As previously mentioned, the deficits associated with the aging brain can be very difficult to generalize. Even within the distribution of healthy aging (i.e., aging without any neuropathologies such as Alzheimer’s disease or Lewy body dementia) there is a great deal of heterogeneity in brain health and function due to many different endogenous and exogenous factors. Although cognitive decline associated with age is highly variable, aging in humans is accompanied by a number of fairly consistent structural and functional changes (for review see Bishop, Lu & Yanker, 2010). Historically it had been thought that cognitive deficits associated with aging were caused by physical cell death in the hippocampus and associated cortical areas (Brody, 1955; Eayrs & Goodhead, 1959). However, recent stereological methods of neuronal quantification have confirmed that humans (Burke & Barnes, 2006; Morrison & Hof, 1997; Pakkenberg & Gundersen, 1997; West, 1993), rodents (Calhoun, Kurth, Phinney, Long, Hengemihle, Mouton, Ingram & Jucker, 1988; Rapp & Gallagher, 1996; Rasmussen, Schliemann, Sorensen, Zimmer & West, 1996), and nonhuman primates (Peters, Rosene, Moss, Kember, Abraham & Tigges, 1996; West, 1993) retain proportionate numbers of principal neurons and that physical cell death due to healthy aging is minimal (Burke & Barnes, 2006; Geinisman, 1999).
A large body of literature has focused on the selective vulnerability of the hippocampus and neocortical circuits to the process of aging (see Hof & Morrison, 2004; Newman & Kaszniak, 2000). A number of age-related changes have been reported in various regions of the hippocampal formation and within the intrinsic circuitry of the hippocampal processing network (Barnes et al., 1994; Geinisman et al., 1995; Wilson, Gallagher, Eichenbaum & Tanila, 2006). As a result, healthy aging has been associated with impairments on tasks that rely on intact functioning of the hippocampus and its surrounding regions. For example, aged nonhuman primates as well as aged rodents have been found to demonstrate parallel impairments to animals with hippocampal damage on a variety of memory paradigms involving spatial memory (Barnes, Nadel & Honig, 1980; Bizon et al., 2009; Gallagher et al., 1993; LaSarge, Montgomery, Tucker, Slaton, Griffith, Setlow & Bizon, 2007; Newman & Kaszniak, 2000; Poe et al., 2000; Robitsek, Fortin, Koh, Gallagher & Eichenbaum, 2008), temporal order memory (Hauser et al., 2009), contextual memory (Luu, Pirogovsky & Gilbert, 2008), delayed recognition memory (Dunnett, Evenden & Iverson, 1988; Moss, Rosene & Peters, 1988; Rapp & Amaral, 1991), and odor memory (Eichenbaum & Robitsek, 2009). As reported by Burke and Barnes (2006) and Geinisman (1999), the changes that occur in the hippocampus are likely due to region-specific changes in dendritic branching and spine density. As previously mentioned, further support comes from studies that have shown aged-rats with profound spatial learning deficits and equally old rats with preserved spatial learning abilities do not have significantly different numbers of principal hippocampal neurons (Rapp & Gallagher, 1996; Rasmussen, Schliemann, Sorensen, Zimmer & West, 1996). The circuits that are the most vulnerable to these types of age- associated alterations are those within the perforant path (connecting EC to the HPC) and the corticocortical projections that link together different association cortices such as inferior temporal cortex and prefrontal cortex (Morrison & Hof, 2002). As reported by Morrison and Hof (2002) these areas undergo a significant loss of presynaptic markers and postsynaptic glutimate receptors, particularly N-methyl-D-aspartate (NMDA) receptors.
NMDA receptors are glutamate-based receptors that are primarily responsible for controlling synaptic plasticity through the regulation of calcium (Ca2+) entry into the cell (Li & Tsien, 2009). The activity of these Ca2+ channels has also been hypothesized to be responsible for the formation of memories via long-term potentiation (LTP). The release of presynaptic glutamate and neighboring cells postsynaptic depolarization is required to remove the obstructing magnesium ion (Mg2+) from the pore of the postsynaptic NMDA receptor. The ejection of Mg2+ allows for Ca2+ to enter the cell, which results in an increased intracellular calcium concentration ([Ca2+]i), and possibly LTP. Numerous studies have reported that the electrophysiology of the hippocampus remains relatively stable with age (Barnes et al., 1994). However, changes in [Ca2+]i have been consistently reported in populations of aged rats (Landfield & Pitler, 1984), humans (Toescu & Vreugdenhil, 2010), and non-human primates (Geula, Bu, Nagykery, Scinto, Chan, Joseph, Parker & Wu, 2003). Specifically, as reported by Thibault and Landfield (1996), CA1 and CA3 pyramidal cells in the aged hippocampus experience disruptions in [Ca2+]i due to an increased density of extracellular Ca2+ channels (see Thibault, Hadley & Landfield, 2001; Toescu, 2005; Toescu, 2000; Toescu & Verkhratsy, 2000). It has also been found that aged rats experience deficits in the maintenance of LTP in the dentate gyrus (Barnes & McNaughton, 1980) as well as in the CA3 region (Dieguez & Barea-Rodriguez, 2004). These fluctuations could be responsible for some of the deficits in neural plasticity experienced by older adults.
Rodent models provide critical insight into the investigation of gerontological research, specifically age-associated disorders related to learning and memory (Kelly, Nadon, Morrison, Thibault, Barnes & Blalock, 2006). The use of aged rodents has been extremely effective in examining the deficits associated with the normal aging process (Barnes et al., 1980; Bizon et al., 2009; Brushfield et al., 2008; Gallagher et al., 1993; Hauser et al., 2009; LaSarge et al., 2007; Luu et al., 2008; Renteria, Silbaugh, Tolentino & Gilbert, 2008; Robitsek, Fortin, Koh, Gallagher & Eichenbaum, 2008). A number of studies have reported deficits in aged rats compared to their younger counterparts on tasks involving spatial memory (Barnes et al., 1980), and olfactory memory (Brushfield et al., 2008). In addition, a number of studies have reported that aged rodents demonstrate similar impairments to rodents with induced hippocampal damage on a variety of tasks measuring spatial memory (Barnes et al., 1980; Bizon et al., 2009; Gallagher et al., 1993; LaSarge et al., 2007; Robitsek et al., 2008), temporal order memory (Hauser et al., 2009), contextual memory (Luu et al., 2008), delayed recognition memory (Dunnett, Evenden & Iversen, 1988; Moss, Rosene & Peters, 1988; Rapp and Amaral, 1991), and memory for odors (Eichenbaum & Robitsek, 2009). Although age-related memory deficits have been well documented in rats, some studies have shown that a subset of aged rats match the performance of young rats (Bizon et al., 2009; Renteria et al., 2008). These studies lend support to other studies that suggest there may be some variability in age-related cognitive decline in rodent models of aging (Burke & Barnes, 2006; Geinisman, 1999), and this is most certainly true for aging in humans as well (see Hedden & Gabrieli, 2004).
A recent study by Brushfield and colleagues (2008) suggests that acquisition rates and retention of memory for olfactory stimuli may be greater than for visual stimuli in young rats and old rats. As suggested by Kraemer and Apfelbach (2004), the modality of a stimulus to be remembered is critical when determining the efficiency of learning. A number of studies have shown that rats can readily learn and maintain a high level of performance on tasks utilizing olfactory memory (Gilbert & Kesner, 2002, 2003; Kesner, Hunsaker & Gilbert, 2005). The study by Brushfield and colleagues (2008) represented the first examination of age-related differences in reversal learning using the same behavioral paradigm for visual and olfactory stimuli in order to facilitate cross-modal comparisons. The present study assessed age-related changes in novelty detection for objects, odors, object-place associations, and odor-place associations using an exploratory-based paradigm utilized in previous studies (Lee, Hunsaker & Kesner, 2005; Save et al., 1992).