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.

PUBLIC HEALTH RELEVANCE: The sense of smell is important to our 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. The Drosophila larva's olfactory system is remarkably similar to higher organisms', including humans', despite having many fewer neurons; this project studies how the larva uses its simple nervous system to perceive odors and make decisions based on those perceptions. Insects are important disease vectors and agricultural pests who rely extensively on their senses of smell to locate food, hosts, and mates, so this work will have important health applications in pest control, as well as advancing our understanding of olfactory and decision-making neural circuits.