Ž . Brain Research 783 1998 286–292 Research report Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period J. Leigh Humm ) , Dorothy A. Kozlowski, Debra C. James, Jeffrey E. Gotts, Timothy Schallert Department of Psychology and Institute for Neuroscience, UniÕersity of Texas at Austin, Austin, TX 78712, USA Accepted 4 November 1997 Abstract For a period of time after unilateral brain injury, surviving neural tissue surrounding the lesion may be vulnerable to extremely high Ž . behavioral demand. Previously, we found that lesions of the forelimb representation area of the sensorimotor cortex FL-SMC in rats increase in size substantially when the intact forelimb is immobilized with a plaster of paris cast during the first 15 days after surgery, which forces overuse of the impaired forelimb. The present study was designed to determine whether the adult brain is more vulnerable to forced overuse of the impaired forelimb during the first 7 days post-lesion than during the second 7 days post-lesion. Using behavioral tests of forelimb use and stereological analysis of remaining tissue volume 40 days after FL-SMC lesions, we found that forced overuse of the impaired forelimb during the first 7 days after the initial damage caused expansion of neural injury and greatly interfered with restoration of function. In contrast, forced overuse of the impaired forelimb during the second 7 days had no significant effect on lesion size but nevertheless interfered with restoration of function. Thus, surviving neural tissue in the damaged hemisphere and recovery of function appear to be vulnerable to prolonged forced overuse of the impaired forelimb throughout the first 15 days, but tissue loss was detectable only when the animal was forced to use the impaired forelimb during the first 7 days after injury. q 1998 Elsevier Science B.V. Keywords: Brain injury; Sensorimotor cortex; Sensitive period; Use-dependency; Recovery of function; Neuroplasticity; Rehabilitation; Glutamate 1. Introduction Unilateral injury to the motor cortex of the rat impairs function of the contralateral limb. Subsequent recovery is observed, yet lasting impairment may remain ww x w xx 8,9,11,20,32–34,40 , for reviews, see Refs. 20,32 . Sim- ilarly, unilateral damage to the forelimb representation area Ž . of the rat sensorimotor cortex FL-SMC causes impair- ment in the capacity to use the contralateral forelimb, causing animals to rely preferentially on the non-impaired forelimb for postural support and exploratory movements w x 1,14,15,22,31 . This impairment, initially severe, is fol- w x lowed by partial restoration of function 22 . During the recovery process, both the impaired and non-impaired forelimbs contribute to overall improvement in motor be- w x havior 30 . Hyper-reliance on the non-impaired limb is associated with morphological changes in layer V pyrami- dal neurons of the homotopic intact FL-SMC, including ) Corresponding author. Fax: q1-512-471-4336; E-mail: humm@mail.utexas.edu dendritic arborization and subsequent pruning of arbors w x w x 14,21 , as well as increases in dendritic spine density 22 . Electron microscopic analysis indicates that these dendritic w x changes are associated with synapse formation 16 . Sev- eral billion more synapses are formed on dendrites of layer V pyramidal neurons within the FL-SMC, and many of these are multiple axodendritic synapses, in which an axon w x terminal innervates more than one dendritic spine 16,17 , and which are the type that are formed during the neuro- Ž . plasticity of long term potentiation LTP and exposure to w x an enriched environment 10,18 . It is possible that den- dritic arborization and synaptogenesis are use-dependent. If rats are prevented from using their non-impaired fore- limb by immobilizing it in a one-sleeved plaster of paris cast, dendritic overgrowth in the intact FL-SMC is blocked w x 15,22 . Thus, use of, and reliance upon the non-impaired limb is necessary for the observed dendritic events. Ž . Deficits in use of the contralateral impaired forelimb w x can be evaluated by a variety of limb use tasks 13–15,22 . FL-SMC lesioned animals show recovery of function on several of these tests by the fifth post-operative week, but 0006-8993r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.