Our laboratory uses the powerful genetics of Drosophila melanogaster to
study fundamental problems of neurobiology. The Drosophila model
system has opened the door to molecular analysis of virtually every
area of neurobiology. The list of accomplishments by workers in the Drosophila field
are too numerous to list, but here are a few highlights: the shaker
mutant led to the cloning of the first potassium channel, Drosophila mutants
with defective circadian rhythms have led to an understanding of the
molecular clocks that drive our sleep and waking, even the complex
processes of learning and memory have been illuminated by the isolation
and cloning of Drosophila genes required for these processes.
The long term goal of the lab is to identify the genes that are responsible
for pain signaling. We use Drosophila to discover the genes
and we hope to ultimately provide novel therapeutic targets for the
treatment of human pain. Projects in the lab range from the level of
the organism to the level of the molecule. Various techniques are employed:
behavioral analysis, molecular genetics, biochemistry, confocal microscopy,
electrophysiology, and functional imaging.
We have discovered that the Drosophila larva produces a stereotyped
behavioral output in response to a variety of stimuli that are considered
painful by humans and rodents. The normal pattern of larval locomotion
resembles the familiar movement rhythmic motor pattern of a caterpillar.
A peristaltic rostral to caudal wave of muscular contraction propels
the larva forward. A light touch, causes the larva to pause its motion
but then continue on its way. In contrast, a light touch of a probe
heated above 39°C causes the larva to produce a writhing escape
response.
To identify the molecules that allow the larva to detect the noxious
heat stimulus. We have performed genetic screens to identify mutants
that fail to show the wild type writhing escape response when touched
with the hot probe. These mutants are a subject of future study in
the lab. Since the Drosophila genome has been fully sequenced,
and since the mutants in our screen were created by transposable elements,
the cloning process is straightforward.
A major focus of the lab is a gene we have named painless. painless mutant
larvae respond to the heated probe as if it were simply producing a
light touch. The painless gene encodes an ion channel of the
TRP family. Remarkably, mammalian homologues of the painless gene
are specifically expressed in pain sensing neurons. Mammalian painless homologues
are activated by compounds that produce a sensations of burning pain
such as wasabi (Japanese horseradish)cinnamon, and raw garlic.
The painless gene is expressed in sensory neurons that are
just beneath the epidermis of the larva. We hypothesize that these
neurons, called multi-dendritic (md) neurons are the "pain sensors." Another
major interest of the lab is to understand structure function relationships
and the developmental biology of these cells.
Potential projects for graduate students and postdocs include characterization
of new pain signalling mutants that we have isolated. Other projects
include functional imaging of md neurons expressing genetically encoded
calcium sensors, mapping brain circuits involved in the “perception
of pain” and functional analysis of the Painless protein.
Publications
Tracey W.D., Wilson R.I., Laurent G., Benzer S. (2003). painless, a Drosophila gene
essential for nociception. Cell Apr; 13(2):261-73.
