Environmental enrichment improves functional and neuropathological indices following stroke in young and aged rats.

PURPOSE: Aging is associated with a temporally dysregulated cellular response to ischemia as well as poor functional recovery. While environmental enrichment has been shown to improve the behavioral outcome of stroke in young animals, the effect of an enriched environment on behavioral and neuropathological recovery in aged animals is not known. METHODS: Focal cerebral ischemia was produced by electrocoagulation of the right middle cerebral artery in 3 month- and 20 month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests conducted over a period of 28 days following surgery. Brain tissue was then immunostained for proliferating astrocytes and the infarct and scar tissue volumes were measured. RESULTS: Aged rats showed more severe behavioral impairments and diminished functional recovery compared to young rats. Most infarcted animals had disturbances of sensorimotor function, with recovery beginning later, progressing more slowly, and reaching a lower functional endpoint in aged animals. However, the enriched environment significantly improved the rate and extent of recovery in aged animals. Correlation analysis revealed that the beneficial effect of the enriched environment on recovery, both in young and aged rats, correlated highly with a reduction in infarct size, in the number of proliferating astrocytes, and in the volume of the glial scar. CONCLUSIONS: These results suggest that temporally modulating astrocytic proliferation and the ensuing scar formation might be a fruitful approach to improving functional recovery after stroke in aged rats.

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery.

Following cerebral ischemia, perilesional astrocytes and activated microglia form a glial scar that hinders the genesis of new axons and blood vessels in the infarcted region. Since glial reactivity is chronically augmented in the normal aging brain, the authors hypothesized that postischemic gliosis would be temporally abnormal in aged rats compared to young rats. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14, and 28 days after surgery. Brain tissue was immunostained for microglia, astrocytes, oligodendrocytes, and endothelial cells. Behaviorally, aged rats were more severely impaired by stroke and showed diminished functional recovery compared with young rats. Histologically, a gradual activation of both microglia and astrocytes that peaked by days 14 to 28 with the formation of a glial scar was observed in young rats, whereas aged rats showed an accelerated astrocytic and microglial reaction that peaked during the first week after stroke. Oligodendrocytes were strongly activated at early stages of infarct development in all rats, but this activation persisted in aged rats. Therefore, the development of the glial scar was abnormally accelerated in aged rats and coincided with the stagnation of recovery in these animals. These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats leads to the premature formation of scar tissue that impedes functional recovery after stroke.

Accelerated accumulation of N- and C-terminal beta APP fragments and delayed recovery of microtubule-associated protein 1B expression following stroke in aged rats.

The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal betaAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal betaAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of betaAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal betaAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal betaAPP, together with the early incorporation of N-terminal betaAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.