30 April 2006. Happy mice, raised in cages filled with toys and exercise wheels, are better learners and show less anxiety than their less privileged littermates housed in standard bare cage conditions. Happy mice also display more neurogenesis in their hippocampi than standard-caged mice, because exercise and environmental stimulation seems to crank up the birth of new neurons in the subgranular zone of the dentate gyrus (see ARF related news story). These new neurons have been assumed to contribute to environmental enrichment effects. But do they? A paper in today’s Nature Neuroscience online suggests that hippocampal neurogenesis is not required for mice to display better spatial learning and lower anxiety in an enriched environment. The results, from Rene Hen and colleagues at Columbia University in New York, stand in direct contradiction to a study published last year by French researchers, which found that turning off neurogenesis blocked environment-induced memory enhancement in rats (Bruel-Jungerman et al., 2005 ).
While differences between studies, or the existence of different pathways to learning, might account for opposite outcomes, the new evidence means the jury must re-evaluate the role of adult neurogenesis in modifying learning and behavior. The verdict is of interest to Alzheimer researchers, because environmental enrichment has been shown to decrease both amyloid pathology and cognitive defects in mouse models of AD (see ARF related news story and Jankowsky et al., 2005).
To investigate the role of neurogenesis in environment, joint first authors Dar Meshi, Michael Drew, and their colleagues used targeted radiation to kill off neuronal progenitors in the hippocampus before upgrading their mice to deluxe accommodations. The researchers showed that bromodeoxyuridine and doublecortin—neurogenesis markers that otherwise appear in the hippocampus after environmental enrichment—were absent from irradiated animals.
Six weeks later, the irradiated and control mice were put through several behavioral tests, including those for anxiety, habituation to a new environment, and for spatial learning in the Morris water maze. In each case, environmental enrichment improved the animals’ performance, and that improvement was unaffected by previous irradiation. From this the authors concluded that, at least for these tasks, the effects of environment do not require adult neurogenesis.
The findings contrast those of Elodie Bruel-Jungerman and colleagues, who reported that ablating neurogenesis by injecting the anti-mitotic drug methylazoxymethanol acetate (MAM) totally blocked the improvement in long-term memory that followed environmental enrichment in rats. The studies use different species, and different ways of knocking out neurogenesis, leading Meshi et al. to speculate that the systemic administration of MAM versus localized irradiation may be one explanation for the discrepancies. The studies also tested the animals on different tasks, raising the possibility that some behavioral changes require neurogenesis while others do not. In support of this, the Cornell group previously showed that hippocampal irradiation blocks the ability of antidepressant drugs to reduce the anxiety response in mice (Santarelli et al., 2003). For the neurogenesis-independent effects, increased levels of growth factors, dendritic branching, or synaptogenesis are all potential explanations for the environmental enrichment observed in irradiated mice.—Pat McCaffrey.
Meshi D, Drew MR, Saxe m, Ansorge MS, David D, Santarelli L, Malapani C, Moore H, Hen R. Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nature Neuroscience. 30 April 2006. Advanced online publication. Abstract