At the end of the 19th century, Ramon y Cajal's application
of the Golgi method revolutionized neurobiology by showing
that the neuron is the brain's organizational unit. For
most of the 20th century, Cajal's wonderful drawings and
analysis remained the last word on the cellular organization
of many regions of the adult and developing brain. However,
all this is changing due to the convergence of two new
sets of technical developments. First are the methods
of genome manipulation that have made it possible to insert
genes from jellyfish and other aquatic creatures that
encode fluorescent proteins stably into lines of transgenic
mice that express these fluorescent proteins in the brain.
Second is the development of a suite of confocal, multi-photon,
low-intensity, and computational methods that allow imaging
of fluorescent neurons in living animals at a resolution
previously obtainable only in thin sections of fixed tissue.
Together, these methods now make it possible to label
different neurons in different colors so that synaptic
circuitry can be untangled. Moreover, it is now possible
to view neurons in living animals so that the same individual
cells and synapses can be monitored over minutes or months
as they change in response to experience, aging or disease.
Perhaps the most exciting use of such transgenic animals
is that they provide the first way to assay the cellular
alterations that underlie behavioral changes such as memory
formation.
My colleagues and I have used such transgenic fluorescent
mice to monitor a dramatic remodeling of synaptic circuits
that takes place in early postnatal life in mammals. This.10
remodeling likely plays a critical part in the way young
mammals use experience to mold their nervous systems to
conform to the world they live in. We have focused on
a particularly accessible system, the connections between
spinal motor neurons and muscle fibers. In adults each
muscle fiber is innervated by exactly one motor neuron
and at just one site, the neuromuscular junction. Each
motor neuron, however, distributes its innervation to
a number of muscle fibers. A "motor unit" is the distributed
subset of the muscle fibers in a muscle that are exclusively
activated by one neuron. In rodents this pattern emerges
in early postnatal life by the sorting of connections
of different motor neurons that initially overlap at multiple
innervated neuromuscular junctions. By time-lapse imaging
in vivo in animals bred such that different axons express
different colored fluorescent proteins, we have begun
to directly observe the way neuromuscular junctions undergo
the transition from multiple to single innervation and
motor units become non-overlapping. These studies reveal
a massive change in connectivity during early postnatal
life that appears to be driven by a highly dynamic competition
between axons that transiently co-occupy the same synaptic
sites.
