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Current Projects

Robin Chemers Neustein Professor
Investigator, Howard Hughes Medical Institute

Click to read about each project.

 

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

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.

Mechanisms of DEET Contact Chemorepellency – Emily Dennis
DEET contact chemorepellency: orco mutant mosquito lands on a DEET-treated arm at 400ms, but does not blood feed

DEET contact chemorepellency: orco mutant mosquito lands on a DEET-treated arm at 400ms, but does not blood feed

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 Aedes aegypti orco mutants cannot smell DEET but will not bite DEET-treated arms. We have started to characterize this behavior using quantitative behavioral analysis and manipulation. Next, we are working towards discovering the molecules mosquitoes use to sense DEET on contact, and confirming these candidates using targeted mutagenesis.

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.

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.

Laura Duvall project logo

Control of Mosquito Host-Seeking Behavior by Neuropeptide Signaling – Laura Duvall PhD
Cyclical suppression of mosquito host-seeking behavior by a blood meal

Cyclical suppression of mosquito host-seeking behavior by a blood meal

Female mosquitoes are attracted to humans by a multitude of sensory cues emitted from hosts, including heat, carbon dioxide (CO2), and body odor. The strong drive to seek a human host for a blood meal is only expressed when the female needs to produce and lay eggs—a process known as oviposition—when protein from a blood meal is required to produce yolk and mature eggs. Previous work suggests that neuropeptide signaling is involved in reprogramming female behavior from host-seeking to oviposition. Previous studies suggest that suppression of host-seeking behavior has been associated with Neuropeptide Y related signaling and our work implicates a specific NPY-like receptor (NPYLR7). These findings suggest that neuropeptides may modulate sensory circuits, including those involved in smell, taste, and CO2 perception, rather than directly inhibit host-seeking behavior itself. This makes neuropeptide signaling a promising candidate for mediating the behavioral switches that occur during mosquito reproductive cycles. The goal of this project is to identify neuropeptide signaling pathways that control the cyclical regulation of host-seeking behavior in female Aedes aegypti mosquitoes.

A Taste of Blood – Veronica Jove
Veronica Jove Project

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.

Modulation of Aedes aegypti mosquito host-seeking behavior by ecdysone – Margaret Herre

Ecdysone is a steroid hormone synthesized in the ovaries. Following a blood-meal, the ovaries secrete high levels of ecdysone, which subsequently is converted to 20-hydroxyecsyone (20E) in the periphery. 20E is required for the production of yolk proteins for developing eggs. 20E inhibits host-seeking drive in Anopheles mosquitoes, but its role in regulating host-seeking drive in Aedes is largely unexplored. The goal of this project is to define the neural and transcriptional targets of this steroid hormone.

Visual contributions to host-seeking in female Aedes aegypti – Molly Liu
A tethered mosquito orienting towards a dark stripe

A tethered mosquito orienting towards a dark stripe

Female mosquitoes require vision to obtain a blood-meal from vertebrate hosts. Without visual feedback, mosquitoes are unable to track hosts, and visual cues may form an important part of a mosquito’s percept of a host. Yet we know neither what specific visual cues host-seeking mosquitoes attend to, nor how these visual inputs interact with other sensory modalities. We are characterizing visual contributions to host-seeking in female Aedes aegypti. We are defining how Aedes aegypti mosquitoes use vision to find hosts using both tethered and free-flying behavioral assays. We are also establishing a platform for studying how these relevant visual stimuli are represented in the mosquito brain. Results will not only illuminate the behavior of a globally important disease vector, but also give insights into how visual inputs interact with other sensory inputs in a robust, ethological context.

Molecular Genetics of Water Sensation and Egg-Laying Behavior in the Mosquito – Ben Matthews PhD
A female Aedes aegypti mosquito laying an egg immediately above the water line of a pool of standing water

A female Aedes aegypti mosquito laying an egg immediately above the water line of a pool of standing water

After taking a blood meal, female mosquitoes undergo a radical behavioral shift. Instead of searching for vertebrate hosts, they instead seek an appropriate aquatic location to lay eggs on a rough surface just above the water line, a behavior known as oviposition. This reproductive behavior involves three critical steps: orienting towards water at long range using cues such as humidity, the detection of standing water, and the evaluation of water osmolarity and quality. We have developed several detailed behavioral assays to investigate mosquito oviposition behavior, and begun a comprehensive analysis of gene expression in sensory tissues of Aedes aegypti with the goal of identifying and mutagenizing genes involved in oviposition and oviposition site selection.

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.

Arousal and Motivation in Female Mosquito Behavior – Trevor Sorrells PhD
Mosquito host-seeking behavior

Mosquito host-seeking behavior is an extended brain state comprised of sequential, coordinated stages that include initiation of flight, searching, landing on host, probing, feeding, and takeoff. In the yellow fever mosquito Aedes aegypti, the decision to seek out a host depends on numerous internal and external cues, and results in directed movement toward a potential reward over an extended period of time. This state is maintained despite the intermittent nature of host cues and despite defensive behavior by the host such as swatting. It is unknown how this motivational drive is signaled in the mosquito brain. In widely diverged species of vertebrates and invertebrates, dopamine signaling is involved in two key aspects of motivation: arousal and encoding of reward. These disparate functions are carried out by different populations of dopaminergic neurons, and often signal through distinct dopamine receptors. We are studying mosquito motivation and persistence by developing genetic tools and behavioral assays to functionally dissect the neuronal circuits underlying host-seeking behavior.

Release of Blood-Meal-Induced Host-Seeking Suppression in Female Aedes aegypti Mosquitoes – Krithika Venkataraman
Investigating the role of endocrine signaling in modulating the host-seeking behavior of female Aedes aegypti mosquitoes during different reproductive states

Investigating the role of endocrine signaling in modulating the host-seeking behavior of female Aedes aegypti mosquitoes during different reproductive states

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. In preliminary experiments, we have shown that egg-laying is a necessary and sufficient trigger for restoring attraction, but the mechanism of this behavioral switch is unknown. Previous reports suggest that circulating factors regulate mosquito host-seeking state. We hypothesize 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 identify candidates, we are profiling circulating factors at different points in the mosquito reproductive cycle during distinct host-seeking and egg-laying states. We will validate candidates with loss-of-function genetics, pharmacology, and behavior, and determine the receptors and cells on which they act. We predict that disrupting candidate factors will cause females to return to host-seeking before laying eggs. This work will reveal how reproductive physiology and endocrine signaling modulate food-seeking drive, and facilitate methods for curbing the cyclic biting behavior of a deadly vector.

Processing Human Cues in the Mosquito Brain – Meg Younger PhD
Models of multi-sensory integration in the antennal lobe of the female mosquito

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.

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

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.

 





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