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.

Learning about stress: neural, endocrine and behavioral adaptations

“…In addition, spontaneous recovery from chronic intermittent restraint stress may take more than four weeks. This strong memory trace for the stressor is not surprising given that young adult laboratory rats exposed to a single, brief footshock during passive avoidance training demonstrate strong memory for the training footshock up to 21 days later (Gold & Korol, 2014). Few investigators have displayed an interest in conducting a systematic evaluation of the neuroendocrine responses to a given stressor or pairings of stressors against the 10 parameters of habituation (Rankin et al, 2009), and some of the parameters add little value to the aims of such experiments.…”

“…These brain areas include the prefrontal cortex, amygdala and BNST (Gold & Korol, 2014;McGaugh, 2004McGaugh, , 2015Reul, 2014;Roozendaal et al, 2009). Corticosterone, which readily crosses the blood-brain barrier, has access to these stress-sensitive brain circuits.…”

“…In contrast, EPI, which does not readily penetrate the blood-brain barrier, has been demonstrated to modulate emotional memories by its effects on ascending vagal fibers, which in turn stimulate neurons in the ventrolateral medulla, locus coeruleus and nucleus of the solitary tract, leading to release of NE from nerve terminals in the amygdala (Chen & Williams, 2012). In addition, EPI stimulates release of glucose from glycogen stores in the liver and stress-induced elevations in circulating glucose have also been shown to modulate memory storage processes (Gold & Korol, 2014).…”

Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward

“…Neuroendocrine responses to an experience can regulate brain processes involved in learning and remembering that experience (Gold, 2014; Gold and Korol, 2014). In particular, release of the hormone epinephrine into blood from the adrenal medulla enhances learning and memory across many tasks and species (Gold, 1995; Gold and Korol, 2012).…”

“…Although circulating epinephrine does not readily cross the blood-brain barrier to enter the brain (Axelrod et al, 1959), the hormone’s peripheral actions, largely at the liver, increase blood glucose levels. The increase in blood glucose levels is both necessary and sufficient for the enhancement of learning and memory by epinephrine (Gold, 2014; Gold and Korol, 2014). Glucose itself enhances learning and memory when administered by systemic administration or by direct brain injections (Gold, 2001; Gold and Korol, 2012; Korol, 2002; Korol and Gold, 2007; Messier, 2004; Messier et al, 1999; Smith et al, 2011; Morris and Gold, 2013; van der Zwaluw et al, 2015).…”