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An essential determinant of a neuron’s functionality is its neurotransmitter phenotype. While the prevailing view is that neurotransmitters are fixed and determined during development, our previous work in zebrafish supports a growing body of evidence suggests that neurons retain the ability to switch between different neurotransmitters. In the context of this research proposal, we will address the critical question: Do changes in neurotransmission can contribute to spinal cord regeneration after the injury? The architecture, connectivity, and plasticity of spinal circuits may hold the answer to this fundamental question. For this, we will take a multidisciplinary approach that combines an innovative and comprehensive set of state-of-the-art techniques from systems neuroscience and the stem cell research fields, in adult zebrafish. An animal model with extensive regeneration capacity providing an experimentally tractable system for electrophysiology, pharmacology, anatomy, molecular profiling, and genetics. By a combination of these methods, we will explore the neuronal and non-neuronal functions of spinal neurotransmission and its dynamics during spinal cord restoration. We expect our results to reveal new principles of neuroplasticity with a significant impact on our understanding of the normal and pathological state of the central nervous system. Hence, our overall objective is to promote spinal cord regeneration and reinstate normal locomotor behavior.