Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications


Sleep is essential for memory formation. Active systems consolidation maintains that memory traces that are initially stored in a transient store such as the hippocampus are gradually redistributed towards more permanent storage sites such as the cortex during sleep replay. The complementary synaptic homeostasis theory posits that weak memory traces are erased during sleep through a competitive down-selection mechanism, ensuring the brain’s capability to learn new information. We discuss evidence from neuropharmacological experiments in humans to show how major neurotransmitters and neuromodulators are implicated in these memory processes. As to the major excitatory neurotransmitter glutamate that plays a prominent role in inducing synaptic consolidation, we show that these processes, while strengthening cortical memory traces during sleep, are insufficient to explain the consolidation of hippocampus-dependent declarative memories. In the inhibitory GABAergic system, we will offer insights how drugs may alter the intricate interplay of sleep oscillations that have been identified to be crucial for strengthening memories during sleep. Regarding the dopaminergic reward system, we will show how it is engaged during sleep replay, but that dopaminergic neuromodulation likely plays a side role for enhancing relevant memories during sleep. Also, we briefly go into basic evidence on acetylcholine and cortisol whose low tone during slow wave sleep (SWS) is crucial in supporting hippocampal-to-neocortical memory transmission. Finally, we will outline how these insights can be used to improve treatment of neuropsychiatric disorders focusing mainly on anxiety disorders, depression, and addiction that are strongly related to memory processing.

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  1. 1.

    Abel T, Havekes R, Saletin JM, Walker MP. Sleep, plasticity and memory from molecules to whole-brain networks. Curr Biol. 2013;23:R774–88.

  2. 2.

    Rasch B, Born J. About sleep’s role in memory. Physiol Rev. 2013;93:681–66.

  3. 3.

    Stickgold R. Sleep-dependent memory consolidation. Nature. 2005;437:1272–8.

  4. 4.

    Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 2014;81:12–34.

  5. 5.

    McGaugh JL. Memory–a century of consolidation. Science. 2000;287:248–51.

  6. 6.

    Müller GE, Pilzecker A. Experimentelle Beiträge zur Lehre vom Gedächtnis. Z für Psychol, Ergänzungsband. 1900;1:1–300.

  7. 7.

    Jenkins JG, Dallenbach KM. Obliviscence during sleep and waking. Am J Psychol. 1924;35:605–12.

  8. 8.

    Ebbinghaus H. Über das Gedächtnis. Leipzig: Duncker und Humblot; 1885.

  9. 9.

    Murre JM, Dros J. Replication and analysis of Ebbinghaus’ forgetting curve. PLoS ONE. 2015;10:e0120644.

  10. 10.

    Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electro Clin Neurophysiol. 1957;9:673–90.

  11. 11.

    Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science. 1953;118:273–4.

  12. 12.

    O’Keefe J. Place units in the hippocampus of the freely moving rat. Exp Neurol. 1976;51:78–109.

  13. 13.

    Eichenbaum H, Dudchenko P, Wood E, Shapiro M, Tanila H. The hippocampus, memory, and place cells: is it spatial memory or a memory space? Neuron. 1999;23:209–26.

  14. 14.

    Pavlides C, Winson J. Influences of hippocampal place cell firing in the awake state on the activity of these cells during subsequent sleep episodes. J Neurosci. 1989;9:2907–18.

  15. 15.

    Wilson MA, McNaughton BL. Reactivation of hippocampal ensemble memories during sleep. Science. 1994;265:676–9.

  16. 16.

    Rasch B, Buchel C, Gais S, Born J. Odor cues during slow-wave sleep prompt declarative memory consolidation. Science. 2007;315:1426–9.

  17. 17.

    Diekelmann S, Buchel C, Born J, Rasch B. Labile or stable: opposing consequences for memory when reactivated during waking and sleep. Nat Neurosci. 2011;14:381–6.

  18. 18.

    Rudoy JD, Voss JL, Westerberg CE, Paller KA. Strengthening individual memories by reactivating them during sleep. Science. 2009;326:1079.

  19. 19.

    Schreiner T, Rasch B. Boosting vocabulary learning by verbal cueing during sleep. Cereb Cortex. 2014.

  20. 20.

    Schönauer M, Geisler T, Gais S. Strengthening procedural memories by reactivation in sleep. J Cogn Neurosci. 2014;26:143–53.

  21. 21.

    Antony JW, Gobel EW, O’Hare JK, Reber PJ, Paller KA. Cued memory reactivation during sleep influences skill learning. Nat Neurosci. 2012;15:1114–6.

  22. 22.

    Diekelmann S, Biggel S, Rasch B, Born J. Offline consolidation of memory varies with time in slow wave sleep and can be accelerated by cuing memory reactivations. Neurobiol Learn Mem. 2012;98:103–11.

  23. 23.

    Rihm JS, Sollberger SB, Soravia LM, Rasch B. Re-presentation of olfactory exposure therapy success cues during non-rapid eye movement sleep did not increase therapy outcome but increased sleep spindles. Front Hum Neurosci. 2016;10:340

  24. 24.

    Diekelmann S, Born J. The memory function of sleep. Nat Rev Neurosci. 2010;11:114–26.

  25. 25.

    Sawangjit A, Oyanedel CN, Niethard N, Salazar C, Born J, Inostroza M. The hippocampus is crucial for forming non-hippocampal long-term memory during sleep. Nature. 2018;564:109–13.

  26. 26.

    Westermann J, Lange T, Textor J, Born J. System consolidation during sleep—a common principle underlying psychological and immunological memory formation. Trends Neurosci. 2015;38:585–97.

  27. 27.

    Grossberg S. How does a brain build a cognitive code? Psychol Rev. 1980;87:1–51.

  28. 28.

    Grossberg S. Competitive learning: From interactive activation to adaptive resonance. Cogn Sci. 1987;11:23–63.

  29. 29.

    Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004;55:51–86.

  30. 30.

    McClelland JL, McNaughton BL, O’Reilly RC. Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory. Psychol Rev. 1995;102:419–57.

  31. 31.

    Battaglia FP, Benchenane K, Sirota A, Pennartz CM, Wiener SI. The hippocampus: hub of brain network communication for memory. Trends Cogn Sci. 2011;15:310–8.

  32. 32.

    Bontempi B, Laurent-Demir C, Destrade C, Jaffard R. Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature. 1999;400:671–5.

  33. 33.

    Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6:119–30.

  34. 34.

    Hasselmo ME. Neuromodulation: acetylcholine and memory consolidation. Trends Cogn Sci. 1999;3:351–9.

  35. 35.

    Mitra A, Snyder AZ, Hacker CD, Pahwa M, Tagliazucchi E, Laufs H, et al. Human cortical-hippocampal dialogue in wake and slow-wave sleep. Proc Natl Acad Sci USA. 2016.

  36. 36.

    Sirota A, Csicsvari J, Buhl D, Buzsaki G. Communication between neocortex and hippocampus during sleep in rodents. Proc Natl Acad Sci USA. 2003;100:2065–9.

  37. 37.

    Staresina BP, Bergmann TO, Bonnefond M, van der Meij R, Jensen O, Deuker L, et al. Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat Neurosci. 2015;18:1679–86.

  38. 38.

    Clemens Z, Mölle M, Eross L, Barsi P, Halasz P, Born J. Temporal coupling of parahippocampal ripples, sleep spindles and slow oscillations in humans. Brain. 2007;130:2868–78.

  39. 39.

    Clemens Z, Mölle M, Eross L, Jakus R, Rasonyi G, Halasz P, et al. Fine-tuned coupling between human parahippocampal ripples and sleep spindles. Eur J Neurosci. 2011;33:511–20.

  40. 40.

    Sadowski JH, Jones MW, Mellor JR. Sharp-wave ripples orchestrate the induction of synaptic plasticity during reactivation of place cell firing patterns in the hippocampus. Cell Rep. 2016;14:1916–29.

  41. 41.

    Khodagholy D, Gelinas JN, Buzsaki G. Learning-enhanced coupling between ripple oscillations in association cortices and hippocampus. Science. 2017;358:369–72.

  42. 42.

    Ji D, Wilson MA. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nat Neurosci. 2007;10:100–7.

  43. 43.

    Ognjanovski N, Maruyama D, Lashner N, Zochowski M, Aton SJ. CA1 hippocampal network activity changes during sleep-dependent memory consolidation. Front Syst Neurosci. 2014;8:61.

  44. 44.

    Stella F, Baracskay P, O’Neill J, Csicsvari J. Hippocampal reactivation of random trajectories resembling Brownian diffusion. Neuron. 2019;102:450–61 e457.

  45. 45.

    Giri B, Miyawaki H, Mizuseki K, Cheng S, Diba K. Hippocampal reactivation extends for several hours following novel experience. J Neurosci. 2019;39:866–75.

  46. 46.

    Hebb DO. The organization of behavior: a neuropsychological theory. New York, NY: Wiley; 1949.

  47. 47.

    Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. 2006;10:49–62.

  48. 48.

    Cirelli C, Tononi G. Is sleep essential? PLoS Biol. 2008;6:e216.

  49. 49.

    Vyazovskiy VV, Cirelli C, Pfister-Genskow M, Faraguna U, Tononi G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci. 2008;11:200–8.

  50. 50.

    Maret S, Faraguna U, Nelson AB, Cirelli C, Tononi G. Sleep and waking modulate spine turnover in the adolescent mouse cortex. Nat Neurosci. 2011;14:1418–20.

  51. 51.

    Diering GH, Nirujogi RS, Roth RH, Worley PF, Pandey A, Huganir RL. Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science. 2017;355:511–5.

  52. 52.

    de Vivo L, Bellesi M, Marshall W, Bushong EA, Ellisman MH, Tononi G, et al. Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science. 2017;355:507–10.

  53. 53.

    Kuhn M, Wolf E, Maier JG, Mainberger F, Feige B, Schmid H, et al. Sleep recalibrates homeostatic and associative synaptic plasticity in the human cortex. Nat Commun. 2016;7:12455.

  54. 54.

    Mander BA, Santhanam S, Saletin JM, Walker MP. Wake deterioration and sleep restoration of human learning. Curr Biol. 2011;21:R183–4.

  55. 55.

    Van Der Werf YD, Altena E, Schoonheim MM, Sanz-Arigita EJ, Vis JC, De Rijke W, et al. Sleep benefits subsequent hippocampal functioning. Nat Neurosci. 2009;12:122–3.

  56. 56.

    Antonenko D, Diekelmann S, Olsen C, Born J, Molle M. Napping to renew learning capacity: enhanced encoding after stimulation of sleep slow oscillations. Eur J Neurosci. 2013;37:1142–52.

  57. 57.

    Norimoto H, Makino K, Gao M, Shikano Y, Okamoto K, Ishikawa T, et al. Hippocampal ripples down-regulate synapses. Science. 2018;359:1524–7.

  58. 58.

    Li W, Ma L, Yang G, Gan WB. REM sleep selectively prunes and maintains new synapses in development and learning. Nat Neurosci. 2017;20:427–37.

  59. 59.

    Yang G, Lai CS, Cichon J, Ma L, Li W, Gan WB. Sleep promotes branch-specific formation of dendritic spines after learning. Science. 2014;344:1173–8.

  60. 60.

    Frank MG, Erasing Synapses in Sleep: Is It Time to Be SHY? Neural Plasticity 2012;2012:1–15.

  61. 61.

    Puentes-Mestril C, Aton SJ. Linking network activity to synaptic plasticity during sleep: hypotheses and recent data. Front Neural Circuits. 2017;11:61.

  62. 62.

    Wilhelm I, Diekelmann S, Molzow I, Ayoub A, Molle M, Born J. Sleep selectively enhances memory expected to be of future relevance. J Neurosci. 2011;31:1563–9.

  63. 63.

    Payne JD, Chambers AM, Kensinger EA. Sleep promotes lasting changes in selective memory for emotional scenes. Front Integr Neurosci. 2012;6:108.

  64. 64.

    Payne JD, Stickgold R, Swanberg K, Kensinger EA. Sleep preferentially enhances memory for emotional components of scenes. Psychol Sci. 2008;19:781–8.

  65. 65.

    Sterpenich V, Albouy G, Boly M, Vandewalle G, Darsaud A, Balteau E, et al. Sleep-related hippocampo-cortical interplay during emotional memory recollection. PLoS Biol. 2007;5:e282.

  66. 66.

    Sterpenich V, Albouy G, Darsaud A, Schmidt C, Vandewalle G, Dang Vu TT, et al. Sleep promotes the neural reorganization of remote emotional memory. J Neurosci. 2009;29:5143–52.

  67. 67.

    Studte S, Bridger E, Mecklinger A. Sleep spindles during a nap correlate with post sleep memory performance for highly rewarded word-pairs. Brain Lang. 2017;167:28–35.

  68. 68.

    Igloi K, Gaggioni G, Sterpenich V, Schwartz S. A nap to recap or how reward regulates hippocampal-prefrontal memory networks during daytime sleep in humans. Elife. 2015;4. ARTN e0790310.7554/eLife.07903

  69. 69.

    Feld GB, Born J. Sculpting memory during sleep: concurrent consolidation and forgetting. Curr Opin Neurobiol. 2017;44:20–7.

  70. 70.

    Chauvette S, Seigneur J, Timofeev I. Sleep oscillations in the thalamocortical system induce long-term neuronal plasticity. Neuron. 2012;75:1105–13.

  71. 71.

    Durkin J, Aton SJ. Sleep-dependent potentiation in the visual system is at odds with the synaptic homeostasis hypothesis. Sleep. 2016;39:155–9.

  72. 72.

    Durkin J, Suresh AK, Colbath J, Broussard C, Wu J, Zochowski M, et al. Cortically coordinated NREM thalamocortical oscillations play an essential, instructive role in visual system plasticity. Proc Natl Acad Sci USA. 2017;114:10485–90.

  73. 73.

    Grosmark AD, Mizuseki K, Pastalkova E, Diba K, Buzsaki G. REM sleep reorganizes hippocampal excitability. Neuron. 2012;75:1001–7.

  74. 74.

    Ognjanovski N, Broussard C, Zochowski M, Aton SJ. Hippocampal network oscillations rescue memory consolidation deficits caused by sleep loss. Cereb Cortex. 2018;28:3711–23.

  75. 75.

    Gais S, Albouy G, Boly M, Dang-Vu TT, Darsaud A, Desseilles M, et al. Sleep transforms the cerebral trace of declarative memories. Proc Natl Acad Sci USA. 2007;104:18778–83.

  76. 76.

    Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21.

  77. 77.

    Malenka RC, Nicoll RA. Long-term potentiation–a decade of progress? Science. 1999;285:1870–4.

  78. 78.

    Aton SJ, Seibt J, Dumoulin M, Jha SK, Steinmetz N, Coleman T, et al. Mechanisms of sleep-dependent consolidation of cortical plasticity. Neuron. 2009;61:454–66.

  79. 79.

    Gais S, Rasch B, Wagner U, Born J. Visual-procedural memory consolidation during sleep blocked by glutamatergic receptor antagonists. J Neurosci. 2008;28:5513–8.

  80. 80.

    Karni A, Sagi D. Where practice makes perfect in texture discrimination: evidence for primary visual cortex plasticity. Proc Natl Acad Sci USA. 1991;88:4966–70.

  81. 81.

    Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory for early visual discrimination skills. Nat Neurosci. 2000;3:1335–9.

  82. 82.

    Henke K, Weber B, Kneifel S, Wieser HG, Buck A. Human hippocampus associates information in memory. Proc Natl Acad Sci USA. 1999;96:5884–9.

  83. 83.

    Plihal W, Born J. Effects of early and late nocturnal sleep on declarative and procedural memory. J Cogn Neurosci. 1997;9:534–47.

  84. 84.

    Yaroush R, Sullivan MJ, Ekstrand BR. Effect of sleep on memory. II. Differential effect of the first and second half of the night. J Exp Psychol. 1971;88:361–6.

  85. 85.

    Ekstrand BR, Barrett TR, West JN, Maier WG. The effect of sleep on human long-term memory. In: Drucker-Colin R, McGaugh J, editors. Neurobiology of sleep and memory. New York, NY: Academic Press; 1977. p. 419–38.

  86. 86.

    Feld GB, Lange T, Gais S, Born J. Sleep-dependent declarative memory consolidation–unaffected after blocking NMDA or AMPA receptors but enhanced by NMDA coagonist D-cycloserine. Neuropsychopharmacology. 2013;38:2688–97.

  87. 87.

    Hood WF, Compton RP, Monahan JB. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett. 1989;98:91–5.

  88. 88.

    Quartermain D, Mower J, Rafferty MF, Herting RL, Lanthorn TH. Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention. Eur J Pharm. 1994;257:7–12.

  89. 89.

    Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, et al. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology. 2009;34:2057–71.

  90. 90.

    Chen HH, Liao PF, Chan MH. mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway. J Biomed Sci. 2011;18:19.

  91. 91.

    Alizadeh Asfestani M, Braganza E, Schwidetzky J, Santiago J, Soekadar S, Born J, et al. Overnight memory consolidation facilitates rather than interferes with new learning of similar materials-a study probing NMDA receptors. Neuropsychopharmacology. 2018;43:2292–8.

  92. 92.

    Graf P, Schacter DL. Selective effects of interference on implicit and explicit memory for new associations. J Exp Psychol-Learn Mem Cogn. 1987;13:45–53.

  93. 93.

    Hardt O, Nader K, Nadel L. Decay happens: the role of active forgetting in memory. Trends Cogn Sci. 2013;17:111–20.

  94. 94.

    Havekes R, Meerlo P, Abel T. Animal studies on the role of sleep in memory: from behavioral performance to molecular mechanisms. Curr Top Behav Neurosci. 2015;25:183–206.

  95. 95.

    Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 2007;53:703–17.

  96. 96.

    Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–63.

  97. 97.

    Gottesmann C. GABA mechanisms and sleep. Neuroscience. 2002;111:231–9.

  98. 98.

    Lancel M. Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep. 1999;22:33–42.

  99. 99.

    Lancel M, Faulhaber J, Deisz RA. Effect of the GABA uptake inhibitor tiagabine on sleep and EEG power spectra in the rat. Br J Pharm. 1998;123:1471–7.

  100. 100.

    Molle M, Born J. Slow oscillations orchestrating fast oscillations and memory consolidation. Prog Brain Res. 2011;193:93–110.

  101. 101.

    Siapas AG, Wilson MA. Coordinated interactions between hippocampal ripples and cortical spindles during slow-wave sleep. Neuron. 1998;21:1123–8.

  102. 102.

    Steriade M. Grouping of brain rhythms in corticothalamic systems. Neuroscience. 2006;137:1087–106.

  103. 103.

    Mölle M, Bergmann TO, Marshall L, Born J. Fast and slow spindles during the sleep slow oscillation: disparate coalescence and engagement in memory processing. Sleep. 2011;34:1411–21.

  104. 104.

    Niethard N, Ngo HV, Ehrlich I, Born J. Cortical circuit activity underlying sleep slow oscillations and spindles. Proc Natl Acad Sci USA. 2018;115:E9220–9.

  105. 105.

    Seibt J, Richard CJ, Sigl-Glockner J, Takahashi N, Kaplan DI, Doron G, et al. Cortical dendritic activity correlates with spindle-rich oscillations during sleep in rodents. Nat Commun. 2017;8:684.

  106. 106.

    Latchoumane CV, Ngo HV, Born J, Shin HS. Thalamic spindles promote memory formation during sleep through triple phase-locking of cortical, thalamic, and hippocampal rhythms. Neuron. 2017;95:424–35 e426.

  107. 107.

    Ognjanovski N, Schaeffer S, Wu J, Mofakham S, Maruyama D, Zochowski M, et al. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation. Nat Commun. 2017;8:15039.

  108. 108.

    Xia F, Richards BA, Tran MM, Josselyn SA, Takehara-Nishiuchi K, Frankland, PW. Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation. Elife. 2017;6.

  109. 109.

    Marshall L, Helgadottir H, Molle M, Born J. Boosting slow oscillations during sleep potentiates memory. Nature. 2006;444:610–3.

  110. 110.

    Marshall L, Molle M, Hallschmid M, Born J. Transcranial direct current stimulation during sleep improves declarative memory. J Neurosci. 2004;24:9985–92.

  111. 111.

    Mathias S, Wetter TC, Steiger A, Lancel M. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging. 2001;22:247–53.

  112. 112.

    Walsh JK, Randazzo AC, Frankowski S, Shannon K, Schweitzer PK, Roth T. Dose-response effects of tiagabine on the sleep of older adults. Sleep. 2005;28:673–6.

  113. 113.

    Feld GB, Wilhelm I, Ma Y, Groch S, Binkofski F, Molle M, et al. Slow wave sleep induced by GABA agonist tiagabine fails to benefit memory consolidation. Sleep. 2013;36:1317–26.

  114. 114.

    Puentes-Mestril C, Roach J, Niethard N, Zochowski M, Aton SJ. How rhythms of the sleeping brain tune memory and synaptic plasticity. Sleep. 2019;42.

  115. 115.

    Barakat M, Doyon J, Debas K, Vandewalle G, Morin A, Poirier G, et al. Fast and slow spindle involvement in the consolidation of a new motor sequence. Behav Brain Res. 2011;217:117–21.

  116. 116.

    Rasch B, Pommer J, Diekelmann S, Born J. Pharmacological REM sleep suppression paradoxically improves rather than impairs skill memory. Nat Neurosci. 2009;12:396–7.

  117. 117.

    Cairney SA, Guttesen AAV, El Marj N, Staresina BP. Memory Consolidation Is Linked to Spindle-Mediated Information Processing during Sleep. Curr Biol. 2018;28:948–54 e944.

  118. 118.

    Clemens Z, Fabo D, Halasz P. Overnight verbal memory retention correlates with the number of sleep spindles. Neuroscience. 2005;132:529–35.

  119. 119.

    Cox R, Hofman WF, Talamini LM. Involvement of spindles in memory consolidation is slow wave sleep-specific. Learn Mem. 2012;19:264–7.

  120. 120.

    Mednick SC, McDevitt EA, Walsh JK, Wamsley E, Paulus M, Kanady JC, et al. The critical role of sleep spindles in hippocampal-dependent memory: a pharmacology study. J Neurosci. 2013;33:4494–504.

  121. 121.

    Antony JW, Schonauer M, Staresina BP, Cairney SA. Sleep spindles and memory reprocessing. Trends Neurosci. 2019;42:1–3.

  122. 122.

    Helfrich RF, Mander BA, Jagust WJ, Knight RT, Walker MP. Old brains come uncoupled in sleep: slow wave-spindle synchrony, brain atrophy, and forgetting. Neuron. 2018;97:221–30 e224.

  123. 123.

    Schultz W. Multiple dopamine functions at different time courses. Annu Rev Neurosci. 2007;30:259–88.

  124. 124.

    Schultz W. Updating dopamine reward signals. Curr Opin Neurobiol. 2013;23:229–38.

  125. 125.

    Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17:524–32.

  126. 126.

    Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: ‘liking’, ‘wanting’, and learning. Curr Opin Pharm. 2009;9:65–73.

  127. 127.

    Lisman JE, Grace AA. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron. 2005;46:703–13.

  128. 128.

    Adcock RA, Thangavel A, Whitfield-Gabrieli S, Knutson B, Gabrieli JD. Reward-motivated learning: mesolimbic activation precedes memory formation. Neuron. 2006;50:507–17.

  129. 129.

    Patil A, Murty VP, Dunsmoor JE, Phelps EA, Davachi L. Reward retroactively enhances memory consolidation for related items. Learn Mem. 2017;24:65–9.

  130. 130.

    Wimmer GE, Shohamy D. Preference by association: how memory mechanisms in the hippocampus bias decisions. Science. 2012;338:270–3.

  131. 131.

    Braun EK, Wimmer GE, Shohamy D. Retroactive and graded prioritization of memory by reward. Nat Commun. 2018;9:4886.

  132. 132.

    Fischer S, Born J. Anticipated reward enhances offline learning during sleep. J Exp Psychol Learn Mem Cogn. 2009;35:1586–93.

  133. 133.

    Stamm AW, Nguyen ND, Seicol BJ, Fagan A, Oh A, Drumm M, et al. Negative reinforcement impairs overnight memory consolidation. Learn Mem. 2014;21:591–6.

  134. 134.

    Groch S, Zinke K, Wilhelm I, Born J. Dissociating the contributions of slow-wave sleep and rapid eye movement sleep to emotional item and source memory. Neurobiol Learn Mem. 2014.

  135. 135.

    Javadi AH, Tolat A, Spiers HJ. Sleep enhances a spatially mediated generalization of learned values. Learn Mem. 2015;22:532–6.

  136. 136.

    Lansink CS, Goltstein PM, Lankelma JV, Joosten RN, McNaughton BL, Pennartz CM. Preferential reactivation of motivationally relevant information in the ventral striatum. J Neurosci. 2008;28:6372–82.

  137. 137.

    Lansink CS, Goltstein PM, Lankelma JV, McNaughton BL, Pennartz CM. Hippocampus leads ventral striatum in replay of place-reward information. PLoS Biol. 2009;7:e1000173.

  138. 138.

    Valdes JL, McNaughton BL, Fellous JM. Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area. J Neurophysiol. 2015;114:1183–95.

  139. 139.

    McNamara CG, Tejero-Cantero A, Trouche S, Campo-Urriza N, Dupret D. Dopaminergic neurons promote hippocampal reactivation and spatial memory persistence. Nat Neurosci. 2014;17:1658–60.

  140. 140.

    Feld GB, Besedovsky L, Kaida K, Munte TF, Born J. Dopamine D2-like receptor activation wipes out preferential consolidation of high over low reward memories during human sleep. J Cogn Neurosci. 2014.

  141. 141.

    Manahan-Vaughan D, Kulla A. Regulation of depotentiation and long-term potentiation in the dentate gyrus of freely moving rats by dopamine D2-like receptors. Cereb Cortex. 2003;13:123–35.

  142. 142.

    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189–225.

  143. 143.

    Alizadeh Asfestani M, Brechtmann V, Santiago JCP, Born J, Feld GB. Consolidation of reward memory during sleep does not require dopaminergic activation. bioRxiv. 2019.

  144. 144.

    Takano A, Suhara T, Yasuno F, Suzuki K, Takahashi H, Morimoto T, et al. The antipsychotic sultopride is overdosed–a PET study of drug-induced receptor occupancy in comparison with sulpiride. Int J Neuropsychopharmacol. 2006;9:539–45.

  145. 145.

    Gomperts SN, Kloosterman F, Wilson MA. VTA neurons coordinate with the hippocampal reactivation of spatial experience. Elife. 2015;4.

  146. 146.

    Schapiro AC, McDevitt EA, Rogers TT, Mednick SC, Norman KA. Human hippocampal replay during rest prioritizes weakly learned information and predicts memory performance. Nat Commun. 2018;9:3920.

  147. 147.

    Drosopoulos S, Schulze C, Fischer S, Born J. Sleep’s function in the spontaneous recovery and consolidation of memories. J Exp Psychol Gen. 2007;136:169–83.

  148. 148.

    Redondo RL, Morris RG. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci. 2011;12:17–30.

  149. 149.

    Murillo-Rodriguez E, Blanco-Centurion C, Sanchez C, Piomelli D, Shiromani PJ. Anandamide enhances extracellular levels of adenosine and induces sleep: an in vivo microdialysis study. Sleep. 2003;26:943–7.

  150. 150.

    Hill MN, Tasker JG. Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2012;204:5–16.

  151. 151.

    Xu J, Antion MD, Nomura T, Kraniotis S, Zhu Y, Contractor A. Hippocampal metaplasticity is required for the formation of temporal associative memories. J Neurosci. 2014;34:16762–73.

  152. 152.

    Chevaleyre V, Castillo PE. Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron. 2004;43:871–81.

  153. 153.

    Solinas M, Goldberg SR, Piomelli D. The endocannabinoid system in brain reward processes. Br J Pharm. 2008;154:369–83.

  154. 154.

    Ghoneim MM, Mewaldt SP. Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory. Psychopharmacologia. 1975;44:257–62.

  155. 155.

    Rothschild G, Eban E, Frank LM. A cortical-hippocampal-cortical loop of information processing during memory consolidation. Nat Neurosci. 2017;20:251–9.

  156. 156.

    Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76:116–29.

  157. 157.

    Gais S, Born J. Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proc Natl Acad Sci. 2004;101:2140–4.

  158. 158.

    Atri A, Sherman S, Norman KA, Kirchhoff BA, Nicolas MM, Greicius MD, et al. Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task. Behav Neurosci. 2004;118:223–36.

  159. 159.

    Rasch B, Born J, Gais S. Combined blockade of cholinergic receptors shifts the brain from stimulus encoding to memory consolidation. J Cogn Neurosci. 2006;18:793–802.

  160. 160.

    Epperly T, Dunay MA, Boice JL. Alzheimer disease: pharmacologic and nonpharmacologic therapies for cognitive and functional symptoms. Am Fam Physician. 2017;95:771–8.

  161. 161.

    Klinzing JG, Kugler S, Soekadar SR, Rasch B, Born J, Diekelmann S. Odor cueing during slow-wave sleep benefits memory independently of low cholinergic tone. Psychopharmacol (Berl). 2018;235:291–9.

  162. 162.

    Schapiro AC, Turk-Browne NB, Botvinick MM, Norman KA. Complementary learning systems within the hippocampus: a neural network modelling approach to reconciling episodic memory with statistical learning. Philos Trans R Soc Lond B Biol Sci. 2017;372.

  163. 163.

    Pardridge WM, Moeller TL, Mietus LJ, Oldendorf WH. Blood-brain barrier transport and brain sequestration of steroid hormones. Am J Physiol. 1980;239:E96–102.

  164. 164.

    Bennett MC, Diamond DM, Fleshner M, Rose, GMJP. Serum corticosterone level predicts the magnitude of hippocampal primed burst potentiation and depression in urethane-anesthetized rats. Psychobiology. 1991;19:301–7.

  165. 165.

    Diamond DM, Bennett MC, Fleshner M, Rose GM. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus. 1992;2:421–30.

  166. 166.

    Krieger DT, Allen W, Rizzo F, Krieger HP. Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab. 1971;32:266–84.

  167. 167.

    Bierwolf C, Struve K, Marshall L, Born J, Fehm HL. Slow Wave Sleep Drives Inhibition of Pituitary‐AdrenalSecretion in Humans. Journal of Neuroendocrinology 2003;9(6):479–84.

  168. 168.

    Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81.

  169. 169.

    Schwabe L, Haddad L, Schachinger H. HPA axis activation by a socially evaluated cold-pressor test. Psychoneuroendocrinology. 2008;33:890–5.

  170. 170.

    Buchanan TW, Lovallo WR. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology. 2001;26:307–17.

  171. 171.

    Cahill L, Gorski L, Le K. Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding. Learn Mem. 2003;10:270–4.

  172. 172.

    Kuhlmann S, Kirschbaum C, Wolf OT. Effects of oral cortisol treatment in healthy young women on memory retrieval of negative and neutral words. Neurobiol Learn Mem. 2005;83:158–62.

  173. 173.

    Buchanan TW, Tranel D, Adolphs R. Impaired memory retrieval correlates with individual differences in cortisol response but not autonomic response. Learn Mem. 2006;13:382–7.

  174. 174.

    Rimmele U, Besedovsky L, Lange T, Born J. Emotional memory can be persistently weakened by suppressing cortisol during retrieval. Neurobiol Learn Mem. 2015;119:102.

  175. 175.

    Schilling TM, Kolsch M, Larra MF, Zech CM, Blumenthal TD, Frings C, et al. For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose-response relationship. Psychoneuroendocrinology. 2013;38:1565–72.

  176. 176.

    Rimmele U, Besedovsky L, Lange T, Born J. Blocking mineralocorticoid receptors impairs, blocking glucocorticoid receptors enhances memory retrieval in humans. Neuropsychopharmacology. 2013;38:884–94.

  177. 177.

    Bennion KA, Mickley Steinmetz KR, Kensinger EA, Payne JD. Sleep and cortisol interact to support memory consolidation. Cereb Cortex. 2015;25:646–57.

  178. 178.

    Dolfen N, King BR, Schwabe L, Swinnen S, Albouy G. Glucocorticoid response to stress induction prior to learning is negatively related to subsequent motor memory consolidation. Neurobiol Learn Mem. 2019;158:32–41.

  179. 179.

    Plihal W, Pietrowsky R, Born J. Dexamethasone blocks sleep induced improvement of declarative memory. Psychoneuroendocrinology. 1999;24:313–31.

  180. 180.

    Wagner U, Degirmenci M, Drosopoulos S, Perras B, Born J. Effects of cortisol suppression on sleep-associated consolidation of neutral and emotional memory. Biol Psychiatry. 2005;58:885–93.

  181. 181.

    Kelemen E, Bahrendt M, Born J, Inostroza M. Hippocampal corticosterone impairs memory consolidation during sleep but improves consolidation in the wake state. Hippocampus. 2014;24:510–5.

  182. 182.

    Joels M, de Kloet E. Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science. 1989;245:1502–5.

  183. 183.

    Weiss EK, Krupka N, Bahner F, Both M & Draguhn A. Fast effects of glucocorticoids on memory-related network oscillations in the mouse hippocampus. J Neuroendocrinol 2008;20:549–557.

  184. 184.

    Delahanty DL, Gabert-Quillen C, Ostrowski SA, Nugent NR, Fischer B, Morris A, et al. The efficacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial. CNS Spectr. 2013;18:103–11.

  185. 185.

    Manoach DS, Pan JQ, Purcell SM, Stickgold R. Reduced sleep spindles in schizophrenia: a treatable endophenotype that links risk genes to impaired cognition? Biol Psychiatry. 2016;80:599–608.

  186. 186.

    Göder R, Baier PC, Beith B, Baecker C, Seeck-Hirschner M, Junghanns K, et al. Effects of transcranial direct current stimulation during sleep on memory performance in patients with schizophrenia. Schizophr Res. 2013;144:153–4.

  187. 187.

    Hofmann SG, Asnaani A, Vonk IJ, Sawyer AT, Fang A. The efficacy of cognitive behavioral therapy: a review of meta-analyses. Cogn Ther Res. 2012;36:427–40.

  188. 188.

    Hofmann SG, Smits JA. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. J Clin Psychiatry. 2008;69:621–32.

  189. 189.

    Cuijpers P, Berking M, Andersson G, Quigley L, Kleiboer A, Dobson KS. A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry. 2013;58:376–85.

  190. 190.

    Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB, Otto MW. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry. 2008;165:179–87.

  191. 191.

    Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363:880–884.

  192. 192.

    Bandelow B, Michaelis S. Epidemiology of anxiety disorders in the 21st century. Dialog- Clin Neurosci. 2015;17:327–35.

  193. 193.

    Kessler RC, Ruscio AM, Shear K, Wittchen HU. Epidemiology of anxiety disorders. Curr Top Behav Neurosci. 2010;2:21–35.

  194. 194.

    Watson JB, Rayner R. Conditioned emotional reactions. J Exp Psychol. 1920;3:1–14.

  195. 195.

    Mowrer OH. On the dual nature of learning—a re-interpretation of “conditioning” and “problem-solving”. Harv Educ Rev. 1947;17:102–48.

  196. 196.

    Hofmann SG. Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders. Clin Psychol Rev. 2008;28:199–210.

  197. 197.

    Hauner KK, Howard JD, Zelano C, Gottfried JA. Stimulus-specific enhancement of fear extinction during slow-wave sleep. Nat Neurosci. 2013;16:1553–5.

  198. 198.

    He J, Sun HQ, Li SX, Zhang WH, Shi J, Ai SZ, et al. Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans. Sleep. 2014;38:423–31.

  199. 199.

    Barnes DC, Wilson DA. Slow-wave sleep-imposed replay modulates both strength and precision of memory. J Neurosci. 2014;34:5134–42.

  200. 200.

    Rolls A, Makam M, Kroeger D, Colas D, de Lecea L, Heller HC. Sleep to forget: interference of fear memories during sleep. Mol Psychiatry. 2013;18:1166–70.

  201. 201.

    Hofmann SG, Sawyer AT, Asnaani A. D-cycloserine as an augmentation strategy for cognitive behavioral therapy for anxiety disorders: an update. Curr Pharm Des. 2012;18:5659–62.

  202. 202.

    Hofmann SG. D-cycloserine for treating anxiety disorders: making good exposures better and bad exposures worse. Depress Anxiety. 2014;31:175–7.

  203. 203.

    Pyszczynski T, Hamilton JC, Herring FH, Greenberg J. Depression, self-focused attention, and the negative memory bias. J Personal Soc Psychol. 1989;57:351–7.

  204. 204.

    Brewin CR. Understanding cognitive behaviour therapy: A retrieval competition account. Behav Res Ther. 2006;44:765–84.

  205. 205.

    Nishida M, Pearsall J, Buckner RL, Walker MP. REM sleep, prefrontal theta, and the consolidation of human emotional memory. Cereb Cortex. 2009;19:1158–66.

  206. 206.

    Wagner U, Gais S, Born J. Emotional memory formation is enhanced across sleep intervals with high amounts of rapid eye movement sleep. Learn Mem. 2001;8:112–9.

  207. 207.

    Wagner U, Hallschmid M, Rasch B, Born J. Brief sleep after learning keeps emotional memories alive for years. Biol Psychiatry. 2006;60:788–90.

  208. 208.

    Walker MP, van der Helm E. Overnight therapy? The role of sleep in emotional brain processing. Psychol Bull. 2009;135:731–48.

  209. 209.

    Bolinger E, Born J, Zinke K. Sleep divergently affects cognitive and automatic emotional response in children. Neuropsychologia. 2018;117:84–91.

  210. 210.

    Wilson S, Argyropoulos S. Antidepressants and sleep. Drugs. 2005;65:927–47.

  211. 211.

    Palagini L, Baglioni C, Ciapparelli A, Gemignani A, Riemann D. REM sleep dysregulation in depression: state of the art. Sleep Med Rev. 2013;17:377–90.

  212. 212.

    Robinson TE, Berridge KC. The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction. 2000;95:S91–117.

  213. 213.

    Vollstadt-Klein S, Loeber S, Kirsch M, Bach P, Richter A, Buhler M, et al. Effects of cue-exposure treatment on neural cue reactivity in alcohol dependence: a randomized trial. Biol Psychiatry. 2011;69:1060–6.

  214. 214.

    Arzi A, Shedlesky L, Ben-Shaul M, Nasser K, Oksenberg A, Hairston IS, Sobel N. Humans can learn new information during sleep. Nat Neurosci. 2012;15:1460–5.

  215. 215.

    Arzi A, Holtzman Y, Samnon P, Eshel N, Harel E, Sobel N, Olfactory Aversive Conditioning during Sleep Reduces Cigarette-Smoking Behavior. J Neurosci. 2014;34:15382–93.

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Feld, G.B., Born, J. Neurochemical mechanisms for memory processing during sleep: basic findings in humans and neuropsychiatric implications. Neuropsychopharmacol. 45, 31–44 (2020).

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