Epinephrine and glucose modulate training-related CREB phosphorylation in old rats: Relationships to age-related memory impairments

Abstract

Epinephrine enhances memory in young adult rats, in part, by increasing blood glucose levels needed to modulate memory. In old rats, epinephrine is deficient at raising blood glucose levels and thus is only moderately effective at enhancing memory. In contrast, systemic glucose injections improve memory in old rats, with resulting memory performance equal to that of young rats. The diminished response of glucose to training in old rats may blunt downstream neurochemical and molecular mechanisms needed to upregulate memory processes. In the first experiment, young adult and old rats were trained on an inhibitory avoidance task with immediate post-training injections of aCSF or glucose into the dorsal hippocampus. Old rats had significant memory impairments compared to young rats 7 days after training. Intrahippocampal injections of glucose reversed age-related deficits, improving memory scores in old rats to values seen in young rats. A second experiment examined age-related changes in activation of the transcription factor CREB, which is widely implicated in memory formation and may act downstream of hormonal and metabolic signals. Activation was assessed in response to training with systemic injections of epinephrine and glucose at doses known to enhance memory. Young adult and old rats were trained on inhibitory avoidance with immediate post-training systemic injections of saline, epinephrine, or glucose. After training, old rats had significant impairments in CREB phosphorylation in area CA1 and the dentate gyrus region of the hippocampus, and in the basolateral and lateral amygdala. Epinephrine and glucose attenuated age-related deficits in CREB phosphorylation, but were more effective in the amygdala and hippocampus, respectively. Together, these results support the view that age-related changes in blood glucose responses to epinephrine contribute to memory impairments, which may be related to alterations in regional patterns of CREB phosphorylation.

Regulation of memory – From the adrenal medulla to liver to astrocytes to neurons

“…In aged rats, the depletion of hippocampal glucose is more extreme, coincident with an absence of a rise in blood glucose levels in aged rats as compared to that seen in young rats and coincident also with memory impairments in the alternation task (McNay and Gold, 2001). In aged rats, peripheral injections of glucose restore memory scores to those seen in young rats and block the depletion of glucose during behavioral testing (McNay and Gold, 2001; Morris et al, 2010; Morris and Gold, 2013). …”

“…Footshock, as used in inhibitory avoidance training, results in increases in both epinephrine and glucose in young adult rats, including young adult Fischer-344 rats (Mabry et al, 1995). In addition, post-training injections of both epinephrine and glucose enhance memory in young adult rats, including 3-month-old Fischer-344 rats (Morris et al, 2010; Morris and Gold, 2013). Compared to young adult rats, two-year-old Fischer-344 rats exhibit rapid forgetting after one-trial inhibitory avoidance training, with substantial and significant impairments in memory tested 1–7 days after training (Gold et al, 1982; Morris et al, 2010; Morris and Gold, 2012, 2013).…”

“…In addition, post-training injections of both epinephrine and glucose enhance memory in young adult rats, including 3-month-old Fischer-344 rats (Morris et al, 2010; Morris and Gold, 2013). Compared to young adult rats, two-year-old Fischer-344 rats exhibit rapid forgetting after one-trial inhibitory avoidance training, with substantial and significant impairments in memory tested 1–7 days after training (Gold et al, 1982; Morris et al, 2010; Morris and Gold, 2012, 2013). The senescent rats also have changes in the profiles of circulating epinephrine and glucose after training (Mabry et al, 1995; Morris et al, 2010).…”

“…Direct injections of glucose into the hippocampus, striatum and amygdala have all been shown to enhance memory as well, generally for those tasks canonically associated with these brain regions (Schroeder and Packard, 2003; Ragozzino et al, 1996, 1998; Stefani and Gold, 2001; Krebs and Parent, 2005; Pych et al, 2006; Morris and Gold, 2013). …”

Forgetfulness during aging: An integrated biology

“…Across many studies, the findings show that aged rats and mice exhibit learning and memory performance comparable to that of young adults when tests are administered soon after training but show poor memory relative to young animals when tests are administered at later times after training (Barnes, 1991; Winocur, 1988; Foster, 1999; Gold, 2001; Korol, 2002; Morris et al, 2010; Morris and Gold 2012, 2013; Wimmer et al, 2012; Gold and Stone, 1988; Gold, 2005). While there are many examples of accelerated forgetting in aged rodents, it is of interest that the specific time courses of forgetting differ by task.…”