An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke

Abstract

Stroke is an age-related disease. Recovery after stroke is associated with axonal sprouting in cortex adjacent to the infarct. The molecular program that induces a mature cortical neuron to sprout a new connection after stroke is not known. We selectively isolated neurons that sprout a new connection in cortex after stroke and compared their whole-genome expression profile to that of adjacent, non-sprouting neurons. This ‘sprouting transcriptome’ identified a neuronal growth program that consists of growth factor, cell adhesion, axonal guidance and cytoskeletal modifying molecules that differed by age and time point. Gain and loss of function in three distinct functional classes showed new roles for these proteins in epigenetic regulation of axonal sprouting, growth factor–dependent survival of neurons and, in the aged mouse, paradoxical upregulation of myelin and ephrin receptors in sprouting neurons. This neuronal growth program may provide new therapeutic targets and suggest mechanisms for age-related differences in functional recovery.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…Stroke triggers new connections to form in motor, somatosensory, and premotor cortex adjacent to the stroke site, and in projections from cortex contralateral to the stroke site into distant connections in the striatum, midbrain, and spinal cord 11, 12, 13, 27, 28, 29, 30, 31, 32. In both the cortex contralateral to the stroke, and ipsilateral or peri‐infarct cortex, animal models indicate that axonal sprouting establishes new patterns of connections that are causally linked to recovery.…”

“…Axonal connections are confined by the expression of glial growth inhibitory molecules, such as NogoA, EphrinA5, and chondroitin sulfate proteoglycans 11, 12, 27, 28, 29, 30, 31, 32, 33. Opposed to these glial growth inhibitors, sprouting neurons activate a unique regenerative molecular program 11, 12, 13. Outside of stroke, behavioral activity in the normal adult brain, such as overuse or learning in a forelimb task, induces local changes in synaptic connections on a small scale within the corresponding motor cortex 33, 40, 41.…”

“…Stroke induces axonal sprouting in motor, somatosensory, and premotor areas in peri‐infarct cortex. When glial growth inhibitors are blocked after stroke, this axonal sprouting response is locally enhanced in these cortical areas 11, 33. When glial growth inhibitors are blocked and the animal is forced to overuse the affected forelimb, a model for the clinical approach of constraint‐induced motor therapy, there is a magnitude of axonal sprouting that is remarkable in the adult brain.…”

“…Neural repair means in part activating a growth program in an adult neuron to form new connections or inducing progenitor responses to tissue injury signals 11, 12, 13, 28. In axonal sprouting, induction of oncogenes such as c‐myc 91 and RAS 92 promote the formation of new connections in stroke and spinal cord injury models.…”

“…These individual neural repair events interact in the aggregate and evolve over time to produce properties that are different, larger, and more important than the properties of the single reactive astrocyte or migrating neuroblast. In a definitional sense, the formation of new neurons,6, 7, 8 new oligodendrocytes,9, 10 or new connections11, 12, 13 has been interchangeably described as “repair” or “regeneration.” Both terms connote a process of renewal and growth of tissues after injury, and are literally true in a limited fashion in the central nervous system (CNS) after injury 12. This review will discuss emergent properties of neural repair from the epidemiology of stroke to the synapse, highlighting areas of clinical translation opportunity.…”