RESUMEN
Stroke causes loss of neurological function. Recovery after stroke is facilitated by forced use of the affected limb and is associated with sprouting of new connections, a process that is sharply confined in the adult brain. We show that ephrin-A5 is induced in reactive astrocytes in periinfarct cortex and is an inhibitor of axonal sprouting and motor recovery in stroke. Blockade of ephrin-A5 signaling using a unique tissue delivery system induces the formation of a new pattern of axonal projections in motor, premotor, and prefrontal circuits and mediates recovery after stroke in the mouse through these new projections. Combined blockade of ephrin-A5 and forced use of the affected limb promote new and surprisingly widespread axonal projections within the entire cortical hemisphere ipsilateral to the stroke. These data indicate that stroke activates a newly described membrane-bound astrocyte growth inhibitor to limit neuroplasticity, activity-dependent axonal sprouting, and recovery in the adult.
Asunto(s)
Axones/metabolismo , Efrina-A5/metabolismo , Plasticidad Neuronal/fisiología , Recuperación de la Función/fisiología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Axones/patología , Conducta Animal , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Efrina-A5/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Actividad Motora/fisiología , Red Nerviosa/fisiopatología , Fosforilación , Transducción de Señal , Coloración y EtiquetadoRESUMEN
Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Destreza Motora/fisiología , Receptores AMPA/metabolismo , Recuperación de la Función/fisiología , Transducción de Señal/fisiología , Accidente Cerebrovascular/metabolismo , Análisis de Varianza , Animales , Western Blotting , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Electrofisiología , Ensayo de Inmunoadsorción Enzimática , Agonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Destreza Motora/efectos de los fármacos , Ratas , Ratas Long-Evans , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Changes in brain circuits occur within specific paradigms of action in the adult brain. These paradigms include changes in behavioral activity patterns, alterations in environmental experience, and direct brain injury. Each of these paradigms can produce axonal sprouting, dendritic morphology changes, and alterations in synaptic connectivity. Activity-, experience-, and injury-dependent plasticity alter neuronal network function and behavioral output, and in the case of brain injury, may produce neurological recovery. The molecular substrate for adult neuronal plasticity overlaps in these three paradigms in key signaling pathways. These common pathways for adult plasticity suggest common mechanisms for activity-, experience-, and injury-dependent plasticity. These common pathways may also interact to enhance or impede each other during adult recovery of function after injury. This review focuses on common molecular changes evoked during the process of adult neuronal plasticity, with a focus on neural repair in stroke.
Asunto(s)
Plasticidad Neuronal/fisiología , Recuperación de la Función , Accidente Cerebrovascular/fisiopatología , Sinapsis/fisiología , Animales , Lesiones Encefálicas/fisiopatología , Humanos , Ratones , RatasRESUMEN
Recent studies show a limited capacity for neural repair after stroke, which includes remapping of sensorimotor functions and sprouting of new connections. However, physiologic and connectional plasticity of sensory maps during long-term functional recovery in the mouse have not been determined. Using a photothrombotic stroke model, we targeted the motor cortex, which we show results in lasting behavioral deficits on the grid-walking and in the cylinder tasks out to 8 weeks after stroke. Mice recovered performance in a skilled reaching task, showing no deficit from week 2 after stroke. Long-term optical intrinsic signal imaging revealed functional reorganization of sensory cortical maps for both forelimb and hindlimb, with more diffuse sensory physiologic maps. There was a small but significant increase in motor neuron projections within the areas of functional cortical reorganization as assessed using the neuroanatomic tracer biotinylated dextran amine. These findings show that the sensorimotor cortex undergoes remapping of cortical functions and axonal sprouting within the same regions during recovery after stroke. This suggests a linked structural and physiologic plasticity underlying recovery. Combined long-term structural and functional mapping after stroke in the mouse is practical and provides a rich data set for mechanistic analysis of stroke recovery.
Asunto(s)
Encéfalo/fisiopatología , Encéfalo/efectos de la radiación , Modelos Animales de Enfermedad , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/fisiopatología , Trombosis/complicaciones , Animales , Encéfalo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Corteza Motora/patología , Corteza Motora/fisiopatología , Corteza Motora/efectos de la radiación , Accidente Cerebrovascular/patología , Trombosis/etiología , CaminataRESUMEN
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.