Dissecting the neural substrates of interhemispheric integration in the larval Drosophila olfactory system

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Project Summary All animals with bilateral symmetry must integrate the sensory input from the left and right sides of their bodies in order to make coherent perceptual decisions. A wide range of neurological and psychiatric disorders have been associated with reduced structural and functional connectivity between the two cerebral hemispheres. However, the detailed causes and effects of this impaired connectivity remain obscure in many cases. Efforts to unravel the neurophysiological mechanisms of interhemispheric integration (IHI) in mammals have been hindered by the overwhelming numerical complexity of the mammalian brain and the lack of sufficiently precise tools for dissecting the underlying neural circuits. I propose to take a novel, reductionist approach to this problem by leveraging the experimental accessibility of the larval Drosophila brain to dissect the circuit basis for IHI in the context of olfactory sensory processing. The Drosophila larva is the ideal system in which to approach this problem owing to the small size of its brain (just ~10,000 neurons), the optical transparency of its body, and the availability of numerous genetic tools for manipulating individual cells and cell types. Furthermore, the overall glomerular architecture of the larva’s olfactory system bears a striking resemblance to that of the mammalian olfactory system: sensory signals originating from the left and right sides of the head are kept largely separate until reaching a higher-order brain center called the mushroom body (MB), where various bilaterally projecting cell types seem to pool input from the two sides of the animal. However, despite a flurry of recent progress in understanding the MB circuit, to date there has not been any concerted attempt to dissect the substrate of IHI in this system. The first aim of my project is to identify the processing layer at which unilateral odor responses are transformed into bilateral stimulus representations. The second aim is to characterize the behavioral manifestation of IHI by unilaterally ablating various cell types in the larval olfactory system and assaying for impairments to chemotaxis. My third aim, inspired by the phenomenon of bistable olfactory perception in humans, is to characterize the circuit and behavioral response to the presentation of conflicting stimuli to the left and right sides of the animal simultaneously. This work, which leverages the Samuel lab’s expertise in functional imaging and behavioral analysis, will begin to address the mechanism by which the brain integrates bilateral sensory stimuli to form a unified internal model of the world. Elucidating the emergence of perceptual unity is a key aspect of my long-term research interests and promises to yield basic conceptual insights bearing on the etiology of many human brain disorders.