Abstract: Stroke is the leading cause of long-term disability in adult. However, there is a limited and spontaneous process of repair and recovery after stroke. In stroke patients, this recovery is associated with re-mapping of sensory and motor functions in peri-infarct and connected cortical areas. In non-human primate and rodent models, stroke induces new connections to form in the same peri-infarct areas, by a process termed axonal sprouting. The process of axonal sprouting after stroke involves three key steps for an adult cortical neuron: stroke sends a signal to adjacent neurons (a trigger), which activates a gene expression program (transcription factor), and the neuron then initiates axonal growth through the brain (extracellular signaling or adhesion proteins). We previously shown that the mechanisms of cell injury and neuroprotection differ between aged and young adults after stroke and that in a mouse model of stroke, axonal sprouting in motor and premotor cortical circuits after stroke is causally associated with motor recovery. These studies identify axonal sprouting as an important cellular target in promoting enhanced recovery post-stroke.  We then identified a "sprouting transcriptome" of sprouting neurons in peri-infarct cortex after stroke and found that the gene expression profile of axonal sprouting after stroke is markedly different in the aged versus young adult brain.  Apparently, neurons in peri-infarct cortex are induced to express an age-related growth-associated genetic program that controls axonal sprouting and mediates the formation of new patterns of connections within the sensorimotor system.  Many studies have also identified important potential therapies that stimulate post-stroke axonal sprouting, including cell transplants, statins, cytokines, and clinically approved drugs. However, there have been relatively few studies of an actual endogenous molecular program that controls axonal growth in the brain after stroke. With gain- and loss-of-function strategies we have further selected a small set of genes that are highly regulated and specifically linked to the process of sprouting in neurons after stroke, and defined the role in vitro and in vivo of some key growth associated molecular systems in the formation of new axonal connections and the process of behavioral recovery after stroke. In particular, functional roles for Atrx, Gdf10, Igf1 and Chn1 in epigenetic and endogenous of axonal sprouting, growth factor–dependent survival of neurons and, in the aged mouse, paradoxical upregulation of ephrin receptors down-stream cascade in sprouting neurons. Axonal regeneration after stroke thus resembles a neurodevelopmental cellular program: a specific molecular program mediates formation of new axonal connections in neurons which require a growth factor for their survival. The axonal sprouting and the formation of new connections over large parts of the motor and sensory cortex may provide the substrate for the establishment of new circuits that compensate for lost functions during the process of rehabilitation.