Forgetfulness during aging: an integrated biology

Abstract

Age-related impairments in memory are often attributed to failures, at either systems or molecular levels, of memory storage processes. A major characteristic of changes in memory with increasing age is the advent of forgetfulness in old vs. young animals. This review examines the contribution of a dysfunction of the mechanisms responsible for modulating the maintenance of memory in aged rats. A memory-modulating system that includes epinephrine, acting through release of glucose from liver glycogen stores, potently enhances memory in young rats. In old rats, epinephrine loses its ability to release glucose and loses its efficacy in enhancing memory. Brain measures of extracellular levels of glucose in the hippocampus during memory testing show decreases in glucose in both young and old rats, but the decreases are markedly greater in extent and duration in old rats. Importantly, the old rats do not have the ability to increase blood glucose levels in response to arousal-related epinephrine release, which is retained and even increased in aged rats. Glucose appears to be able to reverse fully the increased rate of forgetting seen in old rats. This set of findings suggests that physiological mechanisms outside of the brain, i.e. changes in neuroendocrine functions, may contribute substantially to the onset of rapid forgetting in aged animals.

Keywords: Age-related memory impairments; Aging; Astrocytes; Brain metabolism and memory; Epinephrine; Glucose; Memory consolidation and modulation.

FIGURE 1

Age-related differences in forgetting rates. Rats were trained on a one-trial inhibitory avoidance task and memory was assessed at different times after training. Note that the rate of forgetting increased with age. [From Gold et al. 1982.]

FIGURE 2

Plasma levels of epinephrine (EPI) at baseline and at timed intervals after swimming for 15 min. Values are means for groups of 7–10 rats. Old rats had substantially greater levels of epinephrine after immersion in water than did young rats. [From Mabry et al., 1995a.]

FIGURE 3

Plasma epinephrine (left panel) and glucose (right panel) levels after administration of a single footshock at the intensity shown. Note that old rats exhibited exaggerated release of epinephrine compared to young rats but diminished increases in blood glucose levels across the same shock intensities. *P<0.05 vs. young. [From Mabry et al., 1995b.]

FIGURE 4

Effects of epinephrine injections on blood glucose levels in aged vs. young rats. Epinephrine injections increased glucose levels more substantially in young than in old rats, particularly at an epinephrine dose (0.1 mg/kg) that is effective at enhancing memory in young rats. [From Morris et al., 2010.]

FIGURE 5

Enhancement of inhibitory avoidance memory (48 hr) by immediate posttraining injections of epinephrine and glucose. Although the treatments were equally effective at enhancing memory in young rats, glucose was more effective than epinephrine in old rats. [From Morris et al., 2010.]

FIGURE 6

Alternation scores in rats tested for working memory on a 4-arm spontaneous alternation task. Young adult rats performed significantly better than chance on this task, but 24-month-old rats did not; the aged rats had scores significantly lower than those of young adult controls. Glucose enhanced memory in both young and old rats, bringing the memory scores in old rats to values near those of the glucose-enhanced memory of young rats. [From McNay and Gold, 2001.]

FIGURE 7

In vivo microdialysis measurements of extracellular glucose levels in the hippocampus before, during, and after testing on a spontaneous alternation task. Extracellular glucose levels decreased significantly at both ages, but significantly more so in aged rats. [From McNay and Gold, 2001.]

FIGURE 8

Effects of intrahippocampal injections of glucose on memory. Immediately after training on an inhibitory avoidance task, young and old rats received injections of aCSF containing either 1 mM or 33.4 mM glucose. These groups are designated aCSF and GLUCOSE, respectively, in this figure. The 1 mM glucose concentration in aCSF matches baseline extracellular glucose levels in the hippocampus, as measured with zero-net-flux microdialysis methods (McNay and Gold, 1999). Memory was assessed 7 days after training. Glucose enhanced memory in aged rats, bringing the latencies to the ceiling scores of 600 sec. [From Morris and Gold, 2013.]

FIGURE 9

Effects of intrahippocampal infusions of glucose and nicotinic receptor antagonists on working memory assessed in young adult rats using a 4-arm spontaneous alternation task. Chance performance is 44% on this task. Rats pretreated with either an α7 (MLA) or an α4β2 (DHβE) nicotinic receptor antagonist exhibited significantly impaired memory. Co-administration of glucose reversed the impairments produced by the α4β2 antagonist but not the α7 antagonist. *P<0.05 vs. aCSF. MLA: methyllycaconitine; DHβE: dihydro-beta-erythroidine; GLU: glucose; aCSF: artificial cerebrospinal fluid. [From Morris et al., 2013.]

FIGURE 10

Effects of spontaneous alternation testing on extracellular glucose (black diamonds) and lactate (gray circles) levels in the hippocampus of young adult rats. These levels were measured using bioprobes with 1-sec sampling periods, summarized here as 10-sec sampling epochs. Note first that glucose levels decreased near the start of alternation testing, as shown before with microdialysis methods. In contrast, lactate levels increased during testing, mirroring the changes in glucose. Not shown here, pharmacological manipulations that block and restore lactate availability impair and enhance memory, respectively. [From Newman et al., 2011.]

FIGURE 11

Effects of intrahippocampal injections of lactate on working memory scores in a 4-arm spontaneous alternation task. Lactate enhanced memory in an inverted-U manner, as seen also with glucose. [From Newman et al., 2011.]