Elsevier

Neuroscience

Volume 93, Issue 2, July 1999, Pages 527-535
Neuroscience

Environmental enrichment alters nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression after middle cerebral artery occlusion in rats

https://doi.org/10.1016/S0306-4522(99)00183-9Get rights and content

Abstract

Housing rats in an enriched environment after focal brain ischemia improves functional outcome without changes in infarct volume, suggesting neuroplastic changes outside the lesion. In this study, permanent occlusion of the middle cerebral artery was followed by housing in an enriched or a standard environment. Nerve growth factor-induced gene A and glucocorticoid receptor messenger RNA expression were determined by in situ hybridization two to 30 days after middle cerebral artery occlusion. Stroke induced a decrease in nerve growth factor-induced gene A messenger RNA expression in cortical areas outside the ischemic lesion and in the CA1 subregion of the hippocampus two to three days after ischemia. This decrease was more prolonged with environmental enrichment, lasting until 20 days. However, 30 days after focal cerebral ischemia, environmental enrichment increased nerve growth factor-induced gene A expression compared to standard housing. A reduction of hippocampal glucocorticoid receptor (type II) messenger RNA two to 12 days after stroke in standard housed rats was restored by environmental enrichment.

These data suggest that improved functional outcome induced by environmental enrichment after middle cerebral artery occlusion is associated with dynamically altered expression of nerve growth factor-induced gene A messenger RNA in brain regions outside the ischemic lesion, and sustained levels of hippocampal glucocorticoid receptor messenger RNA expression.

Section snippets

Surgery and housing

The experimental protocol was approved by the Ethics Committee for Animal Research at Lund University. All efforts were made to minimize animal discomfort and to reduce the number of animals used. No alternative in vitro techniques were considered adequate for these studies. The data in this work were collected from two separate experiments: (i) two to 12 days after middle cerebral artery (MCA) occlusion and (ii) 20–30 days after brain ischemia. The two experiments were carried out identically:

Infarct volume

The cortical infarct volume did not differ significantly between rats housed in the standard and the enriched environments at any time-point after MCA occlusion (Table 1).

Nerve growth factor-induced gene A messenger RNA expression in the cerebral cortex

NGFI-A was expressed throughout the cerebral cortex outside the infarct, with the highest expression in layers IV and VI (Fig. 1). Two and three days after MCA occlusion, NGFI-A mRNA expression in cortical regions outside the lesion was decreased (44–91%) in rats from both environmental conditions (Fig. 1, Fig. 2). This

Discussion

The major findings of this study are: (i) dynamic changes in NGFI-A mRNA expression two to 30 days after MCA occlusion in brain regions remote from the ischemic lesion, effects profoundly influenced by environmental enrichment; (ii) a decrease in hippocampal GR mRNA levels in standard housed rats that could be counteracted by environmental enrichment. Importantly, these effects were unrelated to cortical infarction volumes, which did not differ significantly between groups.

Two and three days

Conclusion

We have found that NGFI-A and GR mRNA expression after focal cerebral ischemia is significantly influenced by environmental enrichment in spontaneously hypertensive rats. Altered expression of specific transcription factors, in brain areas remote from the primary lesions, may be involved in the improved outcome induced by environmental enrichment after focal cerebral ischemia.

Acknowledgments

We thank Prof. J. Milbrandt, Prof. R. Miesfeld and Prof. J. Arriza for kindly providing us with the NGFI-A, GR and MR cDNA clones, respectively. We also thank Mikaela Háková and Else-Britt Lundström for excellent technical assistance. This study was supported by grants from the Swedish Medical Research Council [projects 14X-12237, 19P-11769 (T.O.) and 14X-4968 (B.B.J.)], Västerbotten County Council, the Söderberg Foundation, the Swedish Society for Medicine, Ostermans Research Funds, the Magnus

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