Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward

Highlights

• ECF lactate increases in hippocampus (HC) and striatum (S) during maze learning.

• Relative increases in lactate during learning varied with reward and strategy.

• Place training for food reward increased lactate in HC more than in S.

• Response training for water increased lactate in S more than in HC.

• Type of reward alters the relative contribution of different memory systems.

Abstract

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.

Introduction

Neuroendocrine responses to an experience can regulate brain processes involved in learning and remembering that experience (Gold, 2014, Gold and Korol, 2014). In particular, release of the hormone epinephrine into blood from the adrenal medulla enhances learning and memory across many tasks and species (Gold, 1995, Gold and Korol, 2012). Although circulating epinephrine does not readily cross the blood-brain barrier to enter the brain (Axelrod, Weil-Malherbe, & Tomchick, 1959), the hormone’s peripheral actions, largely at the liver, increase blood glucose levels. The increase in blood glucose levels is both necessary and sufficient for the enhancement of learning and memory by epinephrine (Gold, 2014, Gold and Korol, 2014). Glucose itself enhances learning and memory when administered by systemic administration or by direct brain injections (Gold, 2001, Gold and Korol, 2012, Korol, 2002, Korol and Gold, 2007, Messier, 2004, Messier et al., 1999, Morris and Gold, 2013, Smith et al., 2011, van der Zwaluw et al., 2015).

Of particular interest here, brain lactate may function downstream from glucose to modulate learning and memory. According to this view, glucose enters astrocytes where it can be converted to lactate, which is subsequently used under conditions of heightened activation such as during cognitive processing (Newman, Korol, & Gold, 2011). Like glucose, direct intrahippocampal injections of lactate enhance working memory (Newman et al., 2011) and memory for inhibitory avoidance training (Suzuki et al., 2011). Interfering with lactate transport into neurons by pharmacological or gene expression manipulations impairs memory and attenuates the ability of lactate or glucose to enhance memory (Newman et al., 2011, Suzuki et al., 2011), suggesting that glucose may enhance memory by conversion to lactate in astrocytes for delivery to neurons.

Past findings indicate that extracellular glucose levels in the hippocampus are diminished by spatial working memory testing (McNay et al., 2000, McNay and Gold, 2001, McNay et al., 2001, Newman et al., 2011), with the magnitude of reduction corresponding to the cognitive load of the task (McNay et al., 2000, McNay et al., 2001). The decrease in extracellular glucose levels in the hippocampus during working memory testing is mirrored by an increase in extracellular lactate levels during testing (Newman et al., 2011). The reciprocal changes in hippocampal extracellular glucose and lactate levels are consistent with the idea that lactate may serve as a supplementary energy substrate to neurons during a time of heightened energy utilization (Brown and Ransom, 2015, Magistretti et al., 1999, Pellerin, 2003, Pellerin and Magistretti, 2012). The use of lactate as an energy source is one of several roles lactate may perform to support cognitive functioning (Fryer & Brown, 2015), such as contributions to astrocytic energy needs, particularly to support glutamate and potassium clearance (Dienel and McKenna, 2014, Sonnewald, 2014), glia-neuronal signaling (Barros, 2013, Bergersen and Gjedde, 2012, Bozzo et al., 2013, Tang et al., 2014), and regulation of neurovascular coupling (Gordon et al., 2008, Lauritzen et al., 2013), that in turn may regulate delivery of energy substrates and nutrients to the brain during demanding tasks.

Extensive evidence indicates that different cognitive attributes are subserved by the activity of multiple memory systems. In particular, place (spatial) and response (habit) learning are particularly sensitive to perturbations of functions in the hippocampus and striatum, respectively (Chang and Gold, 2003a, Chang and Gold, 2004, Gold et al., 2013, Kathirvelu and Colombo, 2013, Korol, 2004, Korol and Pisani, 2015, Packard and Goodman, 2013, Packard and McGaugh, 1992, Poldrack and Packard, 2003, White and McDonald, 2002, White et al., 2013). Support for participation of the hippocampus and striatum in these different cognitive attributes comes from demonstrations of double dissociations of task by brain area using lesions or pharmacological interference (Dagnas et al., 2013, Kosaki et al., 2015, McDonald and White, 1994, Soares et al., 2013), direct injections of glutamate (Packard, 1999), glucose (Canal et al., 2005, Pych et al., 2006, Stefani and Gold, 2001), and estradiol (Korol and Pisani, 2015, Zurkovsky et al., 2007, Zurkovsky et al., 2011) in these brain areas.

Several neurochemical and neurophysiological measures of activity in the hippocampus and striatum also exhibit task-specific differences (Chang and Gold, 2003b, Colombo, 2004, Gold, 2004, McIntyre et al., 2003, Mizumori and Jo, 2013, Pleil et al., 2011, Pych et al., 2005, Rubio et al., 2012). In particular, contrasting the response in the hippocampus, extracellular glucose in the striatum does not decline, and may actually rise, during working memory testing (McNay et al., 2001). Thus, the striatum may have metabolic requirements and responses to experiences that differ from those in the hippocampus. Regional differences in the glucose response to memory testing may also reflect the varying contributions of different brain areas to different types of cognition. These regional differences in physiological responses to experience together with the important role of lactate provisions from astrocytes in modulating hippocampus-sensitive learning and memory (Newman et al., 2011, Suzuki et al., 2011), suggest that, when compared to the hippocampus, the striatum may demonstrate a very different pattern of lactate responses to training on tasks that have selective cognitive attributes.

To test the task and regional specificity of metabolic responses to learning, the present experiments examined fluxes in extracellular lactate levels in the hippocampus and striatum while rats were trained on place and response versions of mazes designed to tap the function of each of these brain regions. The first experiment measured extracellular lactate concentrations in the hippocampus and striatum while rats learned to find food in mazes that rely on those neural systems. Because food intake per se increased lactate levels in the brain, perhaps obscuring training-related changes, we also examined extracellular lactate concentrations in a parallel second experiment in which rats were trained using water as the reward to solve the same mazes. The lactate responses to training in hippocampus and striatum dissociated not only by learning strategy, but, unexpectedly, also by the reward used during training.