Environmental enrichment induces neuroplastic changes in middle age female BalbC mice and increases the hippocampal levels of BDNF, p-Akt and p-MAPK1/2
Introduction
Hippocampus, a brain region that belongs to the limbic system, is involved in learning and memory (Moser et al., 1995, Bannerman et al., 2004, Steffenach et al., 2005, Draganski et al., 2006, Garthe et al., 2009). During aging, it exhibits alterations of dendritic spines and neurogenesis in the dentate gyrus (Kuhn et al., 1996, Calhoun et al., 1998, Cameron and McKay, 1999, Foster, 1999, Kempermann et al., 2002, Kempermann et al., 2002, Bondolfi et al., 2004, Heine et al., 2004, Lawrenson et al., 2004, Kronenberg et al., 2006, Klempin and Kempermann, 2007, Couillard-Despres et al., 2009). Interestingly, during the age-related cognitive decline, dendritic spines change their structure and lose their synaptic function (Calhoun et al., 1998, Phinney et al., 1999, Hof and Morrison, 2004, Govoni et al., 2010). Moreover, in some pathological conditions such as schizophrenia, bipolar disorder, and depression, dendritic spines change their shape and show a decrease in size and density (Rudelli et al., 1985, Comery et al., 1997, Glantz and Lewis, 2000, Ramakers, 2002, Kolomeets et al., 2005, Carlson et al., 2011, Penzes et al., 2011).
Another form of brain plasticity affected by external factors or during aging is hippocampal neurogenesis (Kuhn et al., 1996, Kempermann et al., 2002, Bondolfi et al., 2004, Heine et al., 2004, Couillard-Despres et al., 2009). The changes observed in this type of plasticity have been related to the differences in the content of brain- and systemic-milieu found along aging (Villeda et al., 2011), but also to alterations in the neural stem cell population, at least in the hippocampus (Encinas and Sierra, 2012).
In order to delay or revert the effects of aging on neuroplasticity and hippocampal neurogenesis, several paradigms have been used such as the exposure to a variety of social and physical stimuli called environmental enrichment (ENR) (Ickes et al., 2000, van Praag et al., 2000, Kempermann et al., 2002, Brown et al., 2003, Schneider et al., 2006, Fabel et al., 2009, Goshen et al., 2009, Mirochnic et al., 2009, Ehninger et al., 2011). The benefits of this type of environment have been demonstrated in different mouse strains (Kempermann et al., 1997, Brown et al., 2003, Holmes et al., 2004, Mirochnic et al., 2009, Tanti et al., 2012). ENR promotes neurogenesis in the hippocampus of young and senescent C57Bl6 mice (Kempermann et al., 1998). Also, it promotes differential regulation of neurogenesis through the dorsal–ventral dentate gyrus in young male BalbC mice (Tanti et al., 2012). Interestingly, young mice of this strain are widely used for studies related to chronic stress (Tanti et al., 2012). Recently, we observed a decline of the neurogenic process in BalbC mice at the age of 5–8 months (Ramirez-Rodriguez et al., 2012). However, the impact of ENR on the neuroplasticity of middle age female BalbC mice has not been explored.
Mediators of neuroplasticity have been described; among them is the brain-derived neurotrophic factor (BDNF) (Barde, 1994, Vaynman et al., 2004, Dijkhuizen and Ghosh, 2005, Hattiangady et al., 2005, Sairanen et al., 2005). This neurotrophin is involved in dendritic spine formation, survival of hippocampal newborn neurons, and shows a relevant participation in memory formation (Barde, 1994, Barnabe-Heider and Miller, 2003, Dijkhuizen and Ghosh, 2005, Babu et al., 2009, Minichiello, 2009).
Considering that dendritic spines and hippocampal neurogenesis are altered during aging and that a significant decline of the neurogenic process occurs around the age of 5–8 months in BalbC mice, we hypothesized that ENR may induce neuroplastic changes related to the increase of hippocampal BDNF levels concomitant to the modifications in dendritic spines density and in the different events of the neurogenic process along the dorsal–ventral regions in the dentate gyrus. Thus, we assessed middle age-dependent changes in dendritic spines density and the effects of ENR on middle age hippocampal neurogenesis in subpopulations of cells involved in this process in female BalbC mice.
Section snippets
Animals
Thirty-two female BalbC mice were obtained from Harlan (México, D.F. México). They were housed in standard laboratory cages under 12-h light/12-h dark cycles at a temperature of 23 ± 1 °C in the animal facilities of the National Institute of Psychiatry “Ramón de la Fuente Muñiz”. The light/dark cycle corresponded to the timing of lights on (Zeitgeber time 0; ZT0) at 0700 h and to the timing of lights off (ZT 12; ZT12) at 1900 h. Mice had access to food and water ad libitum and were left to
ENR increases dentritic spines in the dentate gyrus during middle age female BalbC mice
Neuroplastic changes were considered as the number of dendritic spines along the dendrites of granular cells in the dentate gyrus of middle age BalbC mice. ENR exposed mice showed higher number (∼21%) of dendritic spines than the NH mice group (NH = 8.5 ± 0.43 versus ENR = 10.2 ± 0.49; p = 0.024; Fig. 2a). Based on the shape of dendritic spines, their distribution indicated that ENR significantly changed the proportion of mushroom-shape spines (NH = 16.54 ± 3.44% versus ENR = 28.68 ± 2.75%; p < 0.001; Fig. 2b)
Discussion
In the present study, we showed that middle age female BalbC mice exposed to ENR presented neuroplastic changes at the level of dendritic spines of granular cells in the dentate gyrus. Also, ENR housing conditions produced changes in the cellular populations of the hippocampal neurogenic process. In addition, ENR increased the hippocampal levels of BDNF, phospho-Akt-, and phospho-MAPK-proteins, suggesting their involvement in the beneficial effects of ENR. Interestingly, the effects of ENR on
Contributors
All authors participate in the article preparation and approved the final version. GRR, MAOF, NMVR, MTP, LOL, AGS, EEC collaborate in collection and analysis of data. GRR designed the study, wrote the manuscript and interpreted the data. GRR also prepared the final figures with the help of the other co-authors.
Conflict of interest
The authors declare no potential conflict of interests.
Acknowledgements
We wish to thank Prof. Gerd Kempermann for his comments on the present work (Center for Regenerative Therapies of Dresden, CRTD). This work was supported by CONACYT (CB-SEP 101316 and 119182). MAOF was a fellowship-recipient of CONACYT (Grant CB101316), whereas MTP received a fellowship of the Ministry of Health (SSA) through the Program for Initiation in Scientific Research (PROBEI). NMVR was supported by a CONACYT-BMBF cooperation project (147377) to perform the confocal analysis during her
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