When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions.

Homosynaptic long-term depression (LTD) and reversal of long-term potentiation (LTP) were examined extracellularly at CA3-CA1 synapses in stratum radiatum of slices from adult (6-9 months) and aged (20-24 months) Fischer 344 rats. Prolonged low-frequency stimulation (LFS) (900 pulses/1 Hz) of the Schaffer collaterals depressed the initial slope of the excitatory postsynaptic potential (EPSP) in aged but not adult rats. LTD at aged synapses was pathway-specific, persistent, and sensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Adult slices exhibited AP5-sensitive LTD in high [Ca2+] medium, whereas LTD in aged slices was blocked by high [Mg2+], suggesting that differences in Ca2+ regulation may underlie susceptibility to LTD. Despite age-related differences in LTD induction, no age difference in LTP magnitude was revealed. Additionally, LFS delivered 60 min after LTP induction resulted in similar LTP reversal for both age groups. Susceptibility differences to LTP reversal were indicated after multiple short-duration LFS bursts (30 pulses/1 Hz), with each burst separated by 10 min. Aged synapses exhibited significant reversal after a single burst and complete reversal after three LFS episodes. In adult slices, LTP reversal appeared after the fourth burst, and at no time was LTP depressed to initial baseline levels. This study provides the first characterization of homosynaptic LTD/LTP reversal in the aged animal and demonstrates that one form of plasticity, depression attributable to LFS, is increased during aging.

Many findings suggest that changes in circulating estrogen levels influence cognition, in some cases impairing performance and in others enhancing performance. One interpretation of these mixed effects is that estrogen biases the strategy used to solve a task. To test this idea, young adult female rats, ovariectomized for 21 days, were trained after acute hormone or control treatment in 2 very similar tasks with different cognitive requirements. One task required place learning and the other response learning. Rats given two 10-microg injections of estradiol 48 and 24 hr before training learned the place task significantly faster than did rats without estradiol. Conversely, rats without estradiol performed better on the response task than did rats with replacement. These data suggest that the cognitive actions of estrogen may be task-specific by modulating the relative contribution of different learning and memory systems.

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