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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56:B66-B71 (2001)
© 2001 The Gerontological Society of America

Age-Related Differences in Hippocampal Extracellular Fluid Glucose Concentration During Behavioral Testing and Following Systemic Glucose Administration

Ewan C. McNaya and Paul E. Goldb

a Department of Psychology, Yale University, New Haven, Connecticut
b Department of Psychology, University of Illinois at Urbana-Champaign

Paul E. Gold, Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 618201 E-mail: pgold{at}uiuc.edu.

Decision Editor: John A. Faulkner, PhD


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Recent evidence indicates that the level of glucose in the brain's extracellular fluid (ECF) is not constant, as traditionally thought, but fluctuates. We determined the effect of aging on hippocampal ECF glucose before, during, and after spatial memory testing. Fischer-344 rats (24 months old) showed a greater decrease in ECF glucose than 3-month-old rats (48% vs 12%); the decrease seen in 24-month-old rats persisted for much longer following testing. These changes were associated with an age-related deficit in spontaneous alternation performance. Following systemic glucose administration, the decrease in ECF glucose was reversed in both aged and young rats, and performance in aged versus young rats following glucose administration did not differ. These findings suggest that increased susceptibility to depletion of ECF glucose in aged rats may contribute to age-related deficits in learning and memory and that administration of glucose may enhance memory by providing additional glucose to the brain at times of increased cognitive demand.

Avariety of cognitive deficits, including deficits in memory, accompanies aging in many animals, including rodents and humans. For example, aged humans show deficits in working memory (1)(2), perceptuomotor memory (3)(4), and memory for word lists (5). Aged rats show deficits in performance on a variety of tasks including both complex and simple spatial memory tasks (e.g., (6),(7)), conditional discrimination learning tasks (8), and passive-avoidance tasks (9). In addition to the differences seen in performance, rodents and humans show age-related differences in their physiological and psychological responses following administration of glucose, a monosaccharide that influences performance on a wide variety of measures, including memory (10). Administration of glucose to aged humans enhances performance on tasks measuring memory of a prose passage (11)(12)(13)(14)(15) or a list of words (12) and appears to enhance both acquisition and retrieval processes (16); aged rodents receiving glucose injections show enhanced performance in spatial, hippocampus-dependent memory tasks (8)(17).

Testing on many memory tasks reveals differences in performance between young adult and aged animals, which can be attenuated or eliminated by the administration of glucose (10). Often, glucose administration in such cases does not affect the performance of the young adult groups, which are already performing at ceiling levels [e.g., ((8),(13),(18))]. As task difficulty is increased, or following the creation of a deficit by pharmacological manipulation, beneficial effects of glucose administration on task performance can be observed in young adult animals also (10).

Administration of glucose appears to modulate memory processes, at least in part, by reversing task-associated decreases in brain extracellular glucose (19). We previously showed that in young rats, testing in a spontaneous alternation task (a hippocampus-dependent spatial working memory task) (20)(21)(22)(23)(24) is associated with a decrease in hippocampal extracellular glucose and that administration of glucose at a dose that enhances performance on this task reverses this decrease. Moreover, the magnitude of the decrease in extracellular glucose is correlated with alterations in task difficulty (19); testing on a four-arm maze in which young rats do not alternate at ceiling levels produced a 32% decrease in hippocampal extracellular glucose versus a maximum decrease of 11% during testing on a three-arm maze, where performance was at ceiling level. Given the differences in the effect of glucose administration on performance in young versus aged animals, the present experiments sought to extend our previous findings to investigate the effects of age differences on the level of hippocampal glucose during spontaneous alternation testing.

Recently, we showed that the level of glucose in the hippocampal extracellular fluid (ECF) of aged rats does not differ from that in young rats when the animals are at rest (25). However, the brains of aged rats appeared to have a reduced ability to transport glucose to sites of increased demand (25), perhaps due to the increased tortuosity of aged brains (26). Hence, even in the presence of increased peripheral glucose, aged rats may be less able to transport glucose to areas within the brain where it is needed. Moreover, in addition to the changes in brain tortuosity, aged animals show a reduction in glucose transport across the blood-brain barrier (BBB) (27). In combination, the differences in glucose transport capacity between young and aged animals appear likely to produce a significant reduction in brain glucose supply capability in aged animals.

Because high levels of cognitive demand can cause decreases in the level of glucose in the ECF of brain areas involved in the increased processing (19), we hypothesized that the deficits in glucose supply to the brain seen in aged animals would result in a larger decrease in hippocampal ECF glucose during spontaneous alternation testing than is seen in young animals, accompanying an age-related deficit in alternation performance. In animals receiving exogenous glucose before testing, we expected to see an improvement in the performance of both young and aged animals; the spontaneous alternation task was chosen to be of sufficient difficulty that young rats would not perform at ceiling levels but would show enhanced performance following glucose administration (19)(28)(29), in line with the results of glucose administration to young humans on tasks of sufficient difficulty (10). Accompanying the enhanced alternation performance, we predicted attenuation of decreases in hippocampal ECF glucose in both young and aged rats. However, the extent to which systemic glucose administration to aged animals would be able to reverse the decrease in ECF glucose was uncertain given the deficits in glucose transport capacity.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
Male Fischer-344 (F344) rats, either 3 (n = 16) or 24 (n = 15) months old at time of surgery, were purchased from Harlan Laboratories (Dublin, VA). Rats were housed individually and were maintained on a 12/12 hour light/dark cycle (lights on at 7 AM). Three-month-old rats had free access to food and water at all times; 24-month-old rats were maintained at their arrival weight for 1 week prior to surgery.

Surgery
Surgical procedures for implantation of microdialysis guide cannulae into the hippocampus were as described previously (25). With the nose bar set at 5.0 mm above the interaural line, coordinates were 3.8 mm posterior to bregma, +5.0 lateral, and 3.8 ventral from dura. Rats were allowed to recover for at least 2 weeks following surgery, during which time they were handled extensively daily. Microdialysis probes (CMA12; CMA/Microdialysis, Solna, Sweden) were inserted into the guide cannulae 24 hours prior to microdialysis sampling to give optimum measurement conditions (30)(31)(32). Each animal was used only once for microdialysis and behavior.

Microdialysis Procedures
Microdialysis was performed as described previously, with a flow rate of 1.0 µl/min in 3-month-old rats and 0.5 µl/min in 24-month-old rats; the reduced flow rate in aged animals is necessary to ensure linearity of sampling response with changes in ECF glucose concentration across at least the range 0.0 to 3.0 mmol/l (25). In no animal did ECF glucose approach either end of this range. The concentration of glucose in the artificial CSF perfusion fluid was 1.2 mmol/l, which we have shown to be the basal hippocampal concentration in both young and aged F344 rats (25). Samples were analyzed for glucose as described (25) and essentially according to the method of Lowry and Passoneau (33). Glucose concentration in the samples was corrected for probe recovery using the slope of separate in vivo zero-net-flux plots collected at the same flow rate, using the same probes, and in animals from the same cohorts (25). This correction ensured that data from the two age groups were directly comparable.

Behavioral Testing
Spontaneous alternation testing was carried out as described previously (19). Briefly, each rat was moved from its home cage into a novel control chamber of black Plexiglas, and the baseline hippocampal glucose concentration was determined for each rat by averaging the values in the samples immediately prior to testing. All samples were 5 µl; therefore, sample times were 5 minutes for 3-month-old rats and 10 minutes for 24-month-old rats. The difference in sample times was a consequence of the difference in flow rate needed to ensure accurate measurements and allowed for ease of sample comparison; an equally valid approach would have been to equalize sample time and to take samples of differing volumes. Baseline samples were collected for at least 20 minutes in 3-month-old rats and for at least 30 minutes in 24-month-old rats. The baseline concentration was then defined as 100% for each rat. In groups receiving injections of glucose, injections were given 30 minutes prior to the start of testing, which necessitated a longer pretesting period to establish baseline before treatment. After the baseline period, rats were placed into the center of a four-arm maze (also of black Plexiglas) and allowed to explore freely for a period of 20 minutes; rats were then replaced into the control box. Control rats were handled in the same way as maze-tested rats but were not placed in a maze. Samples were collected continuously before, during, and after the test period. When allowed to explore freely, rats spontaneously alternated between all four maze arms, using spatial working memory to retain knowledge of the arms previously visited. The measure of memory performance used was percent four/five alternation, as described previously (19). An alternation is counted when the rat visits all four arms within a span of five arm choices. The rat's alternation (performance) score is calculated by dividing the number of alternations by the total possible number of alternations (which is equal to the total number of arm entries minus four) and converted to a percentage by multiplying by 100. A higher alternation score indicates that the rat more regularly chose to enter the arm that he had least recently visited—hence, alternating between the arms. A review of spontaneous alternation behavior can be found in Dember and Richman (34).

Behavioral Groups
Three-month-old rats were randomly assigned to one of two conditions: maze-only (n = 9) or maze-glucose (n = 6). Rats in the two conditions were handled and tested identically, except that maze-glucose rats received an injection of glucose (250 mg/kg, i.p.) prior to testing. Maze-only rats received a volume-matched injection of saline. We have previously shown that surgery does not affect spontaneous alternation performance in 3-month-old rats (24) and that glucose concentrations in the ECF of 3-month-old rats are stable over the length of the experiment, in the absence of behavioral testing, whether or not glucose is administered (19)(25). Aged rats were randomly assigned to one of three conditions: untested (n = 4), maze-only (n = 5), or maze-glucose (n = 5). Maze-only and maze-glucose conditions were identical to the conditions of the same name for 3-month-old rats; untested rats were handled in the same way as maze-tested rats, including being picked up at times matching the start- and end-point of maze-testing, but were not placed into the maze. In addition, to confirm that microdialysis procedures did not affect performance in aged rats, a group of control 24-month-old rats (not included in n values above; n = 11) were tested on the spontaneous alternation task without microdialysis. In fact, the 24-month control group did not differ from maze-only 24-month-old rats on any performance measure (data not shown); therefore, the alternation performance data from these two groups were combined.

Histology
On completion of testing, placement of microdialysis probes was confirmed. Rats received an overdose of sodium pentobarbital followed by intracardial perfusion with 0.9% saline and then 10% formalin. Brains were removed, stored for a minimum of 3 days in 30% sucrose/10% formalin solution, frozen, and sectioned (40 µm) on a Reichert-Jung cryostat. Sections were stained with cresyl violet, and the probe placement was confirmed; animals with tissue damage or in which the probe had been placed outside the target brain structure were discarded. Data from two 3-month-old and two 24-month-old rats (not included in n values above) were discarded due to probe placements outside the hippocampus.

Statistical Analysis
All comparisons were made using unpaired two-tailed t tests in Microsoft Excel (Redmond, WA), with alpha set at .05. Data are reported as mean ± SE.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Alternation performance data for all rats are shown in Fig. 1. In the absence of glucose administration, 3-month-old rats had alternation scores higher than those of 24-month-old rats (p < .05). Systemic glucose administration improved performance in both age groups (both p values < .05), and performance in 24-month-old rats receiving glucose did not differ from that of 3-month-old rats receiving glucose (p > .05). To confirm that group differences seen were not due to differences in locomotor activity, the number of arms entered was recorded and is shown for all rats in Fig. 2; there were no differences in the number of arms entered between any groups (all p values > .05).



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  		Figure 1. Mean four/five alternation performance on maze, expressed as a percentage of possible alternations. Error bars are SE. Dashed line represents chance alternation performance (44.4%). *p < .05 versus 24-month maze group; **p < .05 versus 3-month maze group; ***p < .05 versus 24-month maze group and not significant versus 3-month glucose group.

 


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  		Figure 2. Mean number of arms entered during alternation testing. Error bars are SE.

 
Microdialysis data for the 3-month-old rats are shown in Fig. 3. In maze-only rats, hippocampal ECF glucose decreased by up to 12% ± 2% during testing, returning to baseline levels following testing. In contrast, maze-glucose rats showed no decrease in ECF glucose at any point. The differences between the two groups are significant both for the overall time of testing (samples 5 to 8) and for the individual samples 5 and 6 (all p values < .05) but not for the individual samples 7 and 8 (both p values > .05). The corresponding data for 24-month-old rats are shown in Fig. 4. Maze-only rats had a decrease in ECF glucose of up to 48% ± 3% during testing, which did not return to baseline for at least 30 minutes following the end of testing. This decrease was completely attenuated in the maze-glucose group, which also showed an increase in ECF glucose of up to 33% ± 4% above baseline during the pretesting period but returned to baseline levels during and following testing. ECF glucose in untested rats fluctuated by a maximum of only 6%. The differences in ECF glucose between maze-only and maze-glucose aged rats were significant for the overall time of testing (samples 4 and 5), for the overall post-test period (samples 6 to 8), and for each of the individual samples 4 to 7 (all p values < .05). The data from 3-month-old and 24-month-old maze-only groups are replotted in Fig. 5 for ease of comparison. To allow direct statistical comparison, ECF glucose data from samples 4 through 7 from 24-month-old rats was compared with the grouped data from the two samples from 3-month-old rats during the same time period. For instance, the data from 24-month-old rats from sample 4 (the first maze sample, covering the first 10 minutes of testing) were compared with the data from 3-month-old rats from samples 5 and 6 (covering the same 10 minutes). The differences were significant in all cases (all p values < .000001).



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  		Figure 3. Mean extracellular hippocampal glucose concentrations in 3-month-old F344 rats during maze testing, expressed as a percentage of baseline concentration. Samples 1 through 4 are pretesting baseline; samples 5 through 8 (boxed area) are during testing; samples 9 through 12 are post-testing. Error bars are SE. Group symbols: {diamondsuit}, maze-only (no treatment);.

, maze-glucose (250 mg/kg, i.p.).

 


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  		Figure 4. Mean extracellular hippocampal glucose concentrations in 24-month-old F344 rats during maze testing, expressed as a percentage of baseline concentration. Samples 1 through 3 are pretesting baseline; samples 4 through 5 (boxed area) are during testing; samples 6 through 8 are posttesting. Error bars are SE. Group symbols:.

, maze-only (no treatment); {Delta}, maze-Glucose (250 mg/kg, i.p.); {diamondsuit}, untested (handled as other groups but not placed on maze; no treatment).

 


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  		Figure 5. Mean extracellular hippocampal glucose concentrations in 3-month-old and 24-month-old maze-only F344 rats during maze testing, expressed as a percentage of baseline concentration. Boxed area represents time on maze. Error bars are SE. Group symbols: {diamondsuit}, 3-month-old;.

, 24-month-old. For explanation of comparison, see text.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
Our primary hypothesis, that aged animals would show greater decreases in ECF glucose associated with cognitive demand, was confirmed: glucose in the hippocampal ECF of 24-month-old rats decreased by up to 48%, compared with a maximum decrease of 12% in 3-month-old rats, and remained decreased not only for the period of testing but also for at least 30 minutes following testing. The decrease seen in the aged F344 rats is particularly striking given that the 3-month-old F344 rats showed a decrease of only 12%, compared with the decrease of around 30% seen repeatedly in 3-month-old Sprague-Dawley rats under the same experimental conditions (19)(35). The magnitude of the decrease in aged rats, and in particular the failure to restore basal levels of ECF glucose for at least 30 minutes following testing, strongly support our hypothesis that one reason for the deficits seen in cognitive performance in aged animals is an increased inability to supply glucose with sufficient speed and/or capacity to meet the demands of increased cognitive load. The results from 24-month-old rats receiving systemic glucose injections suggest that this inability might not be due entirely to alteration in the brain's glucose supply capacity: when the level of systemic glucose is increased, the aged animals are apparently able to transport sufficient glucose from the blood to the hippocampal ECF and thus avoid any decrease in ECF glucose. However, aged rats are known to have deficits in peripheral glucose regulation (36), to have reduced capacity for glucose transport across the BBB (27), and to show reduced capacity to mobilize peripheral glucose in response to, for example, peripheral hormonal signaling (37). Thus, the reversal of decreased ECF glucose following glucose administration may be accompanied by large increases in circulating glucose (above those seen in young animals), which may compensate at least partially for reduced glucose mobilization and transport to the brain. This possibility is supported by the fact that whereas 3-month-old rats receiving glucose show no pretest increase in ECF glucose, the corresponding 24-month-old rats show an increase in the ECF glucose level of up to 33%, suggesting a lack of regulation of peripheral glucose levels and/or glucose transport to the ECF. Seen in this way, the deficit in peripheral glucose regulation found in aged animals may in fact be an adaptive change, offering the possibility of compensating for reduced ability to mobilize and transport glucose; the increased ECF glucose level seen here in aged rats following glucose administration is associated with improved alternation performance.

In addition to the consideration of brain glucose supply, the lower spontaneous alternation performance seen in the 24-month-old rats suggests that they have reduced capacity to respond to increases in cognitive demand, in line with suggestions that cognitive deficits associated with aging are due to a reduction in available cognitive resources (1)(38). There are several possible biological bases for such a reduction in cognitive capacity; within the hippocampus, for instance, the hippocampi of aged rats may have reduced numbers of neurons (39), and the remaining neurons show many changes, including alterations in plasticity (40) and Ca2+ regulation (41). While speculative, a reduction in the number of neurons present might suggest that the remaining neurons are more likely to be required for any given instance of information-processing; reductions in either plasticity or the ability to regulate Ca2+ flux might necessitate increased energy usage during cognitive processing compared with that required by young adult rats to achieve the same level of memory performance through neural activity and/or changes in synaptic strength. Such factors, then, might tend to increase the amount of energy needed by particular brain areas of aged animals to support a given level of cognitive performance. For instance, in the present task, for a 24-month-old rat to alternate at the same rate as a 3-month-old rat, the aged rat might need to supply more energy (i.e., glucose) to the hippocampus and perhaps to other brain areas. We have previously shown that glucose supply to the hippocampi of 24-month-old rats is reduced compared with that in 3-month-old rats (25). Therefore, any constraint on cognitive performance due to an increase in hippocampal glucose demand during cognitive processing would be predicted to be much tighter in aged animals; the present observations of increased inability to meet hippocampal glucose demand associated with an age-related cognitive deficit fit this prediction exactly. Overall, we suggest that the larger task-associated decrease in hippocampal ECF glucose seen in aged rats is due to a combination of (i) a reduction in peripheral glucose regulation and supply; (ii) a reduction in brain glucose transport capacity, including both transport across the BBB and within the brain; and (iii) a reduced cognitive return on energy investment—that is, increased amounts of energy supply needed versus that needed by younger rats to achieve the same level of cognitive performance.


   Acknowledgments
 
This research was supported by research grants from NIA (AG 07648), NINDS (NS 32914), USDA (00-35200-9059), and the Alzheimer's Association to P.E.G., and by an AFAR/Glenn Foundation fellowship, a University of Virginia dissertation fellowship, and a University of Virginia Retired Faculty Association Aging Research award to E.C.M.

Ewan C. McNay's current e-mail is:

Received March 8, 2000

Accepted May 31, 2000


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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