P.2.017 Size does matter: environmental enrichment rescues cognitive and synaptic deficits following olfactory bulbectomy in mice

Abstract

Environmental enrichment (EE) has been shown to improve cognitive performance and enhance synaptic plasticity in various neurodegenerative animal models. Antidepressant efficacy of environmental enrichment, however, remains unclear. To investigate the effect of EE on cognitive and depressive symptoms, and on structural plasticity, we used olfactory bulbectomy (OBX) in mice. OBX is primarily known as a model for predicting antidepressant activity, since its hyperactivity is normalized by chronic antidepressant administration; however, the ablation of olfactory bulbs in a rodent also results in progressive neurodegeneration, behavioral disturbances, and cognitive impairments − symptoms reminiscent of those of Alzheimer’s and depressed patients [1]. Four weeks after the bulbectomy, mice were exposed to EE, consisting of tunnel, toys and nesting material, for 4 weeks. The animals’ locomotor activity was observed, using the open-field paradigm and their cognitive ability was measured throughout the study using passive avoidance (assessing fear memory) and T-maze (assessing spatial memory). Compared to sham-operated controls, OBX mice showed significantly increased locomotor activity (F(3,20) = 4.38, p< 0.05), impaired shortand long-term fear memory in the passive avoidance test, and hindered spatial memory in the T-maze. EE-treated OBX mice demonstrated significantly increased fear (both short and long-term) ((H(4) = 14.11, p< 0.01 and (H(4) = 7.15, p< 0.05, respectively) and spatial memory when compared to the non-enriched bulbectomized mice (H(4) = 8.12, p< 0.05). There was no antidepressant effect of EE on the OBX mice. The brain weights of the EE-OBX mice were significantly larger in comparison to the standard housed bulbectomized mice (F(3,20) = 5.73, p< 0.05) and coincided with improved cognitive functioning. Furthermore, preliminary data demonstrated EE treatment reversed the bulbectomy-induced reduction in dendritic spine density in hippocampus (F(3,8) = 18.86, p< 0.01) without affecting the OBX-mediated decrease in the number of neurons. Thus, despite a substantial neuronal loss, EE induced a refinement of the synaptic network, which may underlie the improved cognitive functioning in the OBX mice following EE, suggesting that the beneficial effects of enrichment on memory stems mainly from enhanced synaptic plasticity rather than impediment of general brain atrophy. Interestingly, in rats, bulbectomy also results in a loss of dendritic spines in hippocampus [2], and although EE recovers the reduced hippocampal weights in the OBX rat, it is unable to alleviate OBX-induced cognitive deficits, yet it exerts antidepressant effects in rats [3]. The lack of EE efficacy on the OBX mediated cognitive impairments in the rat compared to the mouse, may be due to differences in the ability of these species to rewire their brain after severe neurodegeneration. Why EE induced antidepressant effect in the OBX rat but not in mice remains to be elucidated. In addition to possible implications for the development of novel therapeutic agents that enhance the beneficial effects of EE, our findings raise an important question of translational value in animal research: is the mouse or the rat a better animal model for human neurodegenerative disorders and for testing therapeutic interventions for their efficacy? It appears that, after all, size does matter both at the level of the animal strain, brain size and dendritic spines.