insight overview
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.
N
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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insight overview
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
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L. V. BERGMAN/CORBIS
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.
© 2002 Macmillan Magazines Ltd
319
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.
■
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