Regular articleEnvironmental enrichment restores neurogenesis and rapid acquisition in aged rats
Introduction
Altered hippocampal function likely contributes to age-related changes in cognitive ability because hippocampus-dependent tasks are sensitive to age-related cognitive decline (Foster, 1999). Decades ago, the standard Morris water maze task revealed impaired performances among some senescent rats (Gage et al., 1984, Rapp et al., 1987). More recent behavioral assessments have sought to increase task sensitivity to age-related cognitive decline (Kennard and Woodruff-Pak, 2011), so that the deficits and their underlying mechanisms can be better characterized and potentially manipulated. Here we employ a rapid water maze task sensitive to age-related cognitive decline to test whether daily exposure to an enriched environment can reverse the effects of age on hippocampal function concomitantly with hippocampal neurogenesis.
Neurogenesis is a striking form of neural plasticity that persists throughout life in the hippocampus and olfactory bulbs of all mammals investigated, including humans (Altman and Das, 1965, Cameron et al., 1993, Eriksson et al., 1998). Although the precise role that new neurons play in hippocampal integrity is debated, new neuron number in young animals generally correlates with their performance measures in hippocampus-dependent tasks (Deng et al., 2010; but see Epp and Galea, 2009). Manipulations that attenuate neurogenesis chronically associate with impaired performance (Madsen et al., 2003, Raber et al., 2004, Saxe et al., 2006, Shors et al., 2002, Snyder et al., 2005, Winocur et al., 2006) while those that potentiate neurogenesis associate with better performance (Ormerod et al., 2004, van Praag et al., 2005, Dalla et al., 2009). Postmortem signs of hippocampal neurogenesis in human patients who exhibited profound memory impairments are scarce (Coras et al., 2010, Correa et al., 2004, Crossen et al., 1994, Monje et al., 2007, Roman and Sperduto, 1995, Siffert and Allen, 2000).
Hippocampal neurogenesis declines with age in rodents primarily because neural progenitor cells (NPCs) become increasingly quiescent and NPCs that do divide may be less likely to produce surviving neuronal progeny (Cameron and McKay, 1999, Hattiangady and Shetty, 2008, Kempermann et al., 1997, Kuhn et al., 1996, Lichtenwalner et al., 2001, Nacher et al., 2003). While several studies have related new neuron number and cognitive measures in aged rats (Drapeau et al., 2003, Drapeau et al., 2007, Driscoll et al., 2006, Lemaire et al., 2000), dogs (Siwak-Tapp et al., 2007), and nonhuman primates (Aizawa et al., 2009), the strength of this relationship among aged rats tested in the water maze varies. For example, new neuron number appears unrelated to the performance of aged rats in water maze tasks that distribute training across 8–10 days (Bizon and Gallagher, 2003, Bizon et al., 2004, Merrill et al., 2003) but related in protocols that mass training across 2–3 days (Drapeau et al., 2003, Driscoll et al., 2006). Moreover, new neuron survival in the hippocampi of aged rats is enhanced by their participation in early but not later trials of the distributed water maze protocol (Drapeau et al., 2007). These results suggest that the strength of the relationship between neurogenesis and water maze performance in aged rats may depend upon the speed of learning demanded by the task.
In aged rodents, daily exposure to environmental enrichment primarily stimulates neurogenesis by increasing the probability that new neurons survive to maturity (Kempermann et al., 1997, Kempermann et al., 1998, Kempermann et al., 2002, Leal-Galicia et al., 2008, Segovia et al., 2006) and improves the rapid acquisition of spatial information in a condensed water maze task (Kumar et al., 2012). Here we tested the hypothesis that daily exposure to environmental enrichment would reverse age-related impairments in rats' abilities to rapidly acquire a spatial search strategy concomitantly with ongoing rates of neurogenesis.
Section snippets
Subjects
Young (5–8 months old) and aged (20–22 months old) sexually naive male F344 rats obtained from the National Institute of Aging colony at Harlan Sprague Dawley (Indianapolis, IN, USA) were treated in accordance with University of Florida and federal policies regarding the ethical use of animals for experimentation. Rats exhibiting signs of aggression (bites and scratches) or age-related health problems (poor grooming, hunching, excessive porphyrin secretion, weight loss, and tumors) were
Enrichment enhances spatial learning in aged rats
Because measures of path length and latency over trials were correlated positively (r(29) = 0.82; p < 0.0001), we report only path lengths to avoid redundancy. An ANOVA exploring the effects of age (young vs. aged), training block (blocks 1–5), and differential experience (individually housed vs. enriched) on path length (Fig. 2A) revealed significant effects of age (F(1,26) = 15.65; p < 0.001) and training block (F(4,104) = 5.85; p < 0.001) and significant age × environment (F(1,26) = 5.57; p
Discussion
In the current study, we confirmed that hippocampal neurogenesis and spatial learning are compromised by age and that exposure to environmental enrichment potentiates neurogenesis, regardless of age. We found that environmental enrichment improves the performance of aged but not young rats on a water maze task in which the hidden platform location is learned in a single day. We propose that this task requires the ability to rapidly acquire and flexibly use spatial information that appears
Disclosure statement
The authors declare no potential conflicts of interest.
All rats used as subjects in this study were treated in accordance with the policies set forth by the University of Florida Institutional Animal Care and Use Committee and the National Institutes of Health and are in accordance with the guidelines established by the U.S. Public Health Service Policy on the Humane Care and Use of Laboratory Animals. Every effort was made to minimize the number of animals used and their suffering.
Acknowledgements
The authors thank Melissa Ferguson, Prasanna Durairaj, Jose Herrera, and Vijay Parekh for technical assistance and Dr. Gerry Shaw for his gift of chicken anti-GFAP. The study was supported by grants from the National Institutes of Health (AG014979, AG036800, and AG037984) to T.C.F., the McKnight Brain Research Foundation to T.C.F. and B.K.O., and the Broad Foundation for Biomedical Research to B.K.O. and a National Science Foundation Graduate Research Fellowship to R.B.S.
References (77)
- et al.
Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat
Neuroscience
(1993) - et al.
The aging hippocampus: a multi-level analysis in the rat
Neuroscience
(2006) - et al.
Hippocampus-dependent strategy choice predicts low levels of cell proliferation in the dentate gyrus
Neurobiol. Learn. Mem
(2009) Involvement of hippocampal synaptic plasticity in age-related memory decline
Brain Res. Brain Res. Rev
(1999)Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2 channels in senescent synaptic plasticity
Prog. Neurobiol
(2012)- et al.
Susceptibility to induction of long-term depression is associated with impaired memory in aged Fischer 344 rats
Neurobiol. Learn. Mem
(2007) - et al.
Interaction of age and chronic estradiol replacement on memory and markers of brain aging
Neurobiol. Aging
(2003) - et al.
Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice
Neurobiol. Aging
(2003) - et al.
Spatial learning and motor deficits in aged rats
Neurobiol. Aging
(1984) - et al.
Spatial working memory and hippocampal size across pregnancy in rats
Horm. Behav
(2000)