Stroke is the leading cause of adult disability. We have shown that ischemic injury induces the adult brain to sprout a limited set of new connections, a process that correlates in magnitude and location with recovery. Axonal sprouting after injury is limited by the failure of adult neurons to fully activate a growth program and by the inhibitory cellular environment of the adult brain. Neuronal growth programs, or the pattern of inhibitory gene expression, have not been identified after stroke. The goal of this application is to define the growth-promoting and growth-inhibiting genes that mediate axonal sprouting after stroke. Axonal sprouting in the adult has similarities to axonal sprouting during neural development, and growth-promoting and growth inhibiting genes have been considered part of a pattern of developmental gene expression. However, recently a unique set of adult regeneration associated genes has been described. These concepts of developmental- vs. regeneration-associated gene expression have not been tested in stroke. It is hypothesized that, during axonal sprouting, stroke activates a unique set of developmental and regeneration associated genes. A novel model of stroke in the rat barrel cortex will be used to test this hypothesis. The well-characterized anatomy of the barrel cortex allows the neurons that are induced to sprout new axons after stroke to be selectively labeled with retrograde tracers. These neurons will be microdissected using laser capture, and the expression of growth-promoting and growth-inhibiting genes will be quantified in the circuits that undergo axonal sprouting. Differential gene expression will be confirmed at the mRNA and protein level with in situ hybridization and Western blot. We have shown that axonal sprouting in the barrel field is constrained to specific cortical structures. The growth-inhibitory molecules that form these spatial barriers will be identified with immunofluorescence for growth-promoting proteins and the individual inhibitory molecules. The functional role of individual growth-inhibitory molecules will then be identified with enzymatic, antibody and Fc fusion protein alteration of these molecules in vivo after stroke, and quantification of axonal sprouting using anterograde and retrograde tracers. These experiments will identify neuronal growth programs after stroke, and Iocal inhibitory molecules, and provide an understanding of the mechanisms of regeneration in the adult brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Jacobs, Tom P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Kokaia, Zaal; Llorente, Irene L; Carmichael, S Thomas (2018) Customized Brain Cells for Stroke Patients Using Pluripotent Stem Cells. Stroke 49:1091-1098
Carmichael, S Thomas; Kathirvelu, Balachandar; Schweppe, Catherine A et al. (2017) Molecular, cellular and functional events in axonal sprouting after stroke. Exp Neurol 287:384-394
Carmichael, S Thomas (2016) Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol 79:895-906
Carmichael, S Thomas (2016) The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative. Neurotherapeutics 13:348-59
Dobkin, Bruce H; Carmichael, S Thomas (2016) The Specific Requirements of Neural Repair Trials for Stroke. Neurorehabil Neural Repair 30:470-8
Overman, Justine J; Carmichael, S Thomas (2014) Plasticity in the injured brain: more than molecules matter. Neuroscientist 20:15-28
Overman, Justine J; Clarkson, Andrew N; Wanner, Ina B et al. (2012) A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc Natl Acad Sci U S A 109:E2230-9
Carmichael, S Thomas (2012) Brain excitability in stroke: the yin and yang of stroke progression. Arch Neurol 69:161-7
Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng et al. (2011) AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci 31:3766-75
Carmichael, S Thomas (2010) Translating the frontiers of brain repair to treatments: starting not to break the rules. Neurobiol Dis 37:237-42

Showing the most recent 10 out of 19 publications