Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

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

Intrahippocampal muscimol shifts learning strategy in gonadally intact young adult female rats

Learning strategy preferences depend upon circulating estrogen levels, with enhanced hippocampus-sensitive place learning coinciding with elevated estrogen levels. The effects of estrogen on strategy may be mediated by fluctuations in GABAergic function, given that inhibitory tone in the hippocampus is low when estrogen is high. We investigated the effects on learning strategy of intrahippocampal injections of a GABA(A) agonist in gonadally intact female rats. On the day of training, rats received 0.3 μL intrahippocampal infusions of muscimol (0.26 nmol or 2.6 nmol) or saline 20 min prior to training on a T-maze in which place (hippocampus-sensitive) or response (striatum-sensitive) strategies offer effective solutions. Muscimol treatment increased the use of the response strategy in a dose-dependent manner without influencing learning speed, indicating that muscimol modulated strategy and not learning ability. Furthermore, the muscimol-related shift to response strategies varied across the estrous cycle. The results indicate that increasing inhibition in the hippocampus biases rats away from hippocampus-sensitive place learning strategies and toward hippocampus-insensitive response learning strategies without a learning deficit. Furthermore, rats at proestrus demonstrated the most dramatic shift in learning strategy following muscimol treatment compared with control conditions, while rats at estrus demonstrated the most complete bias toward response strategies. The enhanced use of hippocampus-sensitive strategies at proestrus likely results from reduced hippocampal inhibition

Impairment of memory by DAB injections, used to inhibit glycogenolysis.

<p>The impairment was reversed by lactate or glucose, which can act downstream of glycogenolysis. 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) injected into the ventral hippocampus 5 min prior to testing significantly impaired scores on a 4-arm spontaneous alternation task (n = 12; Percent Alternation ± SEM: Saline = 71%±3.7% vs. 5 pmol DAB = 58.8%±3.6%, p<0.02 and vs. 50 pmol DAB = 41.6%±3.2%, p<0.001). The performance deficit created by 100 µM of DAB was significantly reversed by the co-administration of 100 mM lactate or 50 mM glucose (Percent Alternation ± SEM: 50 pmol DAB = 41.6%±3.2% vs. 25 nmol of glucose and 50 pmol DAB = 62.6%±3.1%, p<0.001 and 50 nmol of lactate and 50 pmol DAB = 56.2%±2.9%, p<0.01).</p

Representative histology showing SDH activity in the ventral hippocampus.

<p>In this example, the left hemisphere received infusions of 1% DMSO in saline (left) and the right hemisphere received infusions of 30 pmol 4-CIN. There were no significant differences in optical density between ventral hippocampal areas receiving 30 pmol of 4-CIN or 1% DMSO in saline in CA1, CA3, or dentate gyrus (n = 6; p>0.1).</p

Model of astrocytic contribution of lactate to memory processing.

<p>Pharmacological tests and measures of many aspects of this figure were tested in the present experiments. DAB: 1,4-dideoxy = 1,4-imino-D-aribinitol, 4-CIN: α-cyano-4-hydroxycinnamate, MCT: monocarboxylate transporter.</p

Enhancement of memory with intrahippocampal injections of lactate.

<p>Lactate injected into the ventral hippocampus 5 min before testing improved the percent alternation scores on a 4-arm delayed spontaneous alternation task at the 50 nmol dose (n = 10; F_3,27 = 4.04, p<0.02; Percent Alternation ± SEM: Saline = 34.5%±8.9% vs. 50 nmol Lactate = 61.2%±6.5%). Higher and lower doses of lactate did not significantly improve alternation scores.</p

Effects of Chronic Estradiol Treatment on Delayed Spatial Alternation and Differential Reinforcement of Low Rates of Responding

Estrogens have been shown to both enhance and impair cognitive function depending on several factors, including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2 ± 8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol -treated rats showed a lower ratio of reinforced to nonreinforced presses. These data suggest that chronic estrogen exposure may impair rats\u27 abilities on measures of executive function including working memory and response inhibition. © 2008 American Psychological Association