Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation

Abstract

Radiation therapy is a widely used treatment for brain tumors but it can cause delayed progressive cognitive decline and memory deficits. Previous studies suggested that this neurocognitive dysfunction might be linked to the impairment of hippocampal neurogenesis. However, little is known regarding how to reduce the cognitive impairment caused by radiation therapy. To investigate whether environmental enrichment (EE) promotes neurogenesis and cognitive function after irradiation, irradiated gerbils were housed in EE for 2 months and evaluated by neurobehavioral testing for learning and memory function, and immunohistochemical analysis for neurogenesis. Our results demonstrated that even relatively low doses (5-10 Gy) of irradiation could acutely abolish precursor cell proliferation in the dentate gyrus by more than 90%. This reduction in precursor proliferation was persistent and led to a significant decline in the granule cell population 9 months later. EE housing enhanced the number of newborn neurons and increased residual neurogenesis. EE also significantly increased the total number of immature neurons in the dentate gyrus. Furthermore, irradiated animals after EE housing showed a significant improvement in spatial learning and memory during the water-maze test and in rotorod motor learning over a 5-day training paradigm. In conclusion, EE has a positive impact on hippocampal neurogenesis and functional recovery in irradiated adult gerbils. Our data suggest that there is still a considerable amount of plasticity remaining in the hippocampal progenitor cells in adult animals after radiation injury, which can become a target of therapeutic intervention for radiation-induced cognitive dysfunction.

Alterations in the rat forebrain apoptosis following exposure to ionizing radiation

“…As mentioned above, the experimental studies confirmed that cellular response to fractionated and single dose of irradiation is different; the single dose-response is mostly rapid, within hours or weeks of treatment, whereas the fractionated response is delayed and persisted for months after exposure (Tada et al 1999;Mizumatsu et al 2003;Rola et al 2004;Fan et al 2007). Our experimental model may partially clarify different cellular response to irradiation.…”

“…It has been established that after single irradiation with various radiation doses (2-10 Gy) the numbers of apoptotic cells in hippocampal dentate gyrus dramatically increased 3-6 h after exposure and in the following 6-12 h reached the maximum. However, the extent of apoptosis later decreased, remained unchanged for 1-9 months after initial exposure (Peissner et al 1999;Tada et al 1999;Mizumatsu et al 2003;Raber et al 2004;Rola et al 2004;Fan et al 2007). Simultaneously, the numbers of proliferating cells decreased in greater extent in the following weeks (by 60-79% after three weeks) and months after irradiation (80-90% after three months) (Peissner et al 1999;Kee et al 2002;Mizumatsu et al 2003;Raber et al 2004;Winocur et al 2006).…”

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

“…WBI-induced deficits in hippocampal function have been associated with decreased neurogenesis (11,12,43), which potentially could arise from changes in cell proliferation, commitment, and/or survival. We examined both the density of proliferating, Ki67 + cells in the SGZ of the rodent hippocampus and, more specifically, the density of immature, DCX + neurons.…”

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

“…When testing spatial memory ability, deficits were described in some studies (Snyder et al 2005;Fan et al 2007;Dupret et al 2008;FarioliVecchioli et al 2008;Imayoshi et al 2008;Garthe et al 2009;Lemaire et al 2012), but not in others (Shors et al 2002;Madsen et al 2003;Raber et al 2004;Meshi et al 2006;Saxe et al 2006;Winocur et al 2006;Wojtowicz et al 2008). From our own study, based on a model that consisted in selectively ablating adult hippocampal neurogenesis by overexpressing the proapoptotic protein Bax in neuronal precursors on administration of doxycycline, we concluded that adult-born neurons are required for an allocentric (and not egocentric) strategy and for the flexible use of the acquired information (Dupret et al 2008).…”