Photo: Model organisms we study
Left to right:The fruit fly, Drosophila melanogaster; the yellow fever and Dengue
vector mosquito, Aedes aegypti; normal human subjects.
Stock photo credits: Fotolia.com (ŠStudiotouch ŠEW CHEE GUAN Šsculpies)
The overall goal of work in our laboratory is to understand how complex
behaviors are modulated by external chemosensory cues and internal physiological
states. The lab takes a multi-disciplinary approach spanning cell biology,
genetics, neurobiology and behavior. Our early focus has been to study how
the brain interprets olfactory signals in the environment that signal food, danger, or
potential mating partners. We have been studying these problems in three model
organisms: the fly, the mosquito and the human. The majority of the early work in the
laboratory was carried out in the genetically
tractable fruit fly, Drosophila melanogaster, which displays a rich repertoire
of chemosensory behaviors despite having a nervous system with only 100,000 neurons.
In this animal, we have studied the functional neuroanatomy of the olfactory system,
how this system perceives sex pheromones, and the structure and function of the insect
odorant receptors.
We have recently expanded our research focus in three major directions. First,
we are establishing a mosquito genetics research program to understand host-seeking
and blood-feeding behavior in the mosquito. Second, we are carrying out large-scale
human subjects research to combine olfactory psychophysics with genetic analysis to
understand the mechanisms of olfactory perception in humans. Third, we are getting
increasingly interested in the links between olfaction and feeding behavior and hope
to use
Drosophila as a powerful model to understand how smell intersects with hunger
and satiety in all animals.
The long-term goal of all of our work is to understand how behaviors
emerge from the integration of sensory input with internal physiological states.
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Research in our lab is supported by the Howard Hughes Medical Institute,
the National Institutes of Health/National Institute of Deafness and Other Communication
Disorders (current grants: RO1 DC006711, RO1 DC008600; past grant: RO1 DC005036), the
Klarman Family Foundation Grants Program in Eating Disorders Research, the Irma T. Hirschl
Trust, and the Grand Challenges in Global Health Initiative of the Bill and Melinda
Gates Foundation, administered by the Foundation for the National Institutes of Health.
We are grateful for past support from the National Science Foundation, the John Merck
Foundation, the Arnold and Mabel Beckman Foundation, and the McKnight Endowment Trust
for Neuroscience.
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Current Projects
Fly courtship behavior
A male fly (right) courting a female fly (left) while both walk across a banana slice.
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Pheromones, courtship, and social and sexual behavior in the fly
Michael Crickmore, Ph.D.
Jennifer Bussell
Steve Conway
How complicated behaviors arise from and are regulated by the brain is perhaps the greatest mystery in biology.
Sexual behavior in the fly provides a reductionist and genetically malleable system for addressing this mystery.
Drosophila melanogaster exhibit a particularly well-studied sexually dimorphic set of innate behaviors in their
precopulatory courtship. In the classical view, male Drosophila initiate courtship and perform stereotyped behaviors
in order to woo the female. The female, for her part, may respond by being receptive to copulation or avoiding it.
We are interested in understanding how flies use courtship to make the decision whether, and with whom, to mate.
The decision to mate is based first of all upon the drive to reproduce, and both the fly's internal state and
sensory information from the environment influence the choice. During courtship, flies gather information about
potential mates via visual, auditory, tactile, and chemical cues. We want to understand how these cues are
interpreted by the fly to decide whether or not to mate with a given individual. Some of the most important
chemical cues used by insects are sex pheromones, and previous work in our laboratory identified four
candidate pheromone receptors in Drosophila, suggesting that Drosophila also may use volatile sex pheromones
to communicate prior to mating. We will take advantage of the genetic tools available in this system to approach
the mechanisms of pheromone perception in Drosophila. Finally, previous analyses of courtship have largely focused
on the behavior of the male, but given the equal importance of mating to females, we are working to understand the
female's role in the decision to mate.
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Identification of novel genes and circuits in an animal model of binge eating disorder
Gabriel Gasque, Ph.D.
Steve Conway
The etiology of compulsive feeding behaviors including bulimia nervosa
and binge eating disorder in humans is poorly understood. We propose that
studying these important clinical conditions in a simpler genetic model
system, the larva of the fruit fly Drosophila melanogaster, may shed new
light on this important health problem. Fruit flies go through four distinct
life stages: embryo, larva, pupa, and adult. While adult flies regulate their
feeding according to hunger status and the circadian clock just like normal humans,
the larva resembles a binge eater because it feeds continuously for nearly 72 hrs,
eating 3-5 times its own weight in food. About 24 hrs before puparation, the larva
abruptly leaves the food medium and stops eating. This highly stereotyped behavior
provides an attractive experimental model to explore the neuronal mechanisms that
drive and sustain continuous (compulsive) feeding. We hypothesize
that continuous feeding in the Drosophila larva is a behavior
accessible to genetic and pharmacological modulation. We are carrying out
microarray analysis to identify candidate genes subject to regulation
during continuous feeding. Using a genome-wide RNA interference (RNAi) screen,
we hope to identify genes that modulate food intake. We will complement the RNAi
screen with a small molecule screen that will look for compounds that reduce food intake.
Finally, we will study the neuronal circuits modulating continuous feeding. Our long-term
goal is to identify genes and neuronal circuits mediating the continuous feeding behavior
of larvae and to prove that this compulsive-like behavior can be decreased by specific
pharmacological interventions. We hope to illuminate common principles underlying the
regulation of feeding behavior that will be applicable to parallel processes occurring
in human patients suffering from compulsive eating disorders.
Funded by a grant from the Klarman Family Foundation Grants Program in Eating Disorders Research.
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Molecular biology of the insect odorant receptors
Takao Nakagawa, Ph.D.
Laura Seeholzer
Insects have exquisitely sensitive olfactory systems that are tuned to food odors and pheromonal cues emitted by members of the same species. We have been studying the molecular mechanisms by which insect olfactory neurons respond to and discriminate among the numerous possible odors in the environment. Several years ago, we and others identified a divergent family of seven transmembrane domain receptors now known to be the insect odorant receptors (ORs). One member of the odorant receptor gene family, Or83b, has the unique property that it is expressed in nearly all olfactory neurons. Therefore, each olfactory neuron in the fly is likely to express a conventional odorant receptor along with the co-receptor Or83b. Our recent work has shown that the insect odorant receptor is a heteromeric complex of the OR83b co-receptor with a conventional ligand binding odorant receptor. OR83b is necessary and sufficient to target this OR/OR83b complex to the ciliated dendrite of the olfactory sensory neuron. Together with our collaborator Dr. Kazushige Touhara and colleagues at the University of Tokyo, we investigated whether OR83b has additional signaling functions beyond its role in ciliary trafficking. Our recent work provides strong evidence that the OR/OR83b complex forms an odor-gated non-selective cation channel that does not depend upon G protein signaling. We are carrying out a large-scale in vivo structure-function analysis of OR83b and the conventional odorant receptors to further probe the biology of these unusual membrane receptors. The goal is to map those domains that are necessary for the heteromeric association of the OR/OR83b complex, domains necessary for trafficking, and residues that are necessary for odor signal transduction. We are particularly interested in discovering which residues may contribute to forming the ion-conducting pore. Going beyond conventional genetics, are using chemical biology to probe for small molecules that interfere with heterodimerization, trafficking, or signaling of OR/OR83b complexes. Some of these compounds may be useful elements in a chemical strategy to block olfactory host-seeking behaviors in mosquitoes and other pest insects.
These compounds may act as insect repellents that could be useful to control insect vectors that transmit human infectious diseases.
This work is funded in part by a grant to Richard Axel
and L.B.V. from the Foundation for the National Institutes of Health through
the Grand Challenges in Global Health Initiative
Genetic basis of specific anosmias in humans
Andreas Keller, Ph.D.
Peggy Hempstead, R.N.
As part of our overall mission to understand
the genetic and neuronal basis of how odors guide
behaviors, we are conducting psychophysical studies with
human subjects to find correlations between genetic
variability in odorant receptor genes and variability
in cognitive and physiological responses to odors.
In collaboration with Hiro Matsunami's group at Duke
University we have shown that variability in one odorant
receptor gene, OR7D4, influences the perception of
odorous steroids. Currently we are extending our
studies to include more odors, more odorant receptor
genes, and an array of physiological and psychological
responses to odors. Our most recent study investigates
the genetic basis of changes in salivary cortisol, mood,
and skin conductance (a measure of general arousal)
induced by an odorous steroid.
To learn more about The Rockefeller University Smell Study or to consider
enrolling as a volunteer,
email us
or consult
our web page.
The CAFE assay
A male fly feeding from a capillary containing a dyed sugar solution.
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Olfactory adaptation to feeding state in Drosophila melanogaster
Nilay Yapici, Ph.D.
Isabel Gutierrez
The ability of animals to adapt their feeding behavior in response to hunger and
satiety cues is important for survival and in the natural world where food resources
fluctuate. Prior studies in vertebrates and in worms suggest that this adaptation may
involve modulation of the chemosensory system in response to food intake, though little
is known about the mechanism for this proposed sensory adaptation. We have been examining
the behavioral response of adult Drosophila melanogaster flies to odor cues and
food in starved and in fed states. Flies that have been starved for 24 or 48 hours show
significantly increased olfactory behavior preference for a food odor (3-methylthio-1-propanol)
when tested in a two-choice odor preference assay. There is a corresponding increase in food
intake in such animals. Using whole genome microarrays, we have identified a set of genes in
Drosophila that are regulated by starvation and that are candidates for molecular
regulators of this behavioral phenotype. Forty genes show at least a ten-fold increase or
decrease in fly heads after 24 hours of starvation. These may represent transcripts that
function to modulate behavior in response to feeding state. In antennae, forty genes are
likewise either up or down regulated in response to 24 hours of starvation, suggesting
that feeding state modulates gene expression in peripheral olfactory organs.
Our results demonstrate that insect olfactory preference can depend on feeding state,
and we are investigating candidates genes that may regulate this behavior.
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Mosquito blood-feeding behavior
A female Aedes aegypti mosquito prepares to take a blood meal from a human.
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Regulation of blood-feeding and host-seeking behavior in the mosquito Aedes aegypti
Jeff Liesch
Conor McMeniman, Ph.D.
Jermaine Watson, M.S.
Chloe Goldman
Laura Seeholzer
Olfactory cues guide mosquitoes toward humans, from which the mosquitoes derive the blood
they need to complete ovarian development. We are carrying out two conceptually related
projects in mosquitoes.
In the yellow fever and dengue vector mosquito, Aedes aegypti,
host-seeking is suppressed or inhibited for about 72 hours after the mosquito takes a blood meal.
The molecular basis for how host-seeking behavior is regulated is unknown, but may be explained by a humoral control
mechanism in which the sensitivity of the olfactory system is altered following blood-feeding.
In this project, we are examining the hypothesis that regulation of specific olfactory and neurohumoral genes
modifies the host-seeking behavior of female Aedes aegypti after blood-feeding.
Genetic analysis of skin odor perception in Aedes aegypti
Matthew DeGennaro, Ph.D.
Chloe Goldman
Laura Seeholzer
Skin odor is a long-range, attractive cue that guides mosquitoes to their hosts.
The mosquito perceives differences in skin odor, both between and within species, to determine
which host to feed upon. The molecular mechanism by which mosquitoes translate host odor
information into host-seeking behavior has been inferred but not demonstrated. To shed new
light on mosquito olfaction and host-seeking behavior, we developed a technique for targeted mutagenesis in Aedes aegypti using zinc-finger nucleases.
The establishment of loss-of-function genetics in Aedes aegypti opens new paths of investigation in vector biology including the neurobiology of host-seeking.
We not only seek to understand how the mosquito responds to odor cues from the environment, but how its internal, nutritional status regulates odor perception.
The transmission of vector borne disease involves female mosquitoes making behavioral shifts from host-seeking to oviposition to finding another host during
each gonotrophic cycle. Understanding how these behavioral shifts are accomplished could open up new strategies for vector control. One of the advantages
of Aedes aegypti is its clearly defined cyclical host-seeking behavior that is under humoral control.
These behavioral changes have been correlated with alterations in antennal sensitivity to host-odor stimuli.
We are in the process of identifying candidate genes that regulate the behavioral switch from host-seeking to oviposition.
This project aims to (1) identify the olfactory receptors that mediate human skin odor perception and
(2) determine the relationship between olfactory sensitivity and nutritional status during the gonotrophic cycle.
The genetics of host specialization in the mosquito Aedes aegypti
Lindy McBride, Ph.D.
Laura Seeholzer
Jermaine Watson, M.S.
Outside of Africa, populations of the Yellow-Fever mosquito Aedes aegypti
specialize on humans. They are strongly attracted to human scent, they thrive on
human blood, and they breed in artificial containers in human-disturbed habitats - often
even in water stored inside people's homes. Within Africa, however, many Aedes aegypti
populations appear to be generalized. They are not particularly attracted to humans,
they feed on a wide variety of animals, and they breed in tree holes in natural habitats.
Previous work has shown that these two ecologically divergent forms of the mosquito coexist
in several places along the coast of East Africa - one breeding in villages and the other breeding in surrounding forests.
They appear to be maintaining ecological differences despite their close proximity.
This project aims to (1) identify the genetic basis of ecological differentiation between the two forms and (2) to describe the evolutionary processes by which this differentiation is maintained.
Click here for photos of Lindy McBride's Kenya mosquito collecting trip in January 2009.
This work is funded in part by a grant to Richard Axel
and L.B.V. from the Foundation for the National Institutes of Health through
the Grand Challenges in Global Health Initiative
Completed Projects
Regulation of cellular and neuronal function by the Drosophila Ih channel
Gabriel Gasque, Ph.D.
Rhythmic cellular functions, such as the heartbeat and the timing of daily rhythms
of activity and sleep, are regulated by the activity of cellular pacemakers.
We are using genetic approaches to study the role of the Drosophila
hyperpolarization- and cyclic nucleotide-gated ion channel, DmIh, in these processes.
This is an ongoing collaboration with Dr. Gareth Tibbs at Columbia University and Dr. Michael Nitabach at Yale University.
Genetic analysis of olfactory coding in Drosophila larvae
Kenta Asahina
Matthieu Louis, Ph.D.
Silvia Piccinotti
At an earlier developmental stage, Drosophila larvae display simple and robust olfactory-mediated chemotactic behavior controlled by 21 olfactory neurons expressing a repertoire of 25 odorant receptor genes. We have used a genetic approach to study odor coding in this simple animal by ablating specific sensory neurons and the receptors expressed in them, or by constructing animals with only a single functional olfactory neuron. By combining behavioral analysis with calcium imaging, we are attempting to understand the neural basis of olfactory behavior in this animal.
Genetic and functional subdivison of the Drosophila antennal lobe.
Elane Fishilevich
Using genetic labeling of olfactory sensory neurons expressing a given receptor, we generated a nearly complete map connecting odorant
receptor expression to olfactory neuron
convergence to antennal lobe glomeruli in adult Drosophila.
This work was supported in part by an individual F31 NRSA training
grant from NIH/NIDCD to E.F. (5F31DC006795).
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