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Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron -Astrocyte Metabolic Coupling in Long Term Memory.

Tadi M, Allaman I, Lengacher S, Grenningloh G, Magistretti PJ - PLoS ONE (2015)

Bottom Line: The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner.Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K-ATPase and glucose transporter type 1.Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

ABSTRACT
We examined the expression of genes related to brain energy metabolism and particularly those encoding glia (astrocyte)-specific functions in the dorsal hippocampus subsequent to learning. Context-dependent avoidance behavior was tested in mice using the step-through Inhibitory Avoidance (IA) paradigm. Animals were sacrificed 3, 9, 24, or 72 hours after training or 3 hours after retention testing. The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner. Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K-ATPase and glucose transporter type 1. To assess the functional role for one of these genes in learning, we studied MCT1 deficient mice and found that they exhibit impaired memory in the inhibitory avoidance task. Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

No MeSH data available.


Related in: MedlinePlus

Metabolic mapping of the brain following inhibitory avoidance (IA) learning.(A) IA learning: Mice subjected to IA training (CS-US) show long-term memory while those exposed only to the training session without a foot shock (CS) do not acquire the task. Step-through transfer latencies during training and on the retention testing, 24 hours after training are shown. The baseline latencies were not significantly different between the two groups (P> 0.05). During the retention testing, the CS-US group had longer mean step-through latency than the control mice. Data were statistically analyzed with unpaired t-test (***P < 0.001 vs CS group, n = 40/group). (B) Experimental protocol: Schematic representation of the IA task and time structure of the different experimental groups used for the study. (i) [14C] 2DG technique allowed metabolic mapping of the brain regions activated during retention testing. (ii, iii) Gene expression analysis was performed either after inhibitory avoidance training or testing and accordingly animals were sacrificed either at 3, 9, 24 or 72 hours following training or 3 hours after retention testing. Quantitative mRNA levels for genes related to brain energy metabolism were probed in the dorsal hippocampus. (C, D) Functional activation of the brain during IA retention testing: Representative digitized autoradiograms of the distribution of [14C] 2DG uptake on brain sections from the CS and CS-US group. Arrows point to dorsal hippocampus (C) and basolateral amygdala (BLA, D). Outlines mark boundaries in which optical density was measured. In the autoradiographs the level of [14C] 2DG uptake is shown in a color scale ranging from blue (no uptake at all) to red (maximal uptake). [14C] 2DG uptake was quantified in the region of interests (ROIs) during retention testing. [14C] 2DG uptake (nCi/g) was evaluated by film densitometry and is expressed as mean ± SEM. CS-US group exhibited increased glucose utilization on the retention test, in the hippocampus (C, unpaired t-test with Welch’s correction, P< 0.0001, t = 9.445, df = 14) and in the amygdala (BLA and LA) (D, unpaired t-test with Welch’s correction P< 0.0001, t = 7.416, df = 14).
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pone.0141568.g001: Metabolic mapping of the brain following inhibitory avoidance (IA) learning.(A) IA learning: Mice subjected to IA training (CS-US) show long-term memory while those exposed only to the training session without a foot shock (CS) do not acquire the task. Step-through transfer latencies during training and on the retention testing, 24 hours after training are shown. The baseline latencies were not significantly different between the two groups (P> 0.05). During the retention testing, the CS-US group had longer mean step-through latency than the control mice. Data were statistically analyzed with unpaired t-test (***P < 0.001 vs CS group, n = 40/group). (B) Experimental protocol: Schematic representation of the IA task and time structure of the different experimental groups used for the study. (i) [14C] 2DG technique allowed metabolic mapping of the brain regions activated during retention testing. (ii, iii) Gene expression analysis was performed either after inhibitory avoidance training or testing and accordingly animals were sacrificed either at 3, 9, 24 or 72 hours following training or 3 hours after retention testing. Quantitative mRNA levels for genes related to brain energy metabolism were probed in the dorsal hippocampus. (C, D) Functional activation of the brain during IA retention testing: Representative digitized autoradiograms of the distribution of [14C] 2DG uptake on brain sections from the CS and CS-US group. Arrows point to dorsal hippocampus (C) and basolateral amygdala (BLA, D). Outlines mark boundaries in which optical density was measured. In the autoradiographs the level of [14C] 2DG uptake is shown in a color scale ranging from blue (no uptake at all) to red (maximal uptake). [14C] 2DG uptake was quantified in the region of interests (ROIs) during retention testing. [14C] 2DG uptake (nCi/g) was evaluated by film densitometry and is expressed as mean ± SEM. CS-US group exhibited increased glucose utilization on the retention test, in the hippocampus (C, unpaired t-test with Welch’s correction, P< 0.0001, t = 9.445, df = 14) and in the amygdala (BLA and LA) (D, unpaired t-test with Welch’s correction P< 0.0001, t = 7.416, df = 14).

Mentions: In this study, we investigated some aspects of the molecular mechanisms underlying learning and memory, by focusing on genes involved in energy metabolism, with a particular emphasis on neuron-glia metabolic coupling. We used IA task to study the expression of genes involved in brain energy metabolism following memory formation. This task requires hippocampal-dependent learning and transcription and has been widely used to characterize the biochemical requirements for memory formation, particularly in the hippocampus [20–22]. Two groups were used for this study. A conditioned group of mice (CS-US group) received a footshock after they entered into the dark compartment in the training session. The control (unconditioned) animals were treated similarly, except that they did not receive a footshock in the dark compartment (CS group). Twenty-four hours following training, the CS-US group exhibited 7 times longer latencies (96.5 ± 9.7 vs 13.1 ± 0.5 sec) to enter the dark compartment (Fig 1A), as compared to the CS group. This indicates that only the CS-US group has learned to associate the stepping through to the dark chamber with the aversive foot shock.


Learning-Induced Gene Expression in the Hippocampus Reveals a Role of Neuron -Astrocyte Metabolic Coupling in Long Term Memory.

Tadi M, Allaman I, Lengacher S, Grenningloh G, Magistretti PJ - PLoS ONE (2015)

Metabolic mapping of the brain following inhibitory avoidance (IA) learning.(A) IA learning: Mice subjected to IA training (CS-US) show long-term memory while those exposed only to the training session without a foot shock (CS) do not acquire the task. Step-through transfer latencies during training and on the retention testing, 24 hours after training are shown. The baseline latencies were not significantly different between the two groups (P> 0.05). During the retention testing, the CS-US group had longer mean step-through latency than the control mice. Data were statistically analyzed with unpaired t-test (***P < 0.001 vs CS group, n = 40/group). (B) Experimental protocol: Schematic representation of the IA task and time structure of the different experimental groups used for the study. (i) [14C] 2DG technique allowed metabolic mapping of the brain regions activated during retention testing. (ii, iii) Gene expression analysis was performed either after inhibitory avoidance training or testing and accordingly animals were sacrificed either at 3, 9, 24 or 72 hours following training or 3 hours after retention testing. Quantitative mRNA levels for genes related to brain energy metabolism were probed in the dorsal hippocampus. (C, D) Functional activation of the brain during IA retention testing: Representative digitized autoradiograms of the distribution of [14C] 2DG uptake on brain sections from the CS and CS-US group. Arrows point to dorsal hippocampus (C) and basolateral amygdala (BLA, D). Outlines mark boundaries in which optical density was measured. In the autoradiographs the level of [14C] 2DG uptake is shown in a color scale ranging from blue (no uptake at all) to red (maximal uptake). [14C] 2DG uptake was quantified in the region of interests (ROIs) during retention testing. [14C] 2DG uptake (nCi/g) was evaluated by film densitometry and is expressed as mean ± SEM. CS-US group exhibited increased glucose utilization on the retention test, in the hippocampus (C, unpaired t-test with Welch’s correction, P< 0.0001, t = 9.445, df = 14) and in the amygdala (BLA and LA) (D, unpaired t-test with Welch’s correction P< 0.0001, t = 7.416, df = 14).
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pone.0141568.g001: Metabolic mapping of the brain following inhibitory avoidance (IA) learning.(A) IA learning: Mice subjected to IA training (CS-US) show long-term memory while those exposed only to the training session without a foot shock (CS) do not acquire the task. Step-through transfer latencies during training and on the retention testing, 24 hours after training are shown. The baseline latencies were not significantly different between the two groups (P> 0.05). During the retention testing, the CS-US group had longer mean step-through latency than the control mice. Data were statistically analyzed with unpaired t-test (***P < 0.001 vs CS group, n = 40/group). (B) Experimental protocol: Schematic representation of the IA task and time structure of the different experimental groups used for the study. (i) [14C] 2DG technique allowed metabolic mapping of the brain regions activated during retention testing. (ii, iii) Gene expression analysis was performed either after inhibitory avoidance training or testing and accordingly animals were sacrificed either at 3, 9, 24 or 72 hours following training or 3 hours after retention testing. Quantitative mRNA levels for genes related to brain energy metabolism were probed in the dorsal hippocampus. (C, D) Functional activation of the brain during IA retention testing: Representative digitized autoradiograms of the distribution of [14C] 2DG uptake on brain sections from the CS and CS-US group. Arrows point to dorsal hippocampus (C) and basolateral amygdala (BLA, D). Outlines mark boundaries in which optical density was measured. In the autoradiographs the level of [14C] 2DG uptake is shown in a color scale ranging from blue (no uptake at all) to red (maximal uptake). [14C] 2DG uptake was quantified in the region of interests (ROIs) during retention testing. [14C] 2DG uptake (nCi/g) was evaluated by film densitometry and is expressed as mean ± SEM. CS-US group exhibited increased glucose utilization on the retention test, in the hippocampus (C, unpaired t-test with Welch’s correction, P< 0.0001, t = 9.445, df = 14) and in the amygdala (BLA and LA) (D, unpaired t-test with Welch’s correction P< 0.0001, t = 7.416, df = 14).
Mentions: In this study, we investigated some aspects of the molecular mechanisms underlying learning and memory, by focusing on genes involved in energy metabolism, with a particular emphasis on neuron-glia metabolic coupling. We used IA task to study the expression of genes involved in brain energy metabolism following memory formation. This task requires hippocampal-dependent learning and transcription and has been widely used to characterize the biochemical requirements for memory formation, particularly in the hippocampus [20–22]. Two groups were used for this study. A conditioned group of mice (CS-US group) received a footshock after they entered into the dark compartment in the training session. The control (unconditioned) animals were treated similarly, except that they did not receive a footshock in the dark compartment (CS group). Twenty-four hours following training, the CS-US group exhibited 7 times longer latencies (96.5 ± 9.7 vs 13.1 ± 0.5 sec) to enter the dark compartment (Fig 1A), as compared to the CS group. This indicates that only the CS-US group has learned to associate the stepping through to the dark chamber with the aversive foot shock.

Bottom Line: The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner.Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K-ATPase and glucose transporter type 1.Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

View Article: PubMed Central - PubMed

Affiliation: Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

ABSTRACT
We examined the expression of genes related to brain energy metabolism and particularly those encoding glia (astrocyte)-specific functions in the dorsal hippocampus subsequent to learning. Context-dependent avoidance behavior was tested in mice using the step-through Inhibitory Avoidance (IA) paradigm. Animals were sacrificed 3, 9, 24, or 72 hours after training or 3 hours after retention testing. The quantitative determination of mRNA levels revealed learning-induced changes in the expression of genes thought to be involved in astrocyte-neuron metabolic coupling in a time dependent manner. Twenty four hours following IA training, an enhanced gene expression was seen, particularly for genes encoding monocarboxylate transporters 1 and 4 (MCT1, MCT4), alpha2 subunit of the Na/K-ATPase and glucose transporter type 1. To assess the functional role for one of these genes in learning, we studied MCT1 deficient mice and found that they exhibit impaired memory in the inhibitory avoidance task. Together, these observations indicate that neuron-glia metabolic coupling undergoes metabolic adaptations following learning as indicated by the change in expression of key metabolic genes.

No MeSH data available.


Related in: MedlinePlus