Glucose and age-related changes in memory

doi:10.1016/j.neurobiolaging.2005.09.002

Neurobiology of Aging

Volume 26, Issue 1, Supplement, December 2005, Pages 60-64

https://doi.org/10.1016/j.neurobiolaging.2005.09.002 Get rights and content

Abstract

Epinephrine, released from the adrenal medulla, enhances memory in young rats and mice and apparently does so, at least in part, by increasing blood glucose levels. Like epinephrine, administration of glucose enhances cognitive functions in humans and rodents, including reversing age-related impairments in learning and memory. Epinephrine responses to training are increased in aged rats but the subsequent increase in blood glucose levels is severely blunted. The absence of increases in blood glucose levels during training might contribute to age-related deficits in learning and memory. Also, extracellular glucose levels in the hippocampus are depleted during spontaneous alternation testing to a far greater extent in aged than in young rats. Importantly, systemic injections of glucose block the depletion in the hippocampus and also enhance performance on the alternation task. Thus, the extensive depletion of extracellular glucose during training in aged rats may be associated with age-related memory impairments, an effect that might be related to – or may exacerbate – the effects on learning and memory of an absence of the increases in blood glucose levels to training as seen in young rats. Together, these findings suggest that age-related changes in both peripheral and central glucose physiology contribute to age-related impairments in memory.

Introduction

Cognitive changes accompany aging in humans and other animals, often taking the form of rapid forgetting [1], [6], [9]. We and other laboratories have examined the role of glucose as a cognitive enhancer in both humans and rats [9], [13], [20], [21]. Particularly germane to this brief review, injections of glucose in aged rodents near the time of training reverse age-related impairments in memory, suggesting that changes in blood and brain glucose responses to training may contribute to age-related impairments in memory.

In young rats, extensive evidence indicates that circulating levels of epinephrine, released from the adrenal medulla, enhance memory and act, at least in part, by increasing blood glucose levels. Resting blood and brain extracellular glucose levels are about the same in old and young adult rats. Compared to young rats, aged rats exhibit an exaggerated increase in epinephrine release from the adrenal medulla during training and/or stress. However, the release of epinephrine during training results in only a minimal increase in blood glucose levels in aged rats. These findings are consistent with the view that the excessive rise in epinephrine in the swim task or after a training footshock may be a futile physiological attempt to increase blood glucose levels in response to stress. Of related importance, injections of epinephrine in aged rats result in severely attenuated release of glucose into blood as compared to young rats. Thus, although aged rats have basal blood glucose levels comparable to those of young rats, blood glucose levels in aged rats are not responsive to training or to epinephrine injection.

In addition to changes in blood glucose levels, glucose levels in the extracellular fluid of the brain vary with training and with age. Aged rats show substantially larger decreases in hippocampus extracellular glucose levels during training which accompany age-related cognitive impairments. In addition, systemic injections of glucose at the time of training blunt the depletion in extracellular brain glucose levels and also reverse the impairment in memory in old rats.

Section snippets

Systemic and direct brain administration of glucose enhance learning and memory

Peripheral injections of epinephrine enhance memory in rodents [10], [16] and in humans [3]. Our investigations of glucose as a modulator of memory processes were prompted by the hypothesis that increases in blood glucose levels acted as an intermediary step between peripheral epinephrine release and central modulation of memory processes. In laboratory animals, peripherally administered glucose enhances memory on a wide variety of tasks [9], [13], [21]. Systemic administration of glucose also

Circulating epinephrine and glucose responses to stress and arousal are uncoupled in aged rats

If age-related changes in modulation of memory contribute to impairments in memory, perhaps epinephrine release, and subsequent increases in blood glucose levels, would be impaired in aged rats. The results of several studies indicate that this was only partially correct: circulating epinephrine responses to training and to training-related stress are markedly increased, not decreased, in aged rats. However, blood glucose responses to training and to training-related stress are severely

Brain extracellular glucose levels in the hippocampus decrease during spontaneous alternation tests, an effect reversed by systemic glucose administration, together with enhanced memory on this task

We measured ECF glucose in the hippocampus and striatum of rats during performance of a hippocampus-dependent spontaneous alternation task [17]. Importantly, this task was chosen as one that involved neither aversive nor appetitive rewards or stimuli, in order to minimize any alteration in ECF glucose subsequent to changes in blood glucose after, for example, stress or food reward. The findings indicate that, in young adult rats, hippocampal ECF glucose levels decrease by as much as 30–40%

Conclusions

Glucose appears to make important contributions to age-related changes in memory. In young rats, increases in blood glucose levels appear to mediate the enhancement of memory by epinephrine. Administration of glucose enhances memory and blunts the depletion of brain glucose seen during memory processing. In contrast, aged F-344 rats do not show increases in blood glucose levels after administration of epinephrine, training or stress. Furthermore, the depletion of brain extracellular glucose

Acknowledgements

Research from the author's laboratory described here was supported by research grants from NIA (AG 07648), NINDS (NS 32914), USDA (00-35200-9059), NIDA (DA 16951) and the Alzheimer's Association.

References (33)

C.A. Barnes
Memory changes with age: neurobiological correlates
D. Benton et al.
Blood glucose influences memory and attention in young adults
Neuropsychology
(1994)
L. Cahill et al.
Epinephrine enhancement of human memory consolidation: interaction with arousal at encoding
Neurobiol Learn Mem
(2003)
R.J. Kaplan et al.
Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates
Am J Clin Nutr
(2000)
T.R. Mabry et al.
Age-related changes in plasma catecholamine responses to acute swim stress
Neurobiol Learn Mem
(1995)
T.R. Mabry et al.
Age-related changes in plasma catecholamine and glucose responses of F-344 rats to footshock as in inhibitory avoidance training
Neurobiol Learn Mem
(1995)
J.L. McGaugh et al.
Role of adrenal stress hormones in forming lasting memories in the brain
Curr Opin Neurobiol
(2002)
C. Messier
Glucose improvement of memory: a review
Eur J Pharmacol
(2004)
C. Messier et al.
Dose-dependent action of glucose on memory processes in women: effect on serial position and recall priority
Cogn Brain Res
(1998)
M.B. Parent et al.
Intra-septal infusions of glucose potentiate inhibitory avoidance deficits when co-infused with the GABA agonist muscimol
Brain Res
(1997)

C.R. Park

Cognitive effects of insulin in the central nervous system

Neurosci Biobehav Rev

(2001)

J.A. Salinas et al.

Glucose regulation of memory for reward reduction in young and aged rats

Neurobiol Aging

(2005)

M.R. Stefani et al.

Intra-septal injections of glucose and glibenclamide attenuate galanin-induced spontaneous alternation performance deficits in the rat

Brain Res

(1998)

C.P. Talley et al.

Vagotomy attenuates effects of l-glucose but not d-glucose on spontaneous alternation performance

Physiol Behav

(2002)

G. Winocur et al.

Glucose treatment attenuates spatial learning and memory deficits of aged rats on tests of hippocampal function

Neurobiol Aging

(1998)

Canal C, Stutz SJ, Gold PE. Glucose injections into the hippocampus or striatum of rats prior to T-maze training:...

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Glucose and age-related changes in memory

Abstract

Introduction

Section snippets

Systemic and direct brain administration of glucose enhance learning and memory

Circulating epinephrine and glucose responses to stress and arousal are uncoupled in aged rats

Brain extracellular glucose levels in the hippocampus decrease during spontaneous alternation tests, an effect reversed by systemic glucose administration, together with enhanced memory on this task

Conclusions

Acknowledgements

Neuropsychology

Neurobiol Learn Mem

Am J Clin Nutr

Neurobiol Learn Mem

Neurobiol Learn Mem

Curr Opin Neurobiol

Eur J Pharmacol

Cogn Brain Res

Brain Res

Neurosci Biobehav Rev

Neurobiol Aging

Brain Res

Physiol Behav

Neurobiol Aging