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Brain functionality resides on finely tuned regulation of gene expression by networks of non-coding RNAs (ncRNAs) such as the one composed by the circular RNA ciRS-7, the microRNA miR-7 and the long non-coding RNA Cyrano. However, very little is known on how this network regulates stress responses in neurodegeneration. Here we describe ischemia induced alterations in the ncRNA network bothin vitroandin vivoand in transgenic mice lacking ciRS-7 or miR-7. Our data show that cortical neurons downregulate ciRS-7 and Cyrano and upregulate miR-7 expression upon ischemic insults. Mice lacking ciRS-7 show reduced lesion size and motor impairment, whilst the absence of miR-7 alone leads to an increase in the ischemia induced neuronal death. Moreover, miR-7 levels in pyramidal excitatory neurons regulate dendrite morphology and glutamatergic signaling suggesting a potential molecular link to thein vivophenotype. Our data reveal a new endogenous mechanism by which ciRS-7 and miR-7 regulate the outcome of ischemic stroke and shed new light into the pathophysiological roles of intracellular networks of non-coding RNAs in the brain.