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.

Though atomoxetine is neurochemically selective, it is not wholly specific at doses >0.3 mg/kg. All doses of the drug were similar in their efficacy in reversing the ED deficit, but the effectiveness of the 0.1 mg/kg dose supports the hypothesis that increases in prefrontal NE alone are sufficient to improve attention in NE-LX rats. Moreover, the detrimental effects of the drug in non-lesioned rats support the hypothesis that optimal levels of NE in prefrontal cortex are critical to attentional set shifting with both supra- and sub-optimal levels producing attentional impairments.

As neuropsychiatric disorders such as schizophrenia, attention deficit disorder, and mood disorders all impact executive function and are likely to be diagnosed prior to adulthood, it is important to understand the normal ontogeny of executive function. Previous behavioral research has shown that adolescents' executive function is different than that of adults. In the present study, we use a previously validated cognitive test, the intradimensional/extradimensional (ID/ED) set-shifting task, to assess attentional set shifting and reversal learning in adolescent and adult, male, Long-Evans rats. These data suggest that adolescent rats are more cognitively rigid than adult rats and have impairments in the shifting, but not formation, of an attentional set. Adolescent rats are also more susceptible to distraction than adult rats when an irrelevant stimulus dimension is introduced as part of a complex stimulus. Moreover, we find that attentional set shifting becomes adult-like at an earlier age than reversal learning. As these functions are mediated by distinct prefrontal subregions, that is, the prelimbic and orbitofrontal cortices, respectively, we hypothesize that prefrontal cortical subregions show slightly different developmental trajectories.

The effects of restricted cholinergic deafferentation of prefrontal cortex in rats on sustained attention were assessed. Attentional demands were increased by presentation of distractor stimuli in a different modality (auditory) or the same modality (visual) as target stimuli. Additionally, the effects of the regularity of the distractor on rats' ability to disregard this stimulus were assessed by testing different frequencies of stimuli for each modality. Cholinergically lesioned rats were more sensitive to the effects of auditory distractors than nonlesioned rats, whereas visual distractors of any frequency potently impaired the performance of all subjects. The effects of the auditory stimuli on attentional performance varied depending on the frequency of the tone. A tone with a predictable pattern enhanced signal detection in all rats. An irregular tone selectively impaired performance of rats with cholinergic lesions. Additional tests suggest that rats use the regular tone to time when to attend. Lesioned rats were impaired when the regular tone was presented with a more variable intertrial interval in a subsequent testing session, suggesting impairments in top-down control. In addition to changes in top-down control of attention, differential effects on performance based on the regularity of the tone suggest that stimulus properties encoded by bottom-up processes are also altered after lesioning. The current data suggest that cholinergic deafferentation of prefrontal cortex alters top-down and bottom-up processing of stimuli.

This article reviews evidence showing that neurochemical modulators can regulate the relative participation of the hippocampus and striatum in learning and memory tasks. For example, relative release of acetylcholine increases in the hippocampus and striatum reflects the relative engagement of these brain systems during learning of place and response tasks. Acetylcholine release is regulated in part by available brain glucose levels, which themselves are dynamically modified during learning. Recent findings suggest that glucose acts through astrocytes to deliver lactate to neurons. Brain glycogen is contained in astrocytes and provides a capacity to deliver energy substrates to neurons when needed, a need that can be generated by training on tasks that target hippocampal and striatal processing mechanisms. These results integrate an increase in blood glucose after epinephrine release from the adrenal medulla with provision of brain energy substrates, including lactate released from astrocytes. Together, the availability of peripheral and central energy substrates regulate the processing of learning and memory within and across multiple neural systems. Dysfunctions of the physiological steps that modulate memory-from hormones to neurotransmitters to metabolic substrates-may contribute importantly to some of the cognitive impairments seen during normal aging and during neurodegenerative diseases. V C 2013 Wiley Periodicals, Inc.