Molecular and cellular determinants of Drosophila larva thermotaxis

PROJECT SUMMARY: Molecular and cellular determinants of Drosophila larva thermotaxis How nervous systems integrate internal and peripheral sensory inputs to maintain physiological homeostasis is a major question in neuroscience and physiology. Such integration is particularly salient in the control of body temperature (thermoregulation). Thermoregulation is a classic example of interoception, as animals must integrate input from internal sensors (of core body temperature) with input from peripheral sensors (which often reflect the temperature of the surroundings). In homeotherms like humans, thermoregulation involves both autonomic responses (e.g., shivering, sweating) and behavioral responses (e.g., moving, using clothing). Thermoregulation in animals whose body temperatures track ambient, like Drosophila melanogaster, thermoregulate primarily using behavior (e.g., by exhibiting thermotaxis). Interestingly, although Drosophila are small, they possess both internal and peripheral thermosensors and rely on the integration of input from these sensors to control their body temperature. In this proposal, we seek a circuit-level understanding of this phenomenon, obtaining a mechanistic view of how a nervous system solves such a fundamental challenge. How internal and peripheral thermosensory streams are integrated by the brain to produce coherent thermosensory behaviors is not well understood for any animal. We will address this challenge in the Drosophila larva, as its ease of genetic manipulation, connectome, amenability to optical neurophysiology, and quantifiable and stereotyped behaviors make it an ideal system for a multi-level investigation of such behavior. This proposal is a renewal of a long-standing collaboration initially supported through an NIH P01 and more recently through the R01 we propose to renew here. Using this support, we created the foundation for the proposed work. 1) We discovered peripheral warming and cooling cells, and their associated molecular receptors, that control thermotaxis towards a preferred body temperature. 2) We showed that information from both warming and cooling receptors is combined by cross-inhibition, a homeostatic mechanism known in control theory. 3) We probed – aided by computational modeling - how the Drosophila larva integrates the activity of warming and cooling receptors, and postulated the existence of an unknown receptor(s) for absolute temperatures embedded within the larval core (e.g., in its brain). In this renewal application, we propose to define the mechanisms of larval core temperature sensing, examine how input from these core sensors influences responses to temperature, and investigate how input from internal and peripheral thermosensors is transmitted to the brain. The long-term goal is to trace these pathways into the brain to determine how they are integrated to achieve thermoregulation.