Marc H. Gershow - US grants

The sense of smell is important to humans? daily lives, and its loss is often a precursor to neurodegenerative diseases, but studying the human olfactory system directly, like all studies of human neural function, faces challenges due to the brain?s complexity, large number of neurons, and ethical and technical obstacles. Studying the larva's simplified olfactory system will advance understanding of the basic principles of human sense of smell. Insects are mportant disease vectors and agricultural pests who rely extensively on smells to locate food, hosts, and mates, so this work will have important applications in pest control. Undergraduates and high school students, especially from underrepresented groups, will be actively involved in the research. An additional component of this project is outreach to local elementary students, especially the creation of a program to engage students in tinkering and construction.

How do brains make decisions based on noisy and often conflicting sensory input? Why does the same input elicit variable behaviors, even in the simplest organisms? This project aims to use the fruit fly larva's sense of smell as a model to explore these questions by studying the olfactory system of the Drosophila larva. A given odor stimulates or inhibits a set of odor receptor neurons, yet on the basis of this pattern of stimulation, organisms from flies to humans recognize and classify odors rapidly and reliably. The PI will image the responses of odorant receptor neurons in the larva's dorsal organ (its "nose") to understand how olfactory information is first presented to the brain, taking advantage of the genetic tools available in Drosophila, the larva's transparency, and custom built apparatus developed in the PI's lab. A second goal of this project is to develop the technology necessary to take full advantage of the larva as a model for decoding the neural circuitry of olfaction. To move towards or away from an odor, the larva uses sensory input to drive motor output. In this process, it modulates a number of behaviors, e.g. moving forward, stopping, and sweeping the head to one side or the other. The rules by which the larva changes its motor output in response to sensory input in order to move towards a goal represent a navigational strategy. Using light activated ion channels the PI will evoke activity directly in the sensory neurons in order to measure the computations involved in transforming temporal variations in sensory input into directed motor output. The promise of the larva, a small crawling animal with a transparent skin, is that the neural activity in freely behaving animals can be visualized. In practice, we do not have a microscope capable of keeping up with a moving animal. The project will develop a microscope that can track individual neurons in a moving larva making possible to "read the larva's mind" as it goes about its business, allowing us to link together sensory input, neural activity, and evoked behavior in order to understand the function of neural circuits.

This project is being jointly supported by the Physics of Living Systems program in the Division of Physics the Neural Systems Cluster in the Division of Integrated Orgamismal System, and the Emerging Frontiers program in the Biological Sciences Directorate.

? DESCRIPTION (provided by applicant): This project proposes to study the olfactory system of the Drosophila larva. The sense of smell is important to humans' daily lives and its loss is often a precursor to neurodegenerative diseases. A given odor stimulates or inhibits an arbitrary set of odor receptor neurons, yet on the basis of this pattern of stimulation, organisms from flies to humans recognize and classify odors rapidly and reliably. To move towards or away from an odor, the Drosophila larva uses sensory input to drive motor output. In this process, it modulates a number of behaviors, e.g. moving forward, stopping, and sweeping the head to one side or the other. We seek to understand the rules by which the larva changes its behavior in response to odor input in order to move towards a goal. We will use light activated ion channels to introduce noise into odor receptor neurons and measure the resulting perturbations in behavior. We will determine the rules by which the larva transforms activity from individual neurons into strategic decisions and find out whether these rules are different for different receptor neurons. Natural odors stimulate multiple receptors simultaneously; to begin understanding how the brain interprets these signals, we will measure how the presence of a natural odor changes the meaning of activity in individual odor receptor neurons. To study how organisms in natural environments integrate multi-sensory cues, we will determine the rules by which the larva responds to combined inputs of light and odor. Although we have a sophisticated understanding of individual neurons, we are far from understanding how connected groups of neurons (neural circuits) work together to process information. The complexity and inaccessibility of the mammalian brain complicates our ability to study neural circuits in higher animals. The Drosophila larva, on the other hand, has few neurons but performs complex behaviors. Advances in genetics, protein engineering, and microscopy allow us to optically activate, suppress, and visualize the activity of these neurons through the larva's transparent cuticle. The larva is thus an ideal model system in which to study complete neural circuits. A second goal of this project is to develop the technology necessary to take full advantage of the larva as a model for decoding the neural circuitry of olfactory decision making. We will apply the methods we develop to study how the larva makes decisions on the basis of olfactory sensory neuron activity to learn how the larva makes decisions on the basis of activity in other neurons throughout its olfactory circuit. We will directly measure the larva's neural responses to odor using optical microscopy. The promise of the larva, a small crawling animal with a transparent skin, is that we can visualize neural activity in freely behaving animals, but in practice, we do not have a microscope capable of keeping up with a moving animal. We will develop a microscope that can track individual neurons in a moving larva. We will be able to read the larva's mind as it goes about its business, allowing us to link together sensory input, neural activity, and evoked behavior in order to understand the function of neural circuits.