The Cellular and Neural Circuit Basis of Flexible Escape Behavior

PROJECT SUMMARY In response to painful cues, protective withdrawal behaviors are triggered to reduce potential bodily insult. These withdrawal behaviors are vital for survival and highly flexible depending on the ever-changing sensory context. In pathological states, pain can be induced from otherwise innocuous stimuli like a gentle touch in cases of allodynia, or one can become hypersensitive to pain in cases of hyperalgesia. How painful stimuli are detected by primary nociceptors in the skin is well understood, as well as some of the nociceptive processing circuits that relay this information to the brain. However, the neural mechanisms underlying the flexibility of escape and withdrawal behaviors are much less understood, especially how these behaviors are altered in pathological conditions. I propose to study the neural mechanisms that underlie multimodal integration of nociception and mechanosensation that may allow for flexible escape behavior using Drosophila larvae, as this is the ideal model organism to investigate this question. Larvae perform stereotyped escape behaviors in response to various noxious stimuli. An abundance of genetic tools allows us to perform cell-specific and circuit manipulations, and a synaptic wiring diagram of the larval central nervous system enables anatomical and circuit dissection at nanometer resolution. We have found that mechanosensory neuron activation sensitizes escape behavior in larvae and the relative balance of mechanosensory and nociceptive input may bias larvae to exhibit different escape and mechanosensory behaviors. Here, I aim to 1) test the effect that different properties of mechanosensory input have on generating flexible escape behavior through optogenetics and behavioral analysis, and 2) determine the cellular and circuit mechanisms by which mechanosensory and nociceptive input may be integrated via functional imaging and computational neuron modeling. This proposal will reveal general principles of how mechanosensory and nociceptive input interact at the cellular and circuit levels to promote flexible escape behaviors and provide insights for studying pain states and modulation in analogous vertebrate systems.