We will continue to investigate the disruptive effects of diazepam and related drugs on recovery of sensorimotor function after unilateral damage to anteromedial cortical regions. Moreover, experiments carried out during the current funding period have led to an additional focus on novel anatomical events that appear to have an important role in restoration of function. The general strategy outlined in this proposal is to manipulate the recovery process using disruptive or facilitating treatments, to define sensitive periods during which the treatments are effective, to analyze behavior in detail, and to describe relevant structural changes in subcortical and cortical regions of the ipsilateral and contralateral hemisphere. We very recently found that in response to injury of the sensorimotor cortex a large increase in thickness occurred exclusively in the homotopic area of the contralateral hemisphere, followed by a reduction in thickness but not a complete return to baseline. Maximum increases in thickness corresponded in time with excessive use of the unimpaired limb in home-cage postural-motor behavior, especially movements having weight-bearing/shifting consequences. This raises the possibility that the morphological changes may be related to behavioral strategies adopted by the animals to compensate for lesion-induced impairments in the contralateral forelimb. In a followup experiment, we found that in the region of increased thickness there was a time-dependent dramatic growth of layer V neuronal dendrites, followed by partial pruning. Pruning may represent an adjustment to the recovery of more symmetrical limb use or may correspond to improved cross-midline coordination of both forelimbs. We plan to characterize further the novel biphasic (growth-pruning) dendritic sequence and its potential behavioral significance, and to manipulate each phase independently by drug and behavioral interventions in an effort to establish how it might be involved in restoration of function after brain damage. For example, one sleeve casts or open-sleeve (control) casts will be used to permit use of the ipsilateral, contralateral, or both forelimbs during home-cage behaviors in rats with unilateral sensorimotor cortex lesions or sham operations. Preliminary results suggest that the dramatic arborization in the intact cortex occurs only after brain injury combined with limb use experience. The long-term goal is to better understand plasticity after brain damage while assessing time-dependent influences of pharmacological and behavioral interventions.
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