Timothy Schallert - US grants

This project explores the possibility that there is a critical period shortly following brain damage during which the mechanisms of recovery of function are highly vulnerable to disruption. As a model of brain damage, rats will receive unilateral antero-medial cortex lesions, which yield a precisely-quantified sensory asymmetry that reliably recovers within about 8 days. Some of the animals will be exposed postoperatively to daily injections of diazepam. In recent work we found that a diazepam regimen beginning at 12 hrs after surgery and continuing for 3 postoperative weeks completely disrupts recovery from the lesion-induced sensory asymmetry for an indefinite period. Sedation or ataxia could be ruled out because the efficiency and speed (as opposed to the symmetry) of behavior were not impaired. As long as 10 weeks after discontinuation of the drug (the duration of our observations), no recovery occurred. We also found that if the initial injection of diazepam is administered after recovery occurs, only a very transient (or no) asymmetry appears, even if the dose of chronic diazepam is raised. We plan to confirm these observations, to extend the duration of testing to 12 months or more after the discontinuation of the drug regimen, and to determine whether other lesions and other symptoms of brain damage are affected in the same way. It seems especially noteworthy that there may be a critical stage of events after brain damage in which the recovery process is vulnerable to profound, perhaps permanent, disruption. The onset and length of this critical period, the minimum effective dose of diazepam, the effects of co-administration of benzodiazepine antagonists, and the effects of other agents on recovery (including GABA agonists or other drugs with anti-convulsant properties commonly used clinically to treat or prevent seizures following brain damage) are among the questions we plan to address.

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.

experimental designs; neuropsychological tests; behavior test; Parkinson's disease; diagnosis design /evaluation; biomedical facility; brain disorder diagnosis; technology /technique development; sensorimotor system; biomarker; early diagnosis; laboratory rat; laboratory mouse;