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.

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...

Smaller spinal cord injuries often allow some degree of spontaneous behavioral improvements because of structural rearrangements within different descending fiber tracts or intraspinal circuits. In this study, we investigate whether rehabilitative training of the forelimb (forced limb use) influences behavioral recovery and plastic events after injury to a defined spinal tract, the corticospinal tract (CST). Female adult Lewis rats received a unilateral CST injury at the brainstem level. Use of the contralateral impaired forelimb was either restricted, by a cast, or forced, by casting the unimpaired forelimb immediately after injury for either 1 or 3 weeks. Forced use of the impaired forelimb was followed by full behavioral recovery on the irregular horizontal ladder, whereas animals that could not use their affected side remained impaired. BDA (biotinylated dextran amine) labeling of the intact CST showed lesion-induced growth across the midline where CST collaterals increased their innervation density and extended fibers toward the ventral and the dorsal horn in response to forced limb use. Gene chip analysis of the denervated ventral horn revealed changes in particular for growth factors, adhesion and guidance molecules, as well as components of synapse formation suggesting an important role for these factors in activity-dependent intraspinal reorganization after unilateral CST injury.

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Fine finger and hand movements in humans, monkeys, and rats are under the direct control of the corticospinal tract (CST). CST lesions lead to severe, long-term deficits of precision movements. We transected completely both CSTs in adult rats and treated the animals for 2 weeks with an antibody that neutralized the central nervous system neurite growth inhibitory protein Nogo-A (mAb IN-1). Anatomical studies of the rubrospinal tracts showed that the number of collaterals innervating the cervical spinal cord doubled in the mAb IN-1-but not in the control antibody-treated animals. Precision movements of the forelimb and fingers were severely impaired in the controls, but almost completely recovered in the mAb IN-1-treated rats. Low threshold microstimulation of the motor cortex induced a rapid forelimb electromyography response that was mediated by the red nucleus in the mAb IN-1 animals but not in the controls. These findings demonstrate an unexpectedly high capacity of the adult central nervous system motor system to sprout and reorganize in a targeted and functionally meaningful way. In the case of incomplete injuries of the central nervous system (CNS), spontaneous recovery processes can be observed in humans (1, 2) as well as in different animal models (3, 4). However, in the adult mammalian CNS, this recovery remains largely incomplete. This inability of the CNS to fully recover from an incomplete lesion appears gradually during development at a time coincident with the appearance of myelin (5, 6). Several myelin-associated proteins and proteoglycans show inhibitory properties to neurite growth; among them are Nogo-A͞NI-250 (7, 8), myelin-associated glycoprotein (9, 10), tenascin-R (J1 160͞180; janusin) (11), and sulfated proteoglycans (12, 13). The inhibitory effect of these proteins can be overcome in different ways: e.g., by a direct masking of the inhibitory substrate. Neutralization of Nogo-A by mAb IN-1 leads to a large decrease in the inhibitory activity of oligodendrocytes and myelin in vitro (14, 15) as well as in vivo, resulting in long-distance regeneration of lesioned spinal cord (16).Recent experiments have also pointed to a role of Nogo-A in inhibiting the plastic reorganization of the lesioned adult CNS. Infusion of the Nogo-A-neutralizing mAb IN-1 into the cerebrospinal fluid of unilaterally pyramidotomized rats induced corticorubral and corticopontine fibers to sprout across the midline and establish bilateral, anatomically specific projections (17). At spinal cord level, the unlesioned corticospinal tract (CST) sprouted into the contralateral denervated spinal cord (18). These anatomical changes were associated with an almost complete functional recovery in different behavioral tasks. These studies, however, focused on the CST, i.e., the lesioned system, and raised the interesting question of the limits of such repair processes. Thus, after complete transection of the CST, other descending motor tracts may also undergo reorganization and thereby contribute to the functional recovery. The ru...