Introduction
The functional role of adult neurogenesis in the hippocampal dentate gyrus remains controversial. Dentate gyrus as a whole is thought to be strongly related to cognitive decline in old age but the exact contribution of neurogenesis vs. other forms of plasticity is uncertain (Small et al., 2004; Burke and Barnes, 2006). There is convincing evidence that experimentally-induced decline in neurogenesis produces severe impairments in performance on some but not all memory tasks (Deng et al., 2010). Studies attempting to correlate natural decline of neurogenesis and memory with age have been controversial. In one such study, a sub-population of old (20 months) rats showed cognitive impairment in correlation with the number of adult-produced new neurons (Drapeau et al., 2003). Interestingly, old unimpaired rats performed nearly as well as the young (2 months) rats even though the former had only a fraction of the new neurons in comparison to the young. Other studies failed to demonstrate a relationship between neurogenesis and memory performance (Bizon and Gallagher, 2003; Merrill et al., 2003). Methodological reasons may account for these discrepancies between studies. For example, it would appear that spatial memory tasks may not be optimal for testing the influence of neurogenesis since many studies failed to demonstrate a clear cause-effect relationship in such tasks (Leuner et al., 2006) while others produced varied effects on either short-term or long-term memory (Dupret et al., 2008; Imayoshi et al., 2008; Jessberger et al., 2009). Species differences should also be considered since neurogenesis varies in its rate and physiological significance among species (Snyder et al., 2009a; Johnson et al., 2010).
Emerging evidence indicates that memory tasks involving detection and processing of context are most sensitive to changes in neurogenesis and should be good indicators of deteriorating memory performance at old age (Wojtowicz et al., 2008). Thus, a working hypothesis suggests that aging animals can adapt to low levels of neurogenesis, but fundamental dependence of memory on new neurons persists in old age. It is therefore of interest to test whether rate of neurogenesis can be manipulated in old animals. Studies by Kempermann et al. (1998, 2002) have shown that neurogenesis in middle-aged mice is responsive to stimulation by enriched environment and the increases are correlated with modest improvements in learning. In addition, other forms of physiological and pathological stimulation can enhance neurogenesis in aging animals albeit often to a limited extent (Cameron and McKay, 1999; van Praag et al., 2005; Hattiangady et al., 2008).
Changes in neurogenesis are also of interest with regard to possible recovery from ischemic damage. The discovery by Liu et al. (1998), showing that global ischemia is followed by increase in hippocampal neurogenesis, opened up a possibility that neurogenesis may be a compensatory, adaptive mechanism that could represent functional recovery after stroke or injury. Since adult neurogenesis is often mentioned as an ultimate mechanism of brain repair after injury (Kokaia and Lindvall, 2003; Lichtenwalner and Parent, 2006) we explore the extent of post-ischemic neurogenesis in middle-aged rats that may be representative of the aging, stroke-prone human population. Injury-triggered neurogenesis has been observed after global or focal ischemia in a variety of animal models (Sharp et al., 2002; Lichtenwalner and Parent, 2006). Yagita et al. (2001) reported increased proliferation, but reduced survival of new neurons following global ischemia in middle-aged Wistar rats in comparison to young adults. (Darsalia et al., 2005) claim reduced post-ischemic neurogenesis in dentate gyrus of 15-months-old Wistar rats but in parallel with retained enhancement of neurogenesis in the subventricular zone. Jin et al. (2004) have found blunted neurogenesis in old (24 months) Fisher 344 rats following a focal ischemia. In the present study we have used the two vessel occlusion (2VO) with hypotension in middle-aged male S-D rats in comparison to our previous study on young adult (3 months) animals (Kee et al., 2001).