, 1997). This behavior involves an expansion and backwards shift of place-specific firing of hippocampal cells that can be observed when rats engage in repeated route following behaviors. Mehta et al. (1997) have called this phenomenon place field expansion plasticity.

Although the description of hippocampal cell firing characteristics is elaborated below, it is important to note here that, along with age-related deficits in plasticity measured in response to artificial electrical stimulation, behaviorally-driven LTP-like plasticity mechanisms are also observed to change with age. Moreover, this place field expansion plasticity is reminiscent of Hebb’s (1949) theoretical idea of phase sequences in cell assemblies, Metformin manufacturer which he postulated could provide a means to encode sequences or episodes of experience. Together, these data suggest clear changes in synaptic plasticity mechanisms in the normally aging brain as well as potential mechanisms through which therapeutic targets can be developed (e.g., Bach et al., 1999; Burke et al., 2005; Foster, 2006; Huang & Kandel, 2006; Rose et al., 2007; Bodhinathan et al., 2010). There have been a number of experiments that have investigated the potential causes for these

types of age-related plasticity deficits in aging. One approach has been to examine the role of immediate–early genes Regorafenib in vivo in these processes. Arc (Lyford et al., 1995) has been useful in this regard because when Arc protein is knocked down in hippocampus of young rats, LTP decays significantly faster than when normal levels of Arc are present, and spatial memory consolidation is also disrupted (Guzowski et al., 2000; Plath et al., 2006). Penner et al. (2011) examined Arc mRNA activity in hippocampal cells of young and aged rats induced by spatial behaviors. The expression of Arc within cells provides an activity marker for those neurons that participate in a recent behavioral event (Guzowski et al., Fludarabine cell line 1999). They used methods that allowed behavior-induced Arc-positive cells to be counted, and Arc mRNA to be quantified by real-time

PCR within the same animal and cell type. For example, in CA1 the same numbers of pyramidal cells across age groups express Arc following exploratory behavior, but old pyramidal cells transcribe less Arc (Penner et al., 2011). Epigenetic mechanisms such as DNA methylation are known to affect RNA expression, and can influence cell function by altering the amount of RNA transcribed from a gene. Interestingly, Penner et al. (2011) also observed a very distinct pattern of methylation change with age in the Arc gene in CA1 cells. Thus, it appears that aging is accompanied by significant changes in epigenetic regulation of at least this important plasticity gene. These data, taken together with more recent observations suggesting that there is reduced coordination of epigenetic regulation dynamics of plasticity genes in aging (Castellano et al.