Part 3:Astrocyte Glycogen And Lactate: New Insights Into Learning And Memory Mechanisms
Mar 14, 2022
For more information:ali.ma@wecistanche.com
Conclusions
Although most previous studies on the biological mechanisms of memory formation and storage have centered on neuronal mechanisms, attention has recently been given to the roles of other brain cell types, and in particular glia. Here, we reviewed the evidence for the role of astrocytes in regulating glycogen and glucose metabolisms, and their functional coupling to neurons via lactate transfer, which is necessary for memory formation. Furthermore, we discussed studies performed in different species revealing the critical role of astrocytic βARs in regulating the consolidation and modulation of memory. We suggest that astrocytic glycogenolysis and/or glycolysis in conjunction with astrocytic–neuronal lactate shuttling, provide a mechanistic explanation for a critical role of astrocytes in memory formation and storage. These findings offer only an initial understanding ofthe metabolic cooperation between astrocytes and neurons in memory; future studies shall elucidate the functions of glycogenolysis and lactate in many other important and complex brain functions. Many questions remain to be addressed. In the context of memory research, the outstanding issues include whether the lactate-mediated metabolic coupling is a general mechanism engaged in different types of learning and memory, or only in memories encoded under arousal states. Other important outstanding questions include: Are these mechanisms common to any brain region in response to activity? Are they providing metabolic fuel or also cellular signaling? Which target mechanisms and cellular function do they support? How do these metabolic mechanisms mature during development, when the brain consumes the highest amount of energy? And finally, what are the implications when these mechanisms fail? These questions should be addressed in the near future, and the answers will greatly advance our understanding of the cooperative roles of different cell types in learning and memory processes.
Click to cistanche extract powder and Cistanche for memory
Acknowledgments
This work was supported by NIH Grants MH100822 and MH065635 to CMA and NIH Grant F30 MH098570 to VG.
References
Adamsky A, Goshen I. Astrocytes in memory function: Pioneering findings and future directions. Neuroscience. 2017
Alberini CM. Transcription Factors in Long-Term Memory and Synaptic Plasticity. Physiological Reviews. 2009; 89:121–145. [PubMed: 19126756]
Alberini CM, Kandel ER. The regulation of transcription in memory consolidation. Cold Spring Harb Perspect Biol. 2014; 7:a021741. [PubMed: 25475090]
Alberini CM, Travaglia A. Infantile Amnesia: A Critical Period of Learning to Learn and Remember. J Neurosci. 2017; 37(24):5783–5795. [PubMed: 28615475]
Aubert A, Costalat R, Magistretti PJ, Pellerin L. Brain lactate kinetics: modeling evidence for neuronal lactate uptake upon activation. Proc Natl Acad Sci U S A. 2005; 102:16448–16453. [PubMed: 16260743]
Bailey CH, Kandel ER, Harris KM. Structural Components of Synaptic Plasticity and Memory Consolidation. Cold Spring Harb Perspect Biol. 2015; 7:a021758. [PubMed: 26134321]
Baker KD, Edwards TM. D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick. Neurobiol Learn Mem. 2007; 88:269–276. [PubMed: 17692538]
Bandeira F, Lent R, Herculano-Houzel S. Changing numbers of neuronal and non-neuronal cells underlie postnatal brain growth in the rat. Proceedings of the National Academy of Sciences. 2009;
106:14108–14113.
Basu J, Betz A, Brose N, Rosenmund C. Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. J Neurosci. 2007; 27:1200–10. [PubMed: 17267576]
Bazargani N, Attwell D. Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016; 19:182– 189. [PubMed: 26814587]
Bejar R, Yasuda R, Krugers H, Hood K, Mayford M. Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory. J Neurosci. 2002; 22:5719–26. [PubMed: 12097524]
Bélanger M, Allaman I, Magistretti Pierre J. Brain Energy Metabolism: Focus on Astrocyte-Neuron Metabolic Cooperation. Cell Metabolism. 2011; 14:724–738. [PubMed: 22152301]
Bergersen L, Waerhaug O, Helm J, Thomas M, Laake P, Davies AJ, Wilson MC, Halestrap AP, Ottersen OP. A novel postsynaptic density protein: the monocarboxylate transporter MCT2 is co-localized with delta-glutamate receptors in postsynaptic densities of parallel fiber-Purkinje cell synapses. Exp Brain Res. 2001; 136:523–34. [PubMed: 11291733]
Bergersen LH. Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction. J Cereb Blood Flow Metab. 2015; 35:176–85. [PubMed: 25425080]
Bergersen LH, Magistretti PJ, Pellerin L. Selective postsynaptic co-localization ofMCT2 with AMPA receptor GluR2/3 subunits at excitatory synapses exhibiting AMPA receptor trafficking. Cereb Cortex. 2005; 15:361–70. [PubMed: 15749979]
Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993; 361:31–9. [PubMed: 8421494]
Bolaños JP, Almeida A, Moncada S. Glycolysis: a bioenergetic or a survival pathway? Trends in
Biochemical Sciences. 2010; 35:145–149. [PubMed: 20006513]
Boury-Jamot B, Carrard A, Martin JL, Halfon O, Magistretti PJ, Boutrel B. Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol Psychiatry.2016; 21:1070–1076. [PubMed: 26503760]
Bramham CR, Worley PF, Moore MJ, Guzowski JF. The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J Neurosci. 2008; 28:11760–7. [PubMed: 19005037]
Bredy TW, Lin Q, Wei W, Baker-Andresen D, Mattick JS. MicroRNA regulation of neural plasticity and memory. Neurobiol Learn Mem. 2011; 96:89–94. [PubMed: 21524708]
Brekke E, Morken TS, Sonnewald U. Glucose metabolism and astrocyte-neuron interactions in the neonatal brain. Neurochemistry International. 2015; 82:33–41. [PubMed: 25684072]
Brooks GA. Lactate: the link between glycolytic and oxidative metabolism. Sports Med. 2007; 37:341–3. [PubMed: 17465603]
Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009; 587:5591–600. [PubMed:19805739]
Brooks, GA. Comprehensive Physiology. John Wiley & Sons, Inc; 2011. Bioenergetics of Exercising Humans.
Brooks GA. Energy Flux, Lactate Shuttling, Mitochondrial Dynamics, and Hypoxia. Adv Exp Med Biol. 2016; 903:439–55. [PubMed: 27343113]
Brown AM, Baltan Tekkök S, Ransom BR. Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochemistry International. 2004; 45:529–536. [PubMed: 15186919]
Brown AM, Ransom BR. Astrocyte glycogen is an emergency fuel under conditions ofglucose deprivation or intense neural activity. Metab Brain Dis. 2015; 30:233–9. [PubMed: 25037166]
Brunet JF, Allaman I, Magistretti PJ, Pellerin L. Glycogen Metabolism as a Marker of Astrocyte Differentiation. Journal of Cerebral Blood Flow & Metabolism. 2010; 30:51–55. [PubMed: 19809466]
Buzsáki G. Hippocampal sharp wave-ripple: A cognitive biomarker for episodic memory and planning. Hippocampus. 2015; 25:1073–1188. [PubMed: 26135716]
Cahill L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature. 1994; 371:702–4. [PubMed: 7935815]
Cali C, Baghabra J, Boges DJ, Holst GR, Kreshuk A, Hamprecht FA, et al. Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues. J Comp Neurol. 2016; 524:23–38[PubMed: 26179415]
Cash R, Raisman R, Lanfumey L, Ploska A, Agid Y. Cellular localization of adrenergic receptors in rat and human brain. Brain Res. 1986; 370:127–35. [PubMed: 3085866]
Cataldo AM, Broadwell RD. Cytochemical identification of cerebral glycogen and glucose-6- phosphatase activity under normal and experimental conditions. I. Neuronsandglia. J Electron Microsc Tech. 1986; 3:413–437.
Catus SL, Gibbs ME, Sato M, Summers RJ, Hutchinson DS. Role of beta-adrenoceptors in glucose uptake in astrocytes using beta-adrenoceptor knockout mice. Br J Pharmacol. 2011; 162:1700–15. [PubMed: 21138422]
Chandley MJ, Szebeni A, Szebeni K, Crawford JD, Stockmeier CA, Turecki G, Kostrzewa RM, Ordway GA. Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int J Neuropsychopharmacol. 2014; 17:1569–78. [PubMed: 24925192]
Chih C-P, Lipton P, Roberts EL. Do active cerebral neurons really use lactate rather than glucose? Trends Neurosci. 2001; 24:573–578. [PubMed: 11576670]
Chih C-P, Roberts EL. Energy Substrates for Neurons during Neural Activity: A Critical Review of the Astrocyte-Neuron Lactate Shuttle Hypothesis. Journal of Cerebral Blood Flow & Metabolism.2003; 23:1263–1281. [PubMed: 14600433]
Choi HB, Gordon GR, Zhou N, Tai C, Rungta RL, Martinez J, et al. Metabolic communication
between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron. 2012; 75:1094–1104. [PubMed: 22998876]
Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 2013; 14:311–321. [PubMed: 23595014]
Corcoran KA, Frick BJ, Radulovic J, Kay LM. Analysis of coherent activity between retrosplenial cortex, hippocampus, thalamus, and anterior cingulate cortex during retrieval ofrecent and remote context fear memory. Neurobiology of Learning and Memory. 2016; 127:93–101. [PubMed: 26691782]
Cruz NF, Dienel GA. High Glycogen Levels in Brains ofRats with Minimal Environmental Stimuli: Implications for Metabolic Contributions of Working Astrocytes. Journal of Cerebral Blood Flow & Metabolism. 2002; 22:1476–1489. [PubMed: 12468892]
Davis Ronald L. Traces of drosophila Memory. Neuron. 2011; 70:8–19. [PubMed: 21482352]
Day Jeremy J, Sweatt JD. Epigenetic Mechanisms in Cognition. Neuron. 2011; 70:813–829. [PubMed: 21658577]
de la Fuente V, Federman N, Zalcman G, Salles A, Freudenthal R, Romano A. NF-kappaB transcription factor role in consolidation and reconsolidation of persistent memories. Front Mol Neurosci. 2015; 8:50. [PubMed: 26441513]
Debernardi R, Pierre K, Lengacher S, Magistretti PJ, Pellerin L. Cell-specific expression pattern of monocarboxylate transporters in astrocytes and neurons observed in different mouse brain cortical cell cultures. Journal ofNeuroscience Research. 2003; 73:141–155. [PubMed: 12836157]
Dienel GA, Hertz L. Glucose and lactate metabolism during brain activation. J Neurosci Res. 2001; 66:824–838. [PubMed: 11746408]
Dienel GA, Cruz NF. Nutrition during brain activation: does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought? Neurochem Int. 2004; 45:321–51. [PubMed: 15145548]
Dienel GA. Astrocytes are ‘good scouts’: being prepared also helps neighboring neurons. J Cereb Blood Flow Metab. 2010; 30:1893–1894. [PubMed: 20827263]
Dienel GA, Cruz NF. Contributions of glycogen to astrocytic energetics during brain activation. Metabolic Brain Disease. 2015; 30:281–298. [PubMed: 24515302]
Dienel GA. Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte-neuron lactate shuttle in the brain. J Neurosci Res. 2017 Feb 2.
DiNuzzo M, Mangia S, Maraviglia B, Giove F. Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen-derived lactate shuttling to neurons: evidence from mathematical modeling. J Cereb Blood Flow Metab. 2010; 30:1895–1904. [PubMed: 20827264]
Dombrowski GJ Jr, Swiatek KR, Chao KL. Lactate, 3-hydroxybutyrate, and glucose as substrates for the early postnatal rat brain. Neurochem Res. 1989; 14:667–75. [PubMed: 2779727]
Dong JH, Chen X, Cui M, Yu X, Pang Q, Sun JP. beta2-adrenergic receptor and astrocyte glucose metabolism. J Mol Neurosci. 2012; 48:456–63. [PubMed: 22399228]
Dornelles A, de Lima MN, Grazziotin M, Presti-Torres J, Garcia VA, Scalco FS, Roesler R, Schroder N. Adrenergic enhancement of consolidation of object recognition memory. Neurobiol Learn Mem. 2007; 88:137–42. [PubMed: 17368053]
Du F, Zhu X-H, Zhang Y, Friedman M, Zhang N, Uğurbil K, Chen W. Tightly coupled brain activity and cerebral ATP metabolic rate. Proceedings of the National Academy of Sciences. 2008;105:6409–6414.
Dubnau J, Tully T. Gene discovery in Drosophila: new insights for learning and memory. Annu Rev Neurosci. 1998; 21:407–44. [PubMed: 9530502]
Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004; 55:51–86. [PubMed: 14744210]
Dudai Y, Karni A, Born J. The Consolidation and Transformation of memory. Neuron. 2015; 88:20– 32. [PubMed: 26447570]
Duran J, Saez I, Gruart A, Guinovart JJ, Delgado-García JM. Impairment in Long-Term Memory Formation and Learning-Dependent Synaptic Plasticity in Mice Lacking Glycogen Synthase in the Brain. Journal of Cerebral Blood Flow & Metabolism. 2013; 33:550–556. [PubMed: 23281428]
Eichenbaum H. Remembering: functional organization ofthe declarative memory system. Curr Biol.2006; 16:R643–5. [PubMed: 16920614]
Falkowska A, Gutowska I, Goschorska M, Nowacki P, Chlubek D, Baranowska-Bosiacka I. Energy Metabolism of the Brain, Including the Cooperation between Astrocytes and Neurons, Especially in the Context of Glycogen Metabolism. International Journal of Molecular Sciences. 2015;16:25939.
Fanselow MS, Kim JJ, Yipp J, De Oca B. Differential effects ofthe N-methyl-D-aspartate antagonist DL-2-amino-5-phosphonovalerate on the acquisition of fear of auditory and contextual cues. Behav Neurosci. 1994; 108:235–40. [PubMed: 7913606]
Fields RD. White matter in learning, cognition, and psychiatric disorders. Trends in Neurosciences.2008; 31:361–370. [PubMed: 18538868]
Flint RW Jr, Riccio DC. Post-training Glucose Administration Attenuates Forgetting ofPassive-Avoidance Conditioning in 18-Day-Old Rats. Neurobiology of Learning and Memory. 1999; 72:62–67. [PubMed: 10371716]
Flint RW Jr, Riccio DC. Pretest administration of glucose attenuates infantile amnesia for passive avoidance conditioning in rats. Dev Psychobiol. 1997; 31:207–16. [PubMed: 9386922] Franklin TB, Mansuy IM. The prevalence of epigenetic mechanisms in the regulation of cognitive functions and behavior. Curr Opin Neurobiol. 2010; 20:441–9. [PubMed: 20451368]
Fu W, Jhamandas JH. Role of astrocytic glycolytic metabolism in Alzheimer’s disease pathogenesis. Biogerontology. 2014; 15:579–86. [PubMed: 25106114]
Fukazawa Y, Saitoh Y, Ozawa F, Ohta Y, Mizuno K, Inokuchi K. Hippocampal LTP is accompanied by enhanced F-actin content within the dendritic spine that is essential for late LTP maintenance in vivo. Neuron. 2003; 38:447–60. [PubMed: 12741991]
Gao V, Suzuki A, Magistretti PJ, Lengacher S, Pollonini G, Steinman MQ, Alberini CM. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation. Proceedings of the National Academy of Sciences. 2016; 113:8526–8531.
Gibbs ME. Role of Glycogenolysis in Memory and Learning: Regulation by Noradrenaline, Serotonin and ATP. Frontiers in Integrative Neuroscience. 2016:9. [PubMed: 26973476]
Gibbs ME, Anderson DG, Hertz L. Inhibition of glycogenolysis in astrocytes interrupt memory consolidation in young chickens. Glia. 2006; 54:214–222. [PubMed: 16819764]
Gibbs ME, Hertz L. Inhibition of astrocytic energy metabolism by d-lactate exposure impairs memory. Neurochemistry International. 2008; 52:1012–1018. [PubMed: 18063442]
Gibbs ME, Hutchinson D, Hertz L. Astrocytic involvement in learning and memory consolidation. Neurosci Biobehav Rev. 2008; 32:927–44. [PubMed: 18462796]
Gibbs ME, Hutchinson DS, Summers RJ. Noradrenaline release in the locus coeruleus modulates memory formation and consolidation; roles for alpha- and beta-adrenergic receptors. Neuroscience. 2010; 170:1209–22. [PubMed: 20709158]
Gibbs ME, Lloyd HGE, Santa T, Hertz L. Glycogen is a preferred glutamate precursor during learning in 1-day-old chick: Biochemical and behavioral evidence. Journal of neuroscience Research. 2007; 85:3326–3333. [PubMed: 17455305]
Gjedde A, Marrett S, Vafaee M. Oxidative and Nonoxidative Metabolism of excited Neurons and Astrocytes. Journal of Cerebral Blood Flow & Metabolism. 2002; 22:1–14. [PubMed: 11807388]
Gold P, Korol D. Making Memories Matter. Frontiers in Integrative Neuroscience. 2012:6. [PubMed: 22375106]
Gonzalez-Burgos I, Feria-Velasco A. Serotonin/dopamine interaction in memory formation. Prog Brain Res. 2008; 172:603–23. [PubMed: 18772052]
Gordon GR, Choi HB, Rungta RL, Ellis-Davies GC, MacVicar BA. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature. 2008; 456:745–9. [PubMed: 18971930]
Guzowski JF. Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches. Hippocampus. 2002; 12:86–104. [PubMed: 11918292]
Halestrap AP. The SLC16 gene family – Structure, role and regulation in health and disease. Molecular Aspects ofMedicine. 2013; 34:337–349. [PubMed: 23506875]
Hamberger A, Hydén H. Inverse enzymatic changes in neurons and glia during increased function and hypoxia. The Journal of Cell Biology. 1963; 16:521–525. [PubMed: 13952284]
Harris Julia J, Jolivet R, Attwell D. Synaptic Energy Use and Supply. Neuron. 2012; 75:762–777.[PubMed: 22958818]
Hawkins RA, Williamson DH, Krebs HA. Ketone-body utilization by adult and suckling rat brain in vivo. Biochemical Journal. 1971; 122:13–18. [PubMed: 5124783]
Haydon PG, Nedergaard M. How do astrocytes participate in neural plasticity? Cold Spring Harb Perspect Biol. 2014; 7:a020438. [PubMed: 25502516]
Henneberger C, Papouin T, Oliet SH, Rusakov DA. Long-term potentiation depends on the release ofD- serine from astrocytes. Nature. 2010; 463:232–6. [PubMed: 20075918]
Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009; 11:747–752. [PubMed: 19448625]
Hertz L, Gibbs ME. What learning in day-old chickens can teach a neurochemist: focus on astrocyte metabolism. J Neurochem. 2009; 109(Suppl 1):10–6. [PubMed: 19393003]
Hertz L, Gibbs ME, O’Dowd BS, Sedman GL, Robinson SR, SykovÁ EVA, Hajek I, Hertz E, Liang P, Rong H, et al. Astrocyte-Neuron Interaction During One-trial Aversive Learning in the Neonate Chick. Neuroscience & Biobehavioral Reviews. 1996; 20:537–551. [PubMed: 8880738]
Hertz L, O’Dowd BS, Ng KT, Gibbs ME. Reciprocal changes in forebrain contents of glycogen and of glutamate/glutamine during early memory consolidation in the day-old chick. Brain Research. 2003; 994:226–233. [PubMed: 14642648]
Hu Y, Wilson GS. A Temporary Local Energy Pool Coupled to Neuronal Activity: Fluctuations of Extracellular Lactate Levels in Rat Brain Monitored with Rapid-Response Enzyme-Based Sensor. Journal of Neurochemistry. 1997; 69:1484–1490. [PubMed: 9326277]
Hutchinson DS, Summers RJ, Gibbs ME. Beta2- and beta3-adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement? J Neurochem. 2007; 103:997–1008. [PubMed: 17680985]
Hydén H, Lange PW. A kinetic study ofthe neuron-glia relationship. The Journal of Cell Biology.1962; 13:233–237. [PubMed: 14450328]
Inda MC, Muravieva EV, Alberini CM. Memory Retrieval and the Passage ofTime: From Reconsolidation and Strengthening to Extinction. The Journal of neuroscience. 2011; 31:1635– 1643. [PubMed: 21289172]
Inostroza M, Born J. Sleep for preserving and transforming episodic memory. Annu Rev Neurosci.2013; 36:79–102. [PubMed: 23642099]
Isingrini E, Perret L, Rainer Q, Amilhon B, Guma E, Tanti A, Martin G, Robinson J, Moquin L, Marti F, et al. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons. Nat Neurosci. 2016; 19:560–3. [PubMed: 26878672]
Jensen CJ, Demol F, Bauwens R, Kooijman R, Massie A, Villers A, Ris L, De Keyser J. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice. PLoS One. 2016; 11:e0164721. [PubMed: 27776147]
Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S, Charnay P, Bozon B, Laroche S,Davis S. A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci. 2001; 4:289–96. [PubMed: 11224546]
Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses.Science. 2001; 294:1030–8. [PubMed: 11691980]
Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Molecular Brain. 2012; 5:14. [PubMed: 22583753]
Kandel Eric R, Dudai Y, Mayford Mark R. The Molecular and Systems Biology of memory. Cell. 2014; 157:163–186. [PubMed: 24679534]
Kida S, Serita T. Functional roles of CREB as a positive regulator in the formation and enhancement of memory. Brain Research Bulletin. 2014; 105:17–24. [PubMed: 24811207]
Kim JJ, Baxter MG. Multiple brain-memory systems: the whole does not equal the sum of its parts.Trends in Neurosciences. 2001; 24:324–330. [PubMed: 11356503]
Kim JJ, Fanselow MS. Modality-specific retrograde amnesia of fear. Science. 1992; 256:675–7.[PubMed: 1585183]
Knapp LT, Klann E. Potentiation of hippocampal synaptic transmission by superoxide requires the oxidative activation of protein kinase C. J Neurosci. 2002; 22:674–83. [PubMed: 11826097]
Kuzawa CW, Chugani HT, Grossman LI, Lipovich L, Muzik O, Hof PR, Wildman DE, Sherwood CC, Leonard WR, Lange N. Metabolic costs and evolutionary implications of human brain
development. Proc Natl Acad Sci U S A. 2014; 111:13010–5. [PubMed: 25157149] Lamprecht R, LeDoux J. Structural plasticity and memory. Nat Rev Neurosci. 2004; 5:45–54.
[PubMed: 14708003]
Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, Attramadal H, Storm-Mathisen J, Gjedde A, Bergersen LH. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex. 2014; 24:2784–95. [PubMed: 23696276]
Lee HS, Ghetti A, Pinto-Duarte A, Wang X, Dziewczapolski G, Galimi F, Huitron-Resendiz S, Pina- Crespo JC, Roberts AJ, Verma IM, et al. Astrocytes contribute to gamma oscillations and recognition memory. Proc Natl Acad Sci U S A. 2014; 111:E3343–52. [PubMed: 25071179]
Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock. 2008; 30:417– 21. [PubMed: 18323749]
Li S, Callaghan BL, Richardson R. Infantile amnesia: forgotten but not gone. Learning & Memory. 2014; 21:135–139. [PubMed: 24532837]
Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioral memory. Nat Rev Neurosci. 2002; 3:175–190. [PubMed: 11994750]
Loebrich S, Nedivi E. The Function of Activity-Regulated Genes in the Nervous System. Physiological Reviews. 2009; 89:1079–1103. [PubMed: 19789377]
Lonze BE, Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002; 35:605–23. [PubMed: 12194863]
Lopes LT, Patrone LG, Li KY, Imber AN, Graham CD, Gargaglioni LH, Putnam RW. Anatomical and functional connections between the locus coeruleus and the nucleus tractus solitarius in neonatal rats. Neuroscience. 2016; 324:446–68. [PubMed: 27001176]
Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH-C, Han X, Takano T, Wang S, Sim FJ, et al. The Transcriptome and Metabolic Gene Signature of protoplasmic Astrocytes in the Adult Murine Cortex. The Journal of neuroscience. 2007; 27:12255–12266. [PubMed: 17989291]
Machler P, Wyss MT, Elsayed M, Stobart J, Gutierrez R, von Faber-Castell A, Kaelin V, Zuend M, San Martin A, Romero-Gomez I, et al. In Vivo Evidence for a Lactate Gradient from Astrocytes to Neurons. Cell Metab. 2016; 23:94–102. [PubMed: 26698914]
Madsen HB, Kim JH. Ontogeny of memory: An update on 40 years of work on infantile amnesia.Behavioral Brain Research. 2016; 298(Part A):4–14. [PubMed: 26190765]
Magistretti PJ. Regulation of glycogenolysis by neurotransmitters in the central nervous system.Diabetes Metab. 1988; 14:237–46. [PubMed: 2900788]
Magistretti PJ, Pellerin L. Astrocytes Couple Synaptic Activity to Glucose Utilization in the Brain. News Physiol Sci. 1999; 14:177–182. [PubMed: 11390847]
Makkar SR, Zhang SQ, Cranney J. Behavioral and neural analysis of GABA in the acquisition, consolidation, reconsolidation, and extinction of fear memory. Neuropsychopharmacology. 2010; 35:1625–52. [PubMed: 20410874]
Malenka RC, Bear MF. LTP and LTD. Neuron. 2004; 44:5–21. [PubMed: 15450156]
Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002; 25:103–26. [PubMed: 12052905]
Mantyh PW, Rogers SD, Allen CJ, Catton MD, Ghilardi JR, Levin LA, Maggio JE, Vigna SR. Beta 2- adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit, and human. J Neurosci. 1995; 15:152–64. [PubMed: 7823126]
Maragakis NJ, Rothstein JD. Mechanisms ofDisease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol. 2006; 2:679–89. [PubMed: 17117171]
Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 2011; 14:2013–54. [PubMed: 20649473]
Maxwell DS, Kruger L. The fine structure of astrocytes in the cerebral cortex and their response to focal injury produced by heavy ionizing particles. The Journal of Cell Biology. 1965; 25:141– 157. [PubMed: 19866658]
Mayford M. Protein kinase signaling in synaptic plasticity and memory. Curr Opin Neurobiol. 2007; 17:313–7. [PubMed: 17499495]
McDonald RJ, Hong NS, Devan BD. The challenges of understanding mammalian cognition and memory-based behaviours: an interactive learning and memory systems approach. Neuroscience & Biobehavioral Reviews. 2004; 28:719–745. [PubMed: 15555681]
McGaugh JL. Consolidating memories. Annu Rev Psychol. 2015; 66:1–24. [PubMed: 25559113]
McKenna, MC., Dienel, GA., Sonnewald, U., Waagepetersen, HS., Schousboe, A. Energy metabolism ofthe brain. In: Brady, SGJ.Siegel, G.Albers, RW., Price, DL., editors. Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology. Oxford, UK: Elsevier Academic Press; 2012. p. 200-231.
McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proceedings of the National Academy of Sciences. 2000; 97:2881–2885.
McNay EC, McCarty RC, Gold PE. Fluctuations in Brain Glucose Concentration during Behavioral Testing: Dissociations between Brain Areas and between Brain and Blood. Neurobiology of Learning and Memory. 2001; 75:325–337. [PubMed: 11300738]
McNay EC, Sherwin RS. Effect of recurrent Hypoglycemia on Spatial Cognition and Cognitive Metabolism in Normal and Diabetic Rats. Diabetes. 2004; 53:418–425. [PubMed: 14747293]
Messier C. Glucose improvement of memory: a review. Eur J Pharmacol. 2004; 490:33–57. [PubMed: 15094072]
Milner TA, Shah P, Pierce JP. beta-adrenergic receptors primarily are located on the dendrites of granule cells and interneurons but also are found on astrocytes and a few presynaptic profiles in the rat dentate gyrus. Synapse. 2000; 36:178–93. [PubMed: 10819898]
Miyashita T, Williams CL. Peripheral arousal-related hormones modulate norepinephrine release in the hippocampus via influences on brainstem nuclei. Behav Brain Res. 2004; 153:87–95. [PubMed: 15219710]
Molofsky AV, Deneen B. Astrocyte development: A Guide for the Perplexed. Glia. 2015; 63:1320– 1329. [PubMed: 25963996]
Moraga-Amaro R, Jerez-Baraona JM, Simon F, Stenberg J. Role of astrocytes in memory and psychiatric disorders. Journal of physiology-Paris. 2014; 108:240–251.
Morgello S, Uson RR, Schwartz EJ, Haber RS. The human blood-brain barrier glucose transporter (GLUT1) is a glucose transporter of gray matter astrocytes. Glia. 1995; 14:43–54. [PubMed: 7615345]
Morken TS, Brekke E, Haberg A, Wideroe M, Brubakk AM, Sonnewald U. Neuron-astrocyte interactions, pyruvate carboxylation and the pentose phosphate pathway in the neonatal rat brain. Neurochem Res. 2014; 39:556–69. [PubMed: 23504293]
Morland C, Lauritzen KH, Puchades M, Holm-Hansen S, Andersson K, Gjedde A, Attramadal H, Storm-Mathisen J, Bergersen LH. The lactate receptor, G-protein-coupled receptor 81/ hydroxycarboxylic acid receptor 1: Expression and action in brain. J Neurosci Res. 2015; 93:1045–55. [PubMed: 25881750]
Morris KA, Chang Q, Mohler EG, Gold PE. Age-related memory impairments due to reduced blood glucose responses to epinephrine. Neurobiology of Aging. 2010; 31:2136–2145. [PubMed: 19178987]
Morris RG. NMDA receptors and memory encoding. Neuropharmacology. 2013; 74:32–40. [PubMed: 23628345]
Murase S, Schuman EM. The role of cell adhesion molecules in synaptic plasticity and memory. Curr Opin Cell Biol. 1999; 11:549–53. [PubMed: 10508654]
Murchison CF, Zhang XY, Zhang WP, Ouyang M, Lee A, Thomas SA. A distinct role for norepinephrine in memory retrieval. Cell. 2004; 117:131–43. [PubMed: 15066288]
Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: Redefining the functional architecture ofthe brain. Trends in Neurosciences. 2003; 26:523–530. [PubMed: 14522144]
Nehlig A. Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot Essent Fatty Acids. 2004; 70:265–75. [PubMed: 14769485]
Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends in Endocrinology & Metabolism. 2014; 25:42–52. [PubMed: 24140022]
Newman LA, Korol DL, Gold PE. Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS One. 2011; 6:e28427. [PubMed: 22180782]
Nijland PG, Molenaar RJ, van der Pol SM, van der Valk P, van Noorden CJ, de Vries HE, van Horssen J. Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions. Acta Neuropathol Commun. 2015; 3:79. [PubMed: 26637184]
Nudelman AS, DiRocco DP, Lambert TJ, Garelick MG, Le J, Nathanson NM, Storm DR. Neuronal activity rapidly induces transcription ofthe CREB-regulated microRNA-132, in vivo. Hippocampus. 2010; 20:492–8. [PubMed: 19557767]
O’Dell TJ, Connor SA, Guglietta R, Nguyen PV. beta-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. Learn Mem. 2015; 22:461–71. [PubMed: 26286656]
O’Dowd BS, Gibbs ME, Ng KT, Hertz E, Hertz L. Astrocytic glycogenolysis energizes memory processes in neonate chicks. Brain Res Dev Brain Res. 1994; 78:137–41. [PubMed: 8004768]
Pannasch U, Rouach N. Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci. 2013; 36:405–17. [PubMed: 23659852]
Parkhurst Christopher N, Yang G, Ninan I, Savas Jeffrey N, Yates John R III, Lafaille Juan J, Hempstead Barbara L, Littman Dan R, Gan W-B. Microglia Promote Learning-Dependent Synapse Formation through Brain-Derived Neurotrophic Factor. Cell. 2013; 155:1596–1609. [PubMed: 24360280]
Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism ofLTP. Science. 2006; 313:1141–4. [PubMed: 16931766]
Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994; 91:10625–9. [PubMed: 7938003]
Pellerin L, Magistretti PJ. Food for thought: challenging the dogmas. J. Cereb. Blood Flow Metab. 2003; 23:1282–1286.
Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. J Cereb Blood Flow Metab. 2012; 32:1152–1166. [PubMed: 22027938]
Perea G, Navarrete M, Araque A. Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci. 2009; 32:421–31. [PubMed: 19615761]
Petersen KU. Fine structure ofneuroglia cells in the cerebellar cortex ofmammals. Z Zellforsch Mikrosk Anat. 1969; 100:616–33. [PubMed: 5351199]
Pfeiffer-Guglielmi B, Fleckenstein B, Jung G, Hamprecht B. Immunocytochemical localization of glycogen phosphorylase isozymes in rat nervous tissues by using isozyme-specific antibodies. Journal of Neurochemistry. 2003; 85:73–81. [PubMed: 12641728]
Pierre K, Pellerin L. Monocarboxylate transporters in the central nervous system: distribution, regulation and function. Journal of Neurochemistry. 2005; 94:1–14.
Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, Avison M, Houseman A, Hanstock C, Shulman R. Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A. 1991; 88:5829–31. [PubMed: 2062861]
Przybyslawski J, Roullet P, Sara SJ. Attenuation of emotional and nonemotional memories after their reactivation: role of beta adrenergic receptors. J Neurosci. 1999; 19:6623–8. [PubMed: 10414990]
Purcell AL, Carew TJ. Tyrosine kinases, synaptic plasticity and memory: insights from vertebrates and invertebrates. Trends Neurosci. 2003; 26:625–30. [PubMed: 14585603]
Quach TT, Duchemin AM, Rose C, Schwartz JC. [3H]glycogenolysis in brain slices mediated by beta-
adrenoceptors: comparison of physiological response and [3H]dihydroalprenolol binding parameters. Neuropharmacology. 1988; 27:629–35. [PubMed: 2843784]
Ragozzino ME, Pal SN, Unick K, Stefani MR, Gold PE. Modulation of Hippocampal Acetylcholine Release and Spontaneous Alternation Scores by Intrahippocampal Glucose Injections. The Journal ofNeuroscience. 1998; 18:1595–1601. [PubMed: 9454864]
Ragozzino ME, Unick KE, Gold PE. Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci U S A. 1996; 93:4693–8. [PubMed: 8643466]
Rahn EJ, Guzman-Karlsson MC, David Sweatt J. Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem. 2013; 105:133–50. [PubMed: 23796633]
Rainbow TC, Parsons B, Wolfe BB. Quantitative autoradiography of beta 1- and beta 2-adrenergic receptors in rat brain. Proc Natl Acad Sci U S A. 1984; 81:1585–9. [PubMed: 6324206]
Ramos BP, Colgan L, Nou E, Ovadia S, Wilson SR, Arnsten AF. The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys. Biol Psychiatry. 2005; 58:894–900. [PubMed: 16043136]
Ravaris CL, Friedman MJ, Hauri PJ, McHugo GJ. A controlled study of alprazolam and propranolol in panic-disordered and agoraphobic outpatients. J Clin Psychopharmacol. 1991; 11:344–50. [PubMed: 1770152]
Reemst K, Noctor SC, Lucassen PJ, Hol EM. The Indispensable Roles ofMicroglia and Astrocytes during Brain Development. Front Hum Neurosci. 2016; 10:566. [PubMed: 27877121]
Riedel G. Function of metabotropic glutamate receptors in learning and memory. Trends Neurosci. 1996; 19:219–24. [PubMed: 8761955]
Riedel G, Platt B, Micheau J. Glutamate receptor function in learning and memory. Behavioural Brain Research. 2003; 140:1–47. [PubMed: 12644276]
Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D. Regulation of Oligodendrocyte Development and Myelination by Glucose and Lactate. The Journal of Neuroscience. 2011; 31:538–548. [PubMed: 21228163]
Roozendaal B, McGaugh JL. Memory modulation. Behav Neurosci. 2011; 125:797–824. [PubMed: 22122145]
Rose SP. Cell adhesion molecules and the transition from short- to long-term memory. J Physiol Paris. 1996; 90:387–91. [PubMed: 9089520]
Rudenko A, Tsai LH. Epigenetic regulation in memory and cognitive disorders. Neuroscience. 2014; 264:51–63. [PubMed: 23291453]
Saab BJ, Mansuy IM. Neuroepigenetics of memory formation and impairment: the role ofmicroRNAs. Neuropharmacology. 2014; 80:61–9. [PubMed: 24486712]
Santini E, Huynh TN, Klann E. Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory. Prog Mol Biol Transl Sci. 2014; 122:131– 67. [PubMed: 24484700]
Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009; 10:211–23. [PubMed: 19190638]
Sara SJ, Vankov A, Herve A. Locus coeruleus-evoked responses in behaving rats: a clue to the role of noradrenaline in memory. Brain Res Bull. 1994; 35:457–65. [PubMed: 7859103]
Schutsky K, Ouyang M, Castelino CB, Zhang L, Thomas SA. Stress and glucocorticoids impair memory retrieval via beta2-adrenergic, Gi/o-coupled suppression of cAMP signaling. J Neurosci. 2011; 31:14172–81. [PubMed: 21976502]
Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957; 20:11–21. [PubMed: 13406589]
Shao Y, Sutin J. Expression of adrenergic receptors in individual astrocytes and motor neurons isolated from the adult rat brain. Glia. 1992; 6:108–17. [PubMed: 1328049]
Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R. Rapid spine delivery and redistribution ofAMPA receptors after synaptic NMDA receptor activation. Science. 1999; 284:1811–6. [PubMed: 10364548]
Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci. 1998; 21:127–48. [PubMed: 9530494]
Sotelo-Hitschfeld T, Niemeyer MI, Mächler P, Ruminot I, Lerchundi R, Wyss MT, et al. Channel- mediated lactate release by K+-stimulated astrocytes. J Neurosci. 2015; 35:4168–4178. [PubMed: 25762664]
Squire LR. Memory systems of the brain: A brief history and current perspective. Neurobiology of Learning and Memory. 2004; 82:171–177. [PubMed: 15464402]
Squire LR, Dede AJO. 2015Conscious and Unconscious Memory Systems. Cold Spring Harbor Perspectives in Biology. :7.
Squire LR, Genzel L, Wixted JT, Morris RG. Memory consolidation. Cold Spring Harb Perspect Biol. 2015; 7:a021766. [PubMed: 26238360]
Squire LR, Wixted JT. The cognitive neuroscience of human memory since H.M. Annu Rev Neurosci. 2011; 34:259–88. [PubMed: 21456960]
Subbarao KV, Hertz L. Effect of adrenergic agonists on glycogenolysis in primary cultures of astrocytes. Brain Res. 1990; 536:220–6. [PubMed: 2085749]
Sudhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013; 80:675–90. [PubMed: 24183019]
Summers RJ, Papaioannou M, Harris S, Evans BA. Expression of beta 3-adrenoceptor mRNA in rat brain. Br J Pharmacol. 1995; 116:2547–8. [PubMed: 8590968]
Sun J, Ye X, Xie M, Ye J. Induction of triglyceride accumulation and mitochondrial maintenance in muscle cells by lactate. Sci Rep. 2016; 6:33732. [PubMed: 27645401]
Sun X, Lin Y. Npas4: Linking Neuronal Activity to Memory. Trends Neurosci. 2016; 39:264–75.[PubMed: 26987258]
Sandusky L, Flint RW, McNay EC. Elevated glucose metabolism in the amygdala during an inhibitory avoidance task. Behavioral Brain Resarch. 2013; 245:83–87.
Steinman MQ, Gao V, Alberini CM. The Role ofLactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation. Front Integr Neurosci. 2016; 10:10. [PubMed: 26973477]
Sutherland EW, Rall TW. Formation of adenosine-3,5-phosphate (cyclic adenylate) and its relation to the action of several neurohormones or hormones. Acta Endocrinol Suppl (Copenh). 1960; 34(Suppl 50):171–4. [PubMed: 13918526]
Suzuki A, Stern Sarah A, Bozdagi O, Huntley George W, Walker Ruth H, Magistretti Pierre J, Alberini Cristina M. Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation. Cell. 2011; 144:810–823. [PubMed: 21376239]
Swanson RA, Morton MM, Sagar SM, Sharp FR. Sensory stimulation induces local cerebral glycogenolysis: demonstration by autoradiography. Neuroscience. 1992; 51:451–61. [PubMed: 1465204]
Tadi M, Allaman I, Lengacher S, Grenningloh G, Magistretti PJ. Learning-Induced Gene Expression in the Hippocampus Reveals a Role ofNeuron -Astrocyte Metabolic Coupling in Long Term Memory. PLoS One. 2015; 10:e0141568. [PubMed: 26513352]
Taft VR JR, Perry GW. Distribution of GFAP+ astrocytes in adult and neonatal rat brain. International Journal of neuroscience. 2005; 115:1333–1343. [PubMed: 16048809]
Talley CEP, Kahn S, Alexander LJ, Gold PE. Epinephrine Fails to Enhance Performance ofFood-Deprived Rats on a Delayed Spontaneous Alternation Task. Neurobiology of Learning and Memory. 2000; 73:79–86. [PubMed: 10686125]
Travaglia A, Bisaz R, Sweet ES, Blitzer RD, Alberini CM. Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci. 2016a; 19:1225–33. [PubMed: 27428652]
Travaglia A, Bisaz R, Cruz E, Alberini CM. Developmental changes in plasticity, synaptic, glia and connectivity protein levels in rat dorsal hippocampus. Neurobiol Learn Mem. 2016b; 135:125– 138. [PubMed: 27523749]
Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science. 2012; 337:358–62. [PubMed: 22745251]
Tulving, E. Episodic and semantic memory. In: Donaldson, ETaW, editor. Organization of memory.New York: Academic Press; 1972. p. 381-402.
Vaiva G, Ducrocq F, Jezequel K, Averland B, Lestavel P, Brunet A, Marmar CR. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry. 2003; 54:947–9. [PubMed: 14573324]
Vannucci SJ. Developmental expression of GLUT1 and GLUT3 glucose transporters in rat brain. J Neurochem. 1994; 62:240–6. [PubMed: 8263524]
Vannucci SJ, Seaman LB, Brucklacher RM, Vannucci RC. Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization. Mol Cell Biochem. 1994; 140:177–84. [PubMed: 7898489]
Vannucci SJ, Simpson IA. Developmental switch in brain nutrient transporter expression in the rat. Am J Physiol Endocrinol Metab. 2003; 285:E1127–34. [PubMed: 14534079]
Veyrac A, Besnard A, Caboche J, Davis S, Laroche S. The transcription factor Zif268/Egr1, brain plasticity, and memory. Prog Mol Biol Transl Sci. 2014; 122:89–129. [PubMed: 24484699]
Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B, Criado-Garcia O, Fernandez- Sanchez E, Medrano-Fernandez I, Dominguez J, et al. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007; 10:1407–13. [PubMed: 17952067]
Waeber C, Rigo M, Chinaglia G, Probst A, Palacios JM. Beta-adrenergic receptor subtypes in the basal ganglia of patients with Huntington’s chorea and Parkinson’s disease. Synapse. 1991; 8:270–80. [PubMed: 1656540]
Waitt AE, Reed L, Ransom BR, Brown AM. Emerging Roles for Glycogen in the CNS. Front Mol Neurosci. 2017; 10:73. [PubMed: 28360839]
Williams CL, Men D, Clayton EC. The effects of noradrenergic activation ofthe nucleus tractus solitarius on memory and in potentiating norepinephrine release in the amygdala. Behav Neurosci. 2000; 114:1131–44. [PubMed: 11142645]
Winder DG, Martin KC, Muzzio IA, Rohrer D, Chruscinski A, Kobilka B, Kandel ER. ERK plays a regulatory role in the induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron. 1999; 24:715–26. [PubMed: 10595521]
Wyss MT, Jolivet R, Buck A, Magistretti PJ, Weber B. In Vivo Evidence for Lactate as a Neuronal Energy Source. The Journal of neuroscience. 2011; 31:7477–7485. [PubMed: 21593331]
Xu W, Morishita W, Buckmaster PS, Pang ZP, Malenka RC, SudhofTC. Distinct neuronal coding schemes in memory revealed by selective erasure of fast synchronous synaptic transmission. Neuron. 2012; 73:990–1001. [PubMed: 22405208]
Yager JY, Ashwal S. Animal models of perinatal hypoxic-ischemic brain damage. Pediatr Neurol. 2009; 40:156–67. [PubMed: 19218028]
Yang J, Ruchti E, Petit J-M, Jourdain P, Grenningloh G, Allaman I, Magistretti PJ. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proceedings ofthe National Academy of Sciences. 2014; 111:12228–12233.
Ye X, Kapeller-Libermann D, Travaglia A, Inda MC, Alberini CM. Direct dorsal hippocampalprelimbic cortex connections strengthen fear memories. Nat Neurosci. 2017; 20:52–61. [PubMed: 27869801]
Yin JC, Wallach JS, Del Vechhio M, Wilder EL, Zhou H, Quimm QG, Tully T. Induction ofa dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell. 1994; 79:49–58. [PubMed: 7923376]
Zanto TP, Rubens MT, Thangavel A, Gazzaley A. Causal role of the prefrontal cortex in top-down modulation of visual processing and working memory. Nat Neurosci. 2011; 14:656–661. [PubMed: 21441920]
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N, et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells ofthe Cerebral Cortex. The Journal of neuroscience. 2014; 34:11929–11947. [PubMed: 25186741]
Zhang Y, Xue Y, Meng S, Luo Y, Liang J, Li J, Ai S, Sun C, Shen H, Zhu W, et al. Inhibition of Lactate Transport Erases Drug Memory and Prevents Drug Relapse. Biological Psychiatry. 2016; 79:928–939. [PubMed: 26293178]
Zhao S, Chai X, Frotscher M. Balance between neurogenesis and gliogenesis in the adult hippocampus: role for reelin. Dev Neurosci. 2007; 29:84–90. [PubMed: 17148951]
Zhou HC, Sun YY, Cai W, He XT, Yi F, Li BM, Zhang XH. Activation of beta2-adrenoceptor enhances synaptic potentiation and behavioral memory via cAMP-PKA signaling in the medial prefrontal cortex ofrats. Learn Mem. 2013; 20:274–84. [PubMed: 23596314]
Zhu Y, Kimelberg HK. Cellular expression ofP2Y and beta-AR receptor mRNAs and proteins in freshly isolated astrocytes and tissue sections from the CA1 region ofP8–12 rat hippocampus. Brain Res Dev Brain Res. 2004; 148:77–87. [PubMed: 14757521]
Main Points
Astrocyte glycogenolysis and lactate play a critical role in memory formation. Emotionally salient experiences form strong memories by recruiting astrocytic β2 adrenergic receptors and astrocyte-generated lactate. Glycogenolysis and astrocyte-neuron metabolic coupling may also play critical roles in memory formation during development when the energy requirements of brain metabolism are at their peak.
Figure 1. Schematic example of neuron-centric molecular pathways underlying long-term memory formation
Most literature’s figures available thus far illustrating molecular mechanisms underlying learning and memory depict only pre and postsynaptic neurons and relative mechanisms of interest. One example is the following: learning-induced release of neurotransmitters (e.g. glutamate) and of neuronal growth factors (e.g. BDNF) activate different families of receptors, enabling the recruitment of various intracellular signaling pathways involving second messengers (e.g. Ca2+, cAMP) and protein kinases (e.g. CamKII, PKA). These signaling pathways regulate: 1) post-translational modifications [e.g., phosphorylation (P) of postsynaptic glutamatergic receptors]; 2) activation of a CREB-regulated gene cascade leading to the expression of target genes, including IEGs (e.g., C/EBP, c-Fos, Zif268), which in turn regulate the expression of late response genes critical for long-lasting functional (e.g., membrane translocation of new receptors) and structural neuronal changes (e.g., dendritic spine morphological changes). This gene expression is regulated by epigenetic mechanisms [e.g. histone acetylation and/or methylation (M), DNA methylation] as well as by several
post-transcriptional and translational mechanisms including the mTOR pathway and microRNAs. Abbreviations: AC (adenylyl cyclase); AKT (protein kinase B or Akt); AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor); BDNF (brain- derived neurotrophic factor); CaM (calmodulin); CaMKII/IV (Ca++-calmodulin kinase II/ IV); cAMP (cyclic adenosine monophosphate); C/EBP (CCAAT/enhancer binding protein); CRE (cAMP response element); CREB (cAMP response element binding protein); DAG (diacylglycerol); GPCR (G protein–coupled receptors); IEGs (immediate early genes); IP3 (inositol trisphosphate); IP3R (inositol trisphosphate receptor); MSK (mitogen and stress activated protein kinase); mTOR (mammalian target of rapamycin); NMDAR (N-methyl-D- aspartate receptor); p70S6K (ribosomal protein S6 kinase beta-1); PI3K (phosphoinositide 3-kinase); PKA (protein kinase A); PKC (protein kinase C); PKMζ(protein kinase M zeta); PLC (phospholipase C); PSD-95 (post-synaptic density 95); RSK (ribosomal s6 kinase family); Src (proto-oncogene tyrosine-protein kinase); TGs (target genes); Trk (tyrosine receptor kinase); VSCC (voltage-sensitive calcium channel). Notably, multiple cell types in the brain express many ofthese mechanisms.
Figure 2. Astrocyte–neuron lactate coupling in long-term memory formation
Glucose is taken up by astrocytes from surrounding capillaries via glucose transporters (GLUT1). Glucose can then be stored as glycogen in astrocytes or undergo glycolysis to become pyruvate. In astrocytes, pyruvate can be transported into the mitochondria or converted to lactate, which can be exported out of the astrocyte by the monocarboxylate transporter 1 or 4 (MCT1/4) and transported into neurons via MCT2. In neurons, astrocytic-derived lactate is converted back into pyruvate and transported into the mitochondria to generate ATP. Glucose may also be transported from the capillaries into neurons through the glucose transporter (GLUT3). In Suzuki et al. 2011, we showed that the astrocytic-derived lactate from glycogenolysis is critical for long-term memory formation in rats and for the underlying regulation of molecular changes required for long-term memory formation. These changes include the phosphorylation of the transcription factor CREB, the expression of target genes (TGs), the expression of immediate early genes such as Arc, and the phosphorylation ofthe actin-binding protein cofilin. Whether glucose transport into neurons through GLUT3 is important for memory formation remains to be determined.
Figure 3. Blocking glycogenolysis in the basolateral amygdala impairs long-term memory
Long-term memory retention, expressed as mean latency values ± SEM in seconds (s), tested 1 day (d) after training (Test 1), 6 d later (Test 2),
and after a reminder shock given in a distinct context (RS, Test 3). Vehicle, DAB (300 pmol), or DAB (300 pmol) + L-lactate (100
nmol) was injected bilaterally into the basolateral amygdala (BLA) 15 min prior to inhibitory avoidance (IA) training (red arrow). Statistical significance was assessed by two- way ANOVA
followed by Bonferroni’s post hoc tests compared to vehicle (**p < 0.01; ***p < 0.001; n = 7–8/group).
