the turtle. J. Physiol. 207, 77–92 (1970). 14. Baylor, D. A., Fuortes, M. G. & O’Bryan, P. M. Receptive fields of cones in the retina of the turtle. J. Physiol. 214, 265–294 (1971). 15.Baylor, D. A. & Lamb, T. D. Local effects of bleaching in retinal rods of the toad. J. Physiol. 328, 49–71 (1982). 16. Baylor, D. A., Matthews, G. & Nunn, B. J. Location and function of voltage-sensitive conductances in retinal rods of the salamander, Ambystoma tigrinum. J. Physiol. 354, 203–223 (1984). 17. Carr, C. E. & Konishi, M. A circuit for detection of interaural time differences in the brain stem of the barn owl. J. Neurosci. 10, 3227–3246 (1990). 18. Carr, C. E. & Konishi, M. Axonal delay lines for time measurement in the owl’s brainstem. Proc. Natl Acad. Sci. USA 85, 8311–8315 (1988). 19. Volman, S. F. & Konishi, M. Spatial selectivity and binaural responses in the inferior colliculus of the great horned owl. J. Neurosci. 9, 3083–3096 (1989).
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