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The process of memory consolidation is energy-demanding and brain energy deficits result in memory impairments. Indeed, L-lactate, a preferred neuronal energy substrate, enhances the formation of memory, while blockade of the neuronal uptake of L-lactate by either pharmacological means or using its enantiomer D-lactate, impairs memory. Beyond metabolism, both enantiomers of lactate also have signaling properties through the hydroxycarboxylic acid receptor 1 (HCAR1). Thus far, paradigms testing for an effect of lactate on memory modulation have ignored HCAR1 signaling while also mainly performing manipulations before learning and using intracranial administration techniques. Using an inhibitory avoidance (IA) memory protocol, the present study examined the effects of systemic administration of both L- and D-lactate as well as the specific HCAR1 agonist 3,5-dihydroxybenzoic acid (3,5-DHBA) across pre- and post-training periods. We found that post-training subcutaneous injections of either 3,5-DHBA or D-lactate significantly enhanced memory compared to saline controls, whereas L-lactate had no effect, suggesting that HCAR1 signaling in the absence of lactate metabolism supports memory consolidation processes. When administered 15 minutes prior to training, D-lactate and 3,5-DHBA impaired memory compared to saline controls. In contrast, L-lactate treated rats showed memory enhancements as compared to D-lactate-treated rats. Taken together, these results suggest different roles for lactate at different memory stages. It is likely that a metabolic role is at play during learning while HCAR1 signaling may play a greater role during consolidation., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

One of the now classic tenets of neuroscience is that the brain retains a substantial amount of structural and functional plasticity throughout adulthood and old age. Enriching experiences that stimulate physical and mental activity produce robust changes in subsequent behaviors, including learning and memory, that tap a wide range of neural systems. In this article, we review evidence for cognitive priming with physical and mental exercise through a memory systems lens and present brain-derived neurotrophic factor (BDNF) signaling as one candidate neural mechanism for experience-dependent modulation of learning and memory. We highlight our recent findings showing that priming with voluntary exercise or with spontaneous alternation, a working memory task, enhances new learning of hippocampus-sensitive place, or striatum-sensitive response tasks. Blocking BDNF signaling with infusions of a BDNF receptor inhibitor into hippocampus or striatum just before training on place or response tasks, respectively, abrogated the benefits of priming regardless of the type of priming experience. These results suggest that enhanced BDNF signaling during learning may itself produce the cognitive benefits afforded by prior physical or mental activity., (Copyright © 2013 Wiley Periodicals, Inc.)

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., (Copyright © 2013 Wiley Periodicals, Inc.)

Recent evidence suggests that astrocytes convert glucose to lactate, which is released from the astrocytes and supports learning and memory. This report takes a multiple memory perspective to test the role of astrocytes in cognition using real-time lactate measurements during learning and memory. Extracellular lactate levels in the hippocampus or striatum were determined with lactate biosensors while rats were learning place (hippocampus-sensitive) or response (striatum-sensitive) versions of T-mazes. In the first experiment, rats were trained on the place and response tasks to locate a food reward. Extracellular lactate levels in the hippocampus increased beyond those of feeding controls during place training but not during response training. However, striatal lactate levels did not increase beyond those of controls when rats were trained on either the place or the response version of the maze. Because food ingestion itself increased blood glucose and brain lactate levels, the contribution of feeding may have confounded the brain lactate measures. Therefore, we conducted a second similar experiment using water as the reward. A very different pattern of lactate responses to training emerged when water was used as the task reward. First, provision of water itself did not result in large increases in either brain or blood lactate levels. Moreover, extracellular lactate levels increased in the striatum during response but not place learning, whereas extracellular lactate levels in the hippocampus did not differ across tasks. The findings from the two experiments suggest that the relative engagement of the hippocampus and striatum dissociates not only by task but also by reward type. The divergent lactate responses of the hippocampus and striatum in place and response tasks under different reward conditions may reflect ethological constraints tied to foraging for food and water. [ABSTRACT FROM AUTHOR]