Project Summary Proprioception, the sense of self-movement and body position, is critical for the effective control of motor behavior. Humans lacking proprioceptive feedback, such as patients with peripheral nerve damage, are unable to maintain limb posture or coordinate fine-scale movements of the arms and legs. But despite the importance of proprioception to the control of movement in all animals, little is known about the neural computations that underlie limb proprioception in any animal. This gap is due to two basic challenges: (1) identifying specific neuronal-cell types that detect and process proprioceptive signals, and (2) recording neural activity from proprioceptive circuits during natural limb movements. Here, we propose to overcome these challenges by investigating the neural coding of leg proprioception in a genetic model organism: the fruit fly, Drosophila. We have developed new methods to record from genetically-identified neurons in proprioceptive circuits with in vivo electrophysiology and 2-photon imaging, while manipulating leg position and movement with a magnetic control system. In Aim 1, we will use 2-photon calcium imaging to define the spatial organization of proprioceptive neural coding within a population of mechanosensory neurons. In Aim 2, we will use calcium imaging to test the hypothesis that specific parameters of leg proprioception—such as position and movement— are encoded by genetically distinct subtypes of mechanosensory neurons. In Aim 3, we will test the hypothesis that signals from distinct mechanosensory neuron subtypes are integrated by downstream neurons, using optogenetics and whole-cell patch-clamp electrophysiology. Altogether, these studies will elucidate basic mechanisms of proprioceptive neural processing that have not possible to investigate in other systems. Although there are morphological differences between flies and humans, the basic building blocks of invertebrate and vertebrate somatosensory systems share a striking evolutionary conservation. These similarities suggest that the general principles discovered in circuits of the fruit fly will be highly relevant to somatosensory processing in other animals. A deeper understanding of proprioception has the potential to transform the way in which we treat somatosensory disorders.