Project Summary Damage to the nervous system results in the death of many neurons, leading to adverse outcomes such as locomotor and cognitive defects. Neural injuries may induce neuroplasticity responses in surviving neurons, where they extend their axons and dendrites and form new connections (undergo rewiring) to cope with the loss of their neighboring neurons. Neural circuits are composed of different neuronal types, each with unique intrinsic properties such as neural firing patterns, neurotransmitter identity, and synapses of different types and sizes. Whether different neuron and synapse types are equally capable of undergoing structural plasticity remains unclear. Furthermore, the role of non-neuronal cells (such as glia and muscles), intercellular signaling pathways, and cross-talk between neurons, glia, and muscles during the plasticity response are still under investigation. Addressing these knowledge gaps will help optimize therapeutic strategies, thereby maximizing the chance of the restoration of circuit function after neural injury. The objective of this proposal is to address these problems using the motor circuits underlying locomotion in Drosophila larvae. Two types of motor neurons (MNs) form neuromuscular junctions (NMJs) with larval body wall muscles: tonic-firing MNs with large NMJs and phasic firing MNs with small NMJs. These MNs receive input from excitatory and inhibitory premotor neurons (PMNs). In addition, different subtypes of glial cells in Drosophila are functionally and morphologically comparable to those found in vertebrates. The rich genetic toolkits in larvae provide an unprecedented opportunity to determine how PMN-MN-muscle circuits rewire in response to the death (or inactivation) of PMN and MN subsets and determine the role of glial and denervated muscles in mediating proper circuit rewiring. For the first time, strong preliminary data provided in this proposal demonstrate that in response to the death of MN subsets, the motor