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Projects

Robin Chemers Neustein Professor
Investigator, Howard Hughes Medical Institute

Here are the exciting projects currently being carried out by PhD students and Postdoctoral Fellows in the Vosshall Lab.

Models of multi-sensory integration in the antennal lobe of the female mosquito

Processing Human Cues in the Mosquito Brain – Meg Younger PhD

Models of multi-sensory integration in the antennal lobe of the female mosquito

Female mosquitoes require a blood-meal for reproduction, and show intense attraction to human hosts. They rely on host sensory cues, including carbon dioxide (CO2) in breath, and components of human body odor, such as lactic acid. These stimuli alone elicit little or no attraction, but in combination they synergize to trigger host-seeking behavior.

It is unknown where and how any human host cues are represented in the mosquito brain. It is also unknown how human host cues synergize to drive host attraction and ultimately trigger biting behavior. To address these questions I am using two-photon excitation microscopy and electrophysiology to measure activity in the mosquito central nervous system. I am focusing on the antennal lobe of the brain, a region that is an important site of odor processing in other insects.

Female mosquito brain

mosquitobrains.org: An Online Atlas of the Brain of Aedes aegypti – Meg Younger PhD

Female mosquito brain

As a tool to understand the neural circuitry that underlies mosquito behavior, we have generated a reference brain for Aedes Aegypti. This is the brain from a female mosquito that has different brain regions annotated for viewing in an online browser. 3D-reconstructions are also available for viewing. Brains imaged on a confocal microscope can be registered onto the female reference brain with a free and open source software pipeline, which is available at mosquitobrains.org. This will allow users to examine how expression patterns of new transgenic lines intersect. Lastly, this website will serve as a repository for mosquito neuroanatomy data, as new transgenic reagents are generated in this rapidly growing field.

Model of physiological factors that may contribute to mosquito attraction to vertebrate hosts.

The role of host physiology in mosquito attraction – Maria Elena De Obaldia PhD

Model of physiological factors that may contribute to mosquito attraction to vertebrate hosts.

Unlike most insect species, which feed on plants, female mosquitoes require a vertebrate blood meal to produce each batch of eggs. This mosquito blood-feeding behavior facilitates disease transmission among populations because females feed on multiple humans throughout their lifetime. There is intense interest in developing interventions to diminish mosquito attraction to humans, thus limiting the spread of mosquito-borne disease.

Mosquitoes use multimodal sensory cues to locate human hosts in their environment, including heat, CO2, and human odor. Differences in skin odor alone can modulate mosquito attraction, when temperature and CO2 are held constant. Physiological factors that contribute to odors emanating from human skin are unclear, but may include: genetic factors, diet, immunity, blood metabolites, and the composition of skin microbiome. I will investigate the contribution of physiological factors to human odor and mosquito attraction using mice as model vertebrate hosts. These studies aim to identify mechanisms of mosquito host preference.

Veronica Jove Project

A Taste of Blood – Veronica Jové

When a female mosquito takes a blood meal from a human host, she uses the dedicated blood-feeding appendage, the stylet, to pierce skin and pump blood. The needle-like stylet contains female-specific cells and neuronal processess that may be used to detect blood

A female mosquito must take a blood meal from a vertebrate host to produce eggs, and in doing so she transmits diseases such as Zika. The mechanism by which a female detects blood and initiates this robust behavioral program is unknown. Early studies have demonstrated that protein is not sufficient or required to initiate blood-feeding, although it is essential for egg production. Surprisingly, ATP in saline is sufficient to initiate blood-feeding in the absence of blood components and chemosensory cues from skin. We hypothesize that the decision to engorge on blood is mediated by the rapid sensory detection of ATP as a proxy for blood. To elucidate how the detection of ATP leads to the initiation of blood-feeding behavior, we are focusing on the dedicated blood-feeding appendage, the stylet, which is the only innervated appendage that directly contacts blood. We are using behavior, genomics, and calcium imaging to identify the cells and receptors that detect ATP. We will use this information to map the circuitry that detects blood and regulates a behavior responsible for transmission of vector-borne diseases to millions of people across the globe.

Sex-specific splicing of a representative gene and its expression pattern in male and female mosquito brains

Genes and Neural Circuits underlying Sexual Dimorphism in Mosquito Host-Seeking Behavior – Nipun Basrur

Sex-specific splicing of a representative gene and its expression pattern in male and female mosquito brains

A female mosquito is expertly adapted to find a vertebrate host to take a blood-meal, which she requires to develop her eggs. Only females carry out this specialized innate behavior. Since host-seeking and blood-feeding are sexually dimorphic behaviors, the underlying genes and neural circuits controlling them are likely also sexually dimorphic. I hypothesize that sex-specific splicing of key genes controls sexual dimorphism in host-seeking behavior. To test this, I have identified genes that are sex-specifically spliced in mosquito brains, and I am generating mutants that disrupt the sex-specific isoforms of each gene, and developing transgenic reagents to visualize the cells expressing these genes.

Margo Herre project 2020

Encoding and modulation of Aedes aegypti mosquito host-seeking behavior by internal state – Margaret Herre

(A) A female Ae. aegypti mosquito engorges on a blood-meal from a human host. (B) The QF2-QUAS binary expression system drives expression of dTomato and GCaMP6s in olfactory sensory neurons in one of the mosquito olfactory organs, the antenna.

For my main thesis research, I am studying the role of the steroid hormone 20-hydroxyecdysone (20E) in regulation of mosquito host-seeking behavior. I have established that 20E suppresses host-seeking drive without affecting other feeding behaviors and have shown that receptor for 20E, the ecdysone receptor (EcR) is expressed in olfactory sensory neurons. I hypothesize that 20E is acting directly at the level of the sensory neuron to affect how female mosquitoes perceive human odor. EcR is a nuclear hormone receptor that is required for development. Since we currently are unable to generate a conditional EcR knockout mosquito, I am taking orthogonal approaches to determine the role of EcR and 20E signaling in sensory neurons. These experiments include determining the transcriptional signature of 20E signaling in olfactory organs with RNA-seq and labeling and manipulating EcR chemosensory neurons using the split QF2-QUAS binary expression system.

In collaboration with Meg Younger, a postdoc in our lab, I seek to understand how the mosquito olfactory system is organized. A fundamental molecular feature of olfactory systems is that individual neurons express only one olfactory receptor in each olfactory sensory neuron. In both mice and Drosophila, neurons that express the same olfactory receptor then converge in the same regions in the primary olfactory processing centers in the brain. This organization enables olfactory systems remarkable specificity. We made the surprising discovery that in Aedes aegypti, olfactory sensory neurons express multiple classes of olfactory receptors in each neuron. Our ongoing experiments are determining the functional significance at the level of the sensory neuron, as well as behavioral consequences for discriminating attractive and aversive odorants.

Tasting the heat: Investigating the role of thermal cues driving feeding behavior in mosquitoes – Takeshi Morita PhD
Female mosquitoes differ from many other organisms in that they require large blood meals to initiate egg production. Mosquitoes can feed multiple times throughout their lifetime, making them an effective vector for transmission of deadly infectious diseases such as dengue fever, yellow fever, and malaria. Mosquitoes use various combinations of host cues during their pursuit for blood meals, including carbon dioxide (CO2), volatile compounds, and heat. Among these cues, heat is a robust inducer for host-seeking and blood-feeding behavior. Although temperatures close to human body temperature attract mosquitoes, the genes, sensory neurons, and behavioral patterns underlying mosquito thermosensation have remained enigmatic. This proposal will lead to identification of novel molecular players and neuronal mechanisms mediating mosquito thermosensation during host-seeking and blood-feeding behaviors, which will shed light on better preventative options for vector-based diseases.
Mosquito host-seeking behavior

Sustained motivation during mosquito host seeking – Trevor Sorrells PhD

Finding a human to obtain a blood meal is a challenging task—imagine locating a pizza stand somewhere in a stadium primarily by smell and touch. Yet female mosquitoes must do this to produce eggs and complete their life cycle. I am investigating how mosquitoes maintain the drive to seek out humans despite the intermittent signals they receive from their hosts. To do this, I developed optogenetic tools to deliver precise stimuli to the mosquito brain. Combined with machine learning classification of behavior, this allows us to understand the sustained response of mosquitoes to human host cues, and how these cues are integrated in time in the mosquito brain. With these experiments we hope to understand why mosquitoes are such persistent biters and what human cues they most enticing.
What controls a female Aedes aegypti mosquito’s drive to repeatedly hunt for blood? – Krithika Venkataraman
Female Aedes aegypti mosquitoes are strongly attracted to human hosts before blood-feeding, an adaptation that allows them to obtain the protein necessary to produce eggs. After blood-feeding, concurrent with egg development, attraction to hosts is suppressed for days. We have shown that, to restore attraction once again, females must lay eggs. How the change in ovary state after laying eggs triggers the female mosquito to resume hunting remains unknown, however. Previous reports suggest that circulating factors regulate mosquito attraction. We hypothesized that egg-laying changes the level of such factors, which signal to the nervous system to modulate sensory circuits, thereby releasing host-seeking suppression. To test this hypothesis, we profiled circulating factors at different points in the mosquito reproductive cycle during distinct host-seeking and egg-laying states. We identified two compelling candidate regulators of mosquito attraction, which are uncharacterized, linked, taxon-restricted genes with tightly controlled expression in female reproductive tissues only when they are in specific physiological states during the reproductive cycle. Using loss-of-function genetics and behavior, we are now validating the causal role of these candidates in modulating attraction. Using molecular and imaging tools, we are also identifying the cells in which the candidates are expressed. We predict that disrupting the candidates will inhibit the female mosquito going through repeated biting cycles, thus curbing disease transmission. More broadly, this work will reveal how reproductive physiology and endocrine signaling modulate food-seeking drive in the context of a globally relevant deadly disease vector.
mosquito avoiding DEET with its feet

Chemosensory coding of DEET in Aedes aegypti tarsi – Olivia Goldman

An orco mutant female mosquito avoiding DEET-treated skin.

The insect repellent DEET is a synthetic compound, discovered in 1946 by the USDA as part of a large chemical screen. Since its discovery, DEET has become the most broadly used and effective arthropod repellent available, but the details of how DEET works remain elusive. We discovered that, in addition to being able to smell DEET, Aedes aegypti can detect DEET upon contact via their legs (Dennis et al, 2019). Using a combination of imaging techniques, molecular profiling, and genetic manipulation, we are further investigating the molecular mechanisms of DEET contact detection in the mosquito leg.

Regulation of mosquito host-seeking behavior by visceral tissues – Nadav Shai PhD
Female Aedes aegypti mosquitoes require a blood-meal to initiate egg production, mosquito attraction to humans switches between biting and not-biting depending on the feeding state of the animal. This on/off switch in attraction is hypothesized to comprise an early and a late phase. The early phase lasts for 24 hours and likely involves abdominal distension from a blood- meal. The late phase lasts until the female lays her eggs and is known to involve circulating factors including hormones and neuropeptides. Visceral tissues undergo robust changes in size and development that correlate to the change in behavior, however, we do not know how those changes are signaling to the brain and in turn, change the animal behavior. To this end, I will visualize the neuronal circuits from the midgut and ovaries and examine the effect of blood-feeding related changes on their activity. Additionally, I will carry out genome-wide and tissue-specific screens for genes whose expression correlates with changes in biting state and use newly developed mosquito genetics tools to test causality.
figure image alt title here

Mechanisms of a Lifetime of Behavior in Aedes aegypti Mosquito Females – Leah Houri-Ze’evi PhD

A three step process to study the epigenetic basis of the refractory state.

Female Aedes aegypti mosquitoes mate only once during their lifetime, after which they become refractory to any additional insemination attempts. This shift in behavior is robustly maintained throughout the lifetime of the female (up to 6 weeks) by an unknown mechanism. Although crucial to the understanding of mosquito reproduction and dispersal, little is known about the behavioral or the molecular processes by which females reject males for a lifetime after a single mating event. We would like to mechanistically test the hypothesis that distinct transcriptional and epigenetic changes create the different refractory components and maintain it for a lifetime. Such mechanisms have been linked in the past to social behavior and learning in multiple species and are compelling candidates for sustaining this life-long memory. Refractoriness in female mosquitoes provides a unique system for decoding neuronal and transcriptional changes that modify behavior permanently. Furthermore, understanding of the refractory state in female mosquitoes, and ideally manipulating it, could contribute to the success of controlling the spread of the deadliest animal on the planet.



Completed Projects (2000 - Present)

McBride 2014
McBride et al. (2014) PMID: 25391959
The Vosshall Lab has been carrying out high-risk, high-reward research since 2000. To read about some of our completed projects, click HERE.


Contact Us

Laboratory of Neurogenetics and Behavior
Box No. 63
The Rockefeller University
1230 York Avenue
New York, NY 10065

Ms. Barbara Ghelardi
Lab Administrator

Leslie Vosshall