Stroke is the leading cause of adult disability. However, a limited and spontaneous process of repair and recovery does occur 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 these same areas, by a process termed axonal sprouting. We have recently shown 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 after stroke. 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 have recently identified a """"""""sprouting transcriptome"""""""" of successfully sprouting neurons in peri-infarct cortex after stroke. When this transcriptome is analyzed with stringent statistical testing, and the genes associated with routine cytoskeletal structure removed, a small set of molecules are linked to the process of sprouting in neurons after stroke. Three molecules are highly regulated in sprouting neurons in relationship to these three key cellular steps in post-stroke axonal sprouting. Growth Differentiation Factor 10 (GDF10) is a bone morphogenic protein that is secreted after stroke (potential trigger). Bcl11b is a transcription factor that is also induced in sprouting neurons and has a normal function of promoting cortical axon growth in the developing brain. Matrilin-2 is an extracellular matrix protein that promotes peripheral nerve regeneration and is paradoxically down-regulated in cortical sprouting neurons after stroke. GDF10, Bcl11b and matrilin-2 have not been studied extensively in the adult brain, and have not been studied at all after stroke. Preliminary data links these three molecules to axonal sprouting in vitro and in vivo. The studies in this grant wil use pharmacological and genetic manipulation techniques to determine if these three molecules induce axonal sprouting, and then determine the patterns of motor and sensory maps in the living mouse over time that are associated with gain and loss of function in these molecular systems. Finally, the effect on motor control and recovery after stroke with gain and loss of function in these systems will be determined. This approach uses a novel experimental platform of detailed and structural mapping of brain connections, in vivo mapping of the functional physiology of these connections, and behavioral studies of recovery, for a """"""""molecules to maps to behavior"""""""" approach to confirm highly promising molecular targets for post-stroke neural repair.

Public Health Relevance

Stroke is the leading cause of adult disability. A limited recovery occurs after stroke. This limited recovery is associated with the formation of new connections in the brain adjacent to the stroke, and re-mapping of motor and sensory function in this region. This grant determines the molecules that mediate the formation of new connections in the brain after stroke and how these coordinate to form new brain maps and promote recovery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Kokaia, Zaal; Llorente, Irene L; Carmichael, S Thomas (2018) Customized Brain Cells for Stroke Patients Using Pluripotent Stem Cells. Stroke 49:1091-1098
Bosetti, Francesca; Koenig, James I; Ayata, Cenk et al. (2017) Translational Stroke Research: Vision and Opportunities. Stroke 48:2632-2637
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
Li, Songlin; Nie, Esther H; Yin, Yuqin et al. (2015) GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat Neurosci 18:1737-45
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