Anatomical plasticity and functional recovery after lesions of the rodent corticospinal tract (CST) decrease postnatally in parallel with myelin formation. Myelin-associated neurite growth inhibitory proteins prevent regenerative fiber growth, but whether they also prevent reactive sprouting of unlesioned fibers is less clear. Here we show that after unilateral CST lesion in the adult rat brainstem, both intact and lesioned tracts show topographically appropriate sprouting after treatment with a monoclonal antibody that neutralizes these inhibitory proteins. Antibody-treated animals showed full recovery in motor and sensory tests, whereas untreated lesioned rats exhibited persistent severe deficits. Neutralization of myelin-associated neurite growth inhibitors thus restores in adults the structural plasticity and functional recovery normally found only at perinatal ages.

Stroke is a prevalent and devastating disorder, and no treatment is currently available to restore lost neuronal function after stroke occurs. One unique therapy that may improve functional recovery after stroke is blockade of the neurite inhibitory protein Nogo-A with the monoclonal antibody IN-1, through enhancement of neuroanatomical plasticity from uninjured areas of the central nervous system. In the present study, we combined IN-1 treatment with an ischemic lesion (permanent middle cerebral artery occlusion) to determine the effect of Nogo-A neutralization on cortical plasticity and functional recovery. We report here that, following ischemic stroke and treatment with IN-1, adult rats demonstrated functional recovery on a forelimb-reaching task and new cortico-efferent projections from the opposite, unlesioned hemisphere. These results support the efficacy of Nogo-A blockade as a treatment for ischemic stroke and implicate plasticity from the unlesioned hemisphere as a mechanism for recovery.

After a lesion of the mature CNS, structural plasticity and functional recovery are very limited, in contrast to the developing CNS. The postnatal decrease in plasticity is correlated in time with the formation of myelin. To investigate the possible role of an important myelin-associated neurite growth inhibitor (NI-250; IN-1 antigen), one pyramidal tract of adult Lewis rats was lesioned (pyramidotomy), and the rats were treated with the antibody IN-1, a control antibody, or no antibody. Functional recovery was studied from postoperative day 14 until day 42 using a food pellet reaching task, rope climbing, and a grid walk paradigm. The corticofugal projections to the red nucleus and basilar pontine nuclei were analyzed after survival times of 2 and 16 weeks.Treatment with the monoclonal antibody IN-1 resulted in almost complete restoration of skilled forelimb use, whereas all the control groups showed severe and chronic impairments. This functional recovery was paralleled by sprouting of the corticorubral and the corticopontine fibers across the midline, thus establishing a bilateral, anatomically specific projection. Key words: structural plasticity; rat reaching; motor function; motor system; nucleus ruber; pons; corticospinal tract; injuryFunctional and anatomical repair of the injured adult C NS is very limited (for review, see Donoghue, 1995Donoghue, , 1997Schwab and Bartholdi, 1996). In contrast, neuroanatomical plasticity, or the restructuring of neural connections in response to lesions of the CNS, is a well documented phenomenon in the neonatal age group. After unilateral neonatal pyramidotomy in rodents, corticoefferent fibers from the same side as the lesion were found to cross the midline to form new connections with medullary nuclei and to descend to spinal cord levels . Evidence that new neural connections occur after perinatal brain damage in children is supported by several clinical studies (Farmer et al., 1991;C arr et al., 1993;C ao et al., 1994). Structural neuroplasticity is thought to play an essential role in recovery of function, because animals sustaining C NS lesions at a young age are known to recover much better than those sustaining similar lesions at maturity (Kennard, 1936(Kennard, , 1938Whishaw and Kolb, 1988;Armand and Kably, 1993).The lack of large scale remodeling after adult C NS lesions is not well understood, but may be attributable to several reasons, including a limitation of adult neuronal growth potential, a lack or decrease in trophic factors or guidance molecules, or the presence of growth inhibitory molecules. In this regard, limits on the capacity for mature CNS plasticity may be similar to those recently identified for CNS regeneration, for which inhibitory signals present on CNS myelin have been shown to play a crucial role (for review, see Schwab and Bartholdi, 1996). These specific proteins (NI-35 and NI-250) induce long-lasting growth cone collapse and inhibition of neurite growth in vitro (Caroni and Schwab, 1988a;Bandtlow et al., 1990). Neutralization by the s...