, 1987; Haug & Eggers, 1991). It is now believed that cell numbers in the frontal cortex are preserved through aging in humans (Haug et al., 1981, 1984; Freeman et al., 2008). Similar conclusions have been drawn for frontal areas in nonhuman primates (Peters et al., 1996, 1998a; Smith et al., 2004), with the exception of prefrontal area 8A, a region of the dorsolateral PFC, which was shown

to have a significant decline in Nissl-stained neurons (Smith et al., 2004). In rodents the cell counting results are conflicting. One group reports decreases in neuron numbers in the dorsal PFC areas but preservation in the ventral PFC areas (Stranahan et al., 2012), and another found the opposite, with cell loss in the ventral PFC and preservation in dorsal PFC (Yates et al., 2008). Because the same rat strain was utilized, Stranahan et al. (2012) suggest that different learn more delineation of brain structures high throughput screening compounds during counting could explain the disparate findings. Nonetheless, the current view is that the cell numbers in the PFC are reasonably well preserved during aging, although there may be focal points of cell loss in nonhuman primates and rodents. In line with the overall reduction in frontal lobe volume mentioned above, age-related decreases in gray matter volumes and cortical

thickness have been reported in humans (Haug & Eggers, 1991; Raz et al., 1997, 2005; Good et al., 2001; Tisserand et al., 2002; Salat et al., 2009; Bergfield et al., 2010; Giorgio et al., 2010; Thambisetty et al., 2010; Burzynska et al., 2012; Kalpouzos et al., 2012), nonhuman primates (Alexander et al., 2008; Shamy et al., 2011; Fig. 2B) and rats (Alexander et al., 2011). However, an earlier stereological study performed using Nissl-stained slices from monkeys reported a general preservation of area 46 (O’Donnell et al., 1999), which is in contrast with the findings from MRI studies presented above. These differences may be the result Fludarabine of the research method employed or may be caused by inter-individual variability of age effects on this part of the brain. Nonetheless,

the changes in volume of the dorsolateral PFC in nonhuman primates have also been shown to correlate with accuracy on a recognition memory task (Shamy et al., 2011). Specifically, aged monkeys with larger PFC volumes identified more correct nonmatch objects on the DNMS task than did monkeys with smaller PFC volumes (Shamy et al., 2011; Fig. 2D). This correlation held even when the analysis was restricted to PFC gray matter or white matter volumes separately. Rather than cell loss, the gray matter volume decrease in the PFC is in part caused by age-related changes in neuron morphology, particularly the loss of synapses and the regression of apical dendrites (reviewed in Peters et al., 1996; Markham & Juraska, 2002; Dickstein et al., 2007; Luebke et al., 2010; Pannese, 2011; Morrison & Baxter, 2012). Decreases in spine numbers and density, and changes in spine morphology, have been reported in humans (Jacobs et al.