Cellular and Molecular Life Sciences

, Volume 71, Issue 1, pp 21–42 | Cite as

Generating new neurons to circumvent your fears: the role of IGF signaling



Extinction of fear memory is a particular form of cognitive function that is of special interest because of its involvement in the treatment of anxiety and mood disorders. Based on recent literature and our previous findings (EMBO J 30(19):4071–4083, 2011), we propose a new hypothesis that implies a tight relationship among IGF signaling, adult hippocampal neurogenesis and fear extinction. Our proposed model suggests that fear extinction-induced IGF2/IGFBP7 signaling promotes the survival of neurons at 2–4 weeks old that would participate in the discrimination between the original fear memory trace and the new safety memory generated during fear extinction. This is also called “pattern separation”, or the ability to distinguish similar but different cues (e.g., context). To understand the molecular mechanisms underlying fear extinction is therefore of great clinical importance.


IGF2 IGFBP7 Neurogenesis Fear extinction Learning and memory Epigenetics 


  1. 1.
    Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150PubMedGoogle Scholar
  2. 2.
    Fischer A, Tsai LH (2009) Counteracting molecular pathways regulating the reduction of fear: implications for the treatment of anxiety diseases. In: Shiromani PJ, Keane TM, LeDoux JE (eds) Post-traumatic stress disorder: basic science and clinical practice. Humana, Totowa, NJ.pp 79–103Google Scholar
  3. 3.
    Kandel ER (2001) The molecular biology of memory storage: a dialog between genes and synapses. Biosci Rep 21:565–611PubMedGoogle Scholar
  4. 4.
    Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35:24–35PubMedCentralPubMedGoogle Scholar
  5. 5.
    Friedman MJ, Schnurr PP, McDonagh-Coyle A (1994) Post-traumatic stress disorder in the military veteran. Psychiatr Clin North Am 17:265–277PubMedGoogle Scholar
  6. 6.
    Maren S, Chang CH (2006) Recent fear is resistant to extinction. Proc Natl Acad Sci USA 103:18020–18025PubMedGoogle Scholar
  7. 7.
    Feldner MT, Monson CM, Friedman MJ (2007) A critical analysis of approaches to targeted PTSD prevention: current status and theoretically derived future directions. Behav Modif 31:80–116PubMedGoogle Scholar
  8. 8.
    Pavlov IP (1927) Conditioned reflexes. Oxford University Press, LondonGoogle Scholar
  9. 9.
    Maren S (2011) Seeking a spotless mind: extinction, deconsolidation, and erasure of fear memory. Neuron 70:830–845PubMedCentralPubMedGoogle Scholar
  10. 10.
    Milad MR, Quirk GJ (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129–151PubMedGoogle Scholar
  11. 11.
    Orsini CA, Maren S (2012) Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev 36:1773–1802PubMedCentralPubMedGoogle Scholar
  12. 12.
    Tronson NC, Corcoran KA, Jovasevic V, Radulovic J (2012) Fear conditioning and extinction: emotional states encoded by distinct signaling pathways. Trends Neurosci 35:145–155PubMedCentralPubMedGoogle Scholar
  13. 13.
    Agis-Balboa RC, Arcos-Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, Haladyniak U, Agbemenyah HY, Zovoilis A, Salinas-Riester G, Opitz L, Sananbenesi F, Fischer A (2011) A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J 30:4071–4083PubMedGoogle Scholar
  14. 14.
    Sananbenesi F, Fischer A, Wang X, Schrick C, Neve R, Radulovic J, Tsai LH (2007) A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 10:1012–1019PubMedCentralPubMedGoogle Scholar
  15. 15.
    Parsons RG, Ressler KJ (2013) Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16:146–153PubMedGoogle Scholar
  16. 16.
    Lattal KM, Wood MA (2013) Epigenetics and persistent memory: implications for reconsolidation and silent extinction beyond the zero. Nat Neurosci 16:124–129PubMedCentralPubMedGoogle Scholar
  17. 17.
    McGaugh JL (2000) Memory – a century of consolidation. Science 287:248–251PubMedGoogle Scholar
  18. 18.
    McKenzie S, Eichenbaum H (2011) Consolidation and reconsolidation: two lives of memories? Neuron 71:224–233PubMedCentralPubMedGoogle Scholar
  19. 19.
    Monfils MH, Cowansage KK, Klann E, LeDoux JE (2009) Extinction-reconsolidation boundaries: key to persistent attenuation of fear memories. Science 324:951–955PubMedCentralPubMedGoogle Scholar
  20. 20.
    Alberini CM (2011) The role of reconsolidation and the dynamic process of long-term memory formation and storage. Front Behav Neurosci 5:12PubMedCentralPubMedGoogle Scholar
  21. 21.
    Duvarci S, Nader K (2004) Characterization of fear memory reconsolidation. J Neurosci 24:9269–9275PubMedGoogle Scholar
  22. 22.
    Nader K, Schafe GE, Le Doux JE (2000) Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406:722–726PubMedGoogle Scholar
  23. 23.
    Tronson NC, Wiseman SL, Olausson P, Taylor JR (2006) Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A. Nat Neurosci 9:167–169PubMedGoogle Scholar
  24. 24.
    Alberini CM (2005) Mechanisms of memory stabilization: are consolidation and reconsolidation similar or distinct processes? Trends Neurosci 28:51–56PubMedGoogle Scholar
  25. 25.
    Hupbach A, Gomez R, Hardt O, Nadel L (2007) Reconsolidation of episodic memories: a subtle reminder triggers integration of new information. Learn Mem 14:47–53PubMedGoogle Scholar
  26. 26.
    Tronson NC, Taylor JR (2007) Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 8:262–275PubMedGoogle Scholar
  27. 27.
    Nicoll RA, Malenka RC (1999) Expression mechanisms underlying NMDA receptor-dependent long-term potentiation. Ann N Y Acad Sci 868:515–525PubMedGoogle Scholar
  28. 28.
    Sheinin A, Shavit S, Benveniste M (2001) Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine. Neuropharmacology 41:151–158PubMedGoogle Scholar
  29. 29.
    Walker DL, Ressler KJ, Lu KT, Davis M (2002) Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci 22:2343–2351PubMedGoogle Scholar
  30. 30.
    Hofmann SG (2007) Enhancing exposure-based therapy from a translational research perspective. Behav Res Ther 45:1987–2001PubMedCentralPubMedGoogle Scholar
  31. 31.
    Lee JL, Milton AL, Everitt BJ (2006) Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26:10051–10056PubMedGoogle Scholar
  32. 32.
    Eisenberg M, Kobilo T, Berman DE, Dudai Y (2003) Stability of retrieved memory: inverse correlation with trace dominance. Science 301:1102–1104PubMedGoogle Scholar
  33. 33.
    Pedreira ME, Maldonado H (2003) Protein synthesis subserves reconsolidation or extinction depending on reminder duration. Neuron 38:863–869PubMedGoogle Scholar
  34. 34.
    Suzuki A, Josselyn SA, Frankland PW, Masushige S, Silva AJ, Kida S (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 24:4787–4795PubMedGoogle Scholar
  35. 35.
    Werner-Seidler A, Richardson R (2007) Effects of D-cycloserine on extinction: consequences of prior exposure to imipramine. Biol Psychiatry 62:1195–1197PubMedGoogle Scholar
  36. 36.
    Kaplan GB, Moore KA (2011) The use of cognitive enhancers in animal models of fear extinction. Pharmacol Biochem Behav 99:217–228PubMedGoogle Scholar
  37. 37.
    Myers KM, Carlezon WA Jr, Davis M (2011) Glutamate receptors in extinction and extinction-based therapies for psychiatric illness. Neuropsychopharmacology 36:274–293PubMedGoogle Scholar
  38. 38.
    Quirk GJ, Pare D, Richardson R, Herry C, Monfils MH, Schiller D, Vicentic A (2010) Erasing fear memories with extinction training. J Neurosci 30:14993–14997PubMedCentralPubMedGoogle Scholar
  39. 39.
    Pare D, Duvarci S (2012) Amygdala microcircuits mediating fear expression and extinction. Curr Opin Neurobiol 22:717–723PubMedCentralPubMedGoogle Scholar
  40. 40.
    Xu W, Südhof TC (2013) A neural circuit for memory specificity and generalization. Science 339(6125):1290–1295PubMedGoogle Scholar
  41. 41.
    Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74PubMedGoogle Scholar
  42. 42.
    Hugues S, Garcia R (2007) Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory. Learn Mem 14:520–524PubMedGoogle Scholar
  43. 43.
    Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72PubMedCentralPubMedGoogle Scholar
  44. 44.
    Quirk GJ, Likhtik E, Pelletier JG, Pare D (2003) Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 23:8800–8807PubMedGoogle Scholar
  45. 45.
    Amano T, Duvarci S, Popa D, Pare D (2011) The fear circuit revisited: contributions of the basal amygdala nuclei to conditioned fear. J Neurosci 31:15481–15489PubMedCentralPubMedGoogle Scholar
  46. 46.
    Wojtowicz JM (2012) Adult neurogenesis. From circuits to models. Behav Brain Res 227:490–496PubMedGoogle Scholar
  47. 47.
    Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99:195–231PubMedGoogle Scholar
  48. 48.
    McClelland JL, McNaughton BL, O’Reilly RC (1995) 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 102:419–457PubMedGoogle Scholar
  49. 49.
    Squire LR, Alvarez P (1995) Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 5:169–177PubMedGoogle Scholar
  50. 50.
    Frankland PW, Bontempi B (2005) The organization of recent and remote memories. Nat Rev Neurosci 6:119–130PubMedGoogle Scholar
  51. 51.
    Wang SH, Teixeira CM, Wheeler AL, Frankland PW (2009) The precision of remote context memories does not require the hippocampus. Nat Neurosci 12:253–255PubMedGoogle Scholar
  52. 52.
    Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683PubMedGoogle Scholar
  53. 53.
    Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256:675–677PubMedGoogle Scholar
  54. 54.
    Gale GD, Anagnostaras SG, Godsil BP, Mitchell S, Nozawa T, Sage JR, Wiltgen B, Fanselow MS (2004) Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of rats. J Neurosci 24:3810–3815PubMedGoogle Scholar
  55. 55.
    Fischer A, Sananbenesi F, Schrick C, Spiess J, Radulovic J (2004) Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24:1962–1966PubMedGoogle Scholar
  56. 56.
    Lattal KM, Radulovic J, Lukowiak K (2006) Extinction: (corrected) does it or doesn’t it? The requirement of altered gene activity and new protein synthesis. Biol Psychiatry 60:344–351PubMedCentralPubMedGoogle Scholar
  57. 57.
    Ji J, Maren S (2007) Hippocampal involvement in contextual modulation of fear extinction. Hippocampus 17:749–758PubMedGoogle Scholar
  58. 58.
    Zelikowsky M, Bissiere S, Fanselow MS (2012) Contextual fear memories formed in the absence of the dorsal hippocampus decay across time. J Neurosci 32:3393–3397PubMedCentralPubMedGoogle Scholar
  59. 59.
    Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast T, Zhang WN, Pothuizen HH, Feldon J (2004) Regional dissociations within the hippocampus – memory and anxiety. Neurosci Biobehav Rev 28:273–283PubMedGoogle Scholar
  60. 60.
    Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A, Puchalski RB, Gage FH, Jones AR, Bajic VB, Hawrylycz MJ, Lein ES (2008) Genomic anatomy of the hippocampus. Neuron 60:1010–1021PubMedGoogle Scholar
  61. 61.
    van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of memory: an interactive overview of the parahippocampal–hippocampal network. Nat Rev Neurosci 10:272–282PubMedGoogle Scholar
  62. 62.
    Fanselow MS, Dong HW (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65:7–19PubMedCentralPubMedGoogle Scholar
  63. 63.
    Schmidt B, Marrone DF, Markus EJ (2011) Disambiguating the similar: the dentate gyrus and pattern separation. Behav Brain Res 226:56–65PubMedGoogle Scholar
  64. 64.
    Hawley DF, Morch K, Christie BR, Leasure JL (2012) Differential response of hippocampal subregions to stress and learning. PLoS One 7:e53126PubMedCentralPubMedGoogle Scholar
  65. 65.
    Kheirbek MA, Drew LJ, Burghardt NS, Costantini DO, Tannenholz L, Ahmari SE, Zeng H, Fenton AA, Hen R (2013) Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus. Neuron 77(5):955–968PubMedGoogle Scholar
  66. 66.
    Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling RM, Bahari-Javan S, Benito-Garagorri E, Halder R, Burkhardt S, Stewart AF, Fischer A (2013) Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci 33:3452–3464PubMedGoogle Scholar
  67. 67.
    Zovoilis A, Agbemenyah HY, Agis-Balboa RC, Stilling RM, Edbauer D, Rao P, Farinelli L, Delalle I, Schmitt A, Falkai P, Bahari-Javan S, Burkhardt S, Sananbenesi F, Fischer A (2011) MicroRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308PubMedGoogle Scholar
  68. 68.
    Pitkanen A, Pikkarainen M, Nurminen N, Ylinen A (2000) Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review. Ann N Y Acad Sci 911:369–391PubMedGoogle Scholar
  69. 69.
    Jay TM, Witter MP (1991) Distribution of hippocampal CA1 and subicular efferents in the prefrontal cortex of the rat studied by means of anterograde transport of Phaseolus vulgaris-leucoagglutinin. J Comp Neurol 313:574–586PubMedGoogle Scholar
  70. 70.
    Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51:32–58PubMedGoogle Scholar
  71. 71.
    Hoover WB, Vertes RP (2007) Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct 212:149–179PubMedGoogle Scholar
  72. 72.
    Canteras NS, Swanson LW (1992) Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: a PHAL anterograde tract-tracing study in the rat. J Comp Neurol 324:180–194PubMedGoogle Scholar
  73. 73.
    Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716PubMedGoogle Scholar
  74. 74.
    Treves A, Tashiro A, Witter ME, Moser EI (2008) What is the mammalian dentate gyrus good for? Neuroscience 154:1155–1172PubMedGoogle Scholar
  75. 75.
    Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660PubMedGoogle Scholar
  76. 76.
    Sahay A, Wilson DA, Hen R (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70:582–588PubMedCentralPubMedGoogle Scholar
  77. 77.
    Aimone JB, Deng W, Gage FH (2011) Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70:589–596PubMedCentralPubMedGoogle Scholar
  78. 78.
    Hsieh J (2012) Orchestrating transcriptional control of adult neurogenesis. Genes Dev 26:1010–1021PubMedGoogle Scholar
  79. 79.
    Jobe EM, McQuate AL, Zhao X (2012) Crosstalk among epigenetic pathways regulates neurogenesis. Front Neurosci 6:59PubMedCentralPubMedGoogle Scholar
  80. 80.
    Faigle R, Song H (2013) Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochim Biophys Acta 1830:2435–2448PubMedGoogle Scholar
  81. 81.
    Altman J (1963) Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat Rec 145:573–591PubMedGoogle Scholar
  82. 82.
    Nottebohm F (2004) The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann N Y Acad Sci 1016:628–658PubMedGoogle Scholar
  83. 83.
    Kempermann G, Wiskott L, Gage FH (2004) Functional significance of adult neurogenesis. Curr Opin Neurobiol 14:186–191PubMedGoogle Scholar
  84. 84.
    Jessberger S, Toni N, Clemenson GD Jr, Ray J, Gage FH (2008) Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat Neurosci 11:888–893PubMedCentralPubMedGoogle Scholar
  85. 85.
    Lang MF, Shi Y (2012) Dynamic roles of microRNAs in neurogenesis. Front Neurosci 6:71PubMedCentralPubMedGoogle Scholar
  86. 86.
    Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, Schinder AF (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11:901–907PubMedCentralPubMedGoogle Scholar
  87. 87.
    Schmidt-Hieber C, Jonas P, Bischofberger J (2004) Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429:184–187PubMedGoogle Scholar
  88. 88.
    Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54:559–566PubMedCentralPubMedGoogle Scholar
  89. 89.
    Tashiro A, Makino H, Gage FH (2007) Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 27:3252–3259PubMedGoogle Scholar
  90. 90.
    Deng W, Aimone JB, Gage FH (2010) New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350PubMedCentralPubMedGoogle Scholar
  91. 91.
    Jessberger S, Kempermann G (2003) Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur J Neurosci 18:2707–2712PubMedGoogle Scholar
  92. 92.
    Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493–495PubMedGoogle Scholar
  93. 93.
    van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270PubMedGoogle Scholar
  94. 94.
    Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593PubMedCentralPubMedGoogle Scholar
  95. 95.
    Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, Czeh B (2010) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol 20:1–17PubMedGoogle Scholar
  96. 96.
    Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362PubMedGoogle Scholar
  97. 97.
    Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727–734PubMedGoogle Scholar
  98. 98.
    Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11PubMedGoogle Scholar
  99. 99.
    Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265PubMedGoogle Scholar
  100. 100.
    Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R, Drew MR (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci USA 103:17501–17506PubMedGoogle Scholar
  101. 101.
    Pham K, McEwen BS, Ledoux JE, Nader K (2005) Fear learning transiently impairs hippocampal cell proliferation. Neuroscience 130:17–24PubMedGoogle Scholar
  102. 102.
    Fotuhi M, Do D, Jack C (2012) Modifiable factors that alter the size of the hippocampus with ageing. Nat Rev Neurol 8:189–202PubMedGoogle Scholar
  103. 103.
    Bremner JD, Elzinga B, Schmahl C, Vermetten E (2008) Structural and functional plasticity of the human brain in posttraumatic stress disorder. Prog Brain Res 167:171–186PubMedCentralPubMedGoogle Scholar
  104. 104.
    Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809PubMedGoogle Scholar
  105. 105.
    Pollak DD, Monje FJ, Zuckerman L, Denny CA, Drew MR, Kandel ER (2008) An animal model of a behavioral intervention for depression. Neuron 60:149–161PubMedCentralPubMedGoogle Scholar
  106. 106.
    Takemura NU, Kato N (2008) Adult neurogenesis and systemic adaptation: animal experiments and clinical perspectives for PTSD. Prog Brain Res 167:99–109PubMedGoogle Scholar
  107. 107.
    Siegmund A, Wotjak CT (2007) A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear. J Psychiatr Res 41:848–860PubMedGoogle Scholar
  108. 108.
    Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ (2001) Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron 32:911–926PubMedGoogle Scholar
  109. 109.
    Ko HG, Jang DJ, Son J, Kwak C, Choi JH, Ji YH, Lee YS, Son H, Kaang BK (2009) Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory. Mol Brain 2:1PubMedCentralPubMedGoogle Scholar
  110. 110.
    Deng W, Saxe MD, Gallina IS, Gage FH (2009) Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 29:13532–13542PubMedCentralPubMedGoogle Scholar
  111. 111.
    Noonan MA, Bulin SE, Fuller DC, Eisch AJ (2010) Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J Neurosci 30:304–315PubMedCentralPubMedGoogle Scholar
  112. 112.
    Schipper P, Kiliaan AJ, Homberg JR (2011) A mixed polyunsaturated fatty acid diet normalizes hippocampal neurogenesis and reduces anxiety in serotonin transporter knockout rats. Behav Pharmacol 22:324–334PubMedGoogle Scholar
  113. 113.
    Pan YW, Chan GC, Kuo CT, Storm DR, Xia Z (2012) Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory. J Neurosci 32:6444–6455PubMedCentralPubMedGoogle Scholar
  114. 114.
    Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M, Maynard T, Gonzalez D, Kim S, Ye P, D’Ercole AJ, Wong ET, LaMantia AS, Walsh CA (2011) The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69:893–905PubMedCentralPubMedGoogle Scholar
  115. 115.
    McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK, Lowell BB, Fanselow MS, Wilson MA, Tonegawa S (2007) Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317:94–99PubMedGoogle Scholar
  116. 116.
    Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325:210–213PubMedCentralPubMedGoogle Scholar
  117. 117.
    Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472:466–470PubMedCentralPubMedGoogle Scholar
  118. 118.
    Aimone JB, Wiles J, Gage FH (2006) Potential role for adult neurogenesis in the encoding of time in new memories. Nat Neurosci 9:723–727PubMedGoogle Scholar
  119. 119.
    Aimone JB, Wiles J, Gage FH (2009) Computational influence of adult neurogenesis on memory encoding. Neuron 61:187–202PubMedCentralPubMedGoogle Scholar
  120. 120.
    Tronel S, Belnoue L, Grosjean N, Revest JM, Piazza PV, Koehl M, Abrous DN (2012) Adult-born neurons are necessary for extended contextual discrimination. Hippocampus 22:292–298PubMedGoogle Scholar
  121. 121.
    Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, Barrera VR, Chittajallu R, Iwamoto KS, McBain CJ, Fanselow MS, Tonegawa S (2012) Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149:188–201PubMedCentralPubMedGoogle Scholar
  122. 122.
    Niibori Y, Yu TS, Epp JR, Akers KG, Josselyn SA, Frankland PW (2012) Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region. Nat Commun 3:1253PubMedGoogle Scholar
  123. 123.
    Fernandez AM, Torres-Aleman I (2012) The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci 13:225–239PubMedGoogle Scholar
  124. 124.
    Harris JA, Westbrook RF (1998) Evidence that GABA transmission mediates context-specific extinction of learned fear. Psychopharmacology 140:105–115PubMedGoogle Scholar
  125. 125.
    Corcoran KA, Desmond TJ, Frey KA, Maren S (2005) Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction. J Neurosci 25:8978–8987PubMedGoogle Scholar
  126. 126.
    McGaugh JL, Castellano C, Brioni J (1990) Picrotoxin enhances latent extinction of conditioned fear. Behav Neurosci 104:264–267PubMedGoogle Scholar
  127. 127.
    Berlau DJ, McGaugh JL (2006) Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala. Neurobiol Learn Mem 86:123–132PubMedGoogle Scholar
  128. 128.
    Pezze MA, Feldon J (2004) Mesolimbic dopaminergic pathways in fear conditioning. Prog Neurobiol 74:301–320PubMedGoogle Scholar
  129. 129.
    Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgansberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534PubMedGoogle Scholar
  130. 130.
    Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10PubMedGoogle Scholar
  131. 131.
    Arnaldez FI, Helman LJ (2012) Targeting the insulin growth factor receptor 1. Hematol Oncol Clin North Am 26:527–542; vii–viiiPubMedCentralPubMedGoogle Scholar
  132. 132.
    Yang YL, Lu KT (2005) Facilitation of conditioned fear extinction by D-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala. Neuroscience 134:247–260PubMedGoogle Scholar
  133. 133.
    Koshibu K, Graff J, Beullens M, Heitz FD, Berchtold D, Russig H, Farinelli M, Bollen M, Mansuy IM (2009) Protein phosphatase 1 regulates the histone code for long-term memory. J Neurosci 29:13079–13089PubMedGoogle Scholar
  134. 134.
    Filipkowski RK, Knapska E, Kaczmarek L (2006) c-Fos and Zif268 in learning and memory – studies on expression and function. In: Pinaud R, Tremere LA (eds) Immediate early genes in sensory processing, cognitive performance and neurological disorders. Springer, New York, pp 137–158Google Scholar
  135. 135.
    Wei W, Coelho CM, Li X, Marek R, Yan S, Anderson S, Meyers D, Mukherjee C, Sbardella G, Castellano S, Milite C, Rotili D, Mai A, Cole PA, Sah P, Kobor MS, Bredy TW (2012) p300/CBP-associated factor selectively regulates the extinction of conditioned fear. J Neurosci 32:11930–11941PubMedCentralPubMedGoogle Scholar
  136. 136.
    Tronson NC, Schrick C, Guzman YF, Huh KH, Srivastava DP, Penzes P, Guedea AL, Gao C, Radulovic J (2009) Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear. J Neurosci 29:3387–3394PubMedCentralPubMedGoogle Scholar
  137. 137.
    Fiorenza NG, Sartor D, Myskiw JC, Izquierdo I (2011) Treatment of fear memories: interactions between extinction and reconsolidation. An Acad Bras Cienc 83:1363–1372PubMedGoogle Scholar
  138. 138.
    Soeter M, Kindt M (2011) Disrupting reconsolidation: pharmacological and behavioral manipulations. Learn Mem 18:357–366PubMedGoogle Scholar
  139. 139.
    Bernard A, Lubbers LS, Tanis KQ, Luo R, Podtelezhnikov AA, Finney EM, McWhorter MM, Serikawa K, Lemon T, Morgan R, Copeland C, Smith K, Cullen V, Davis-Turak J, Lee CK, Sunkin SM, Loboda AP, Levine DM, Stone DJ, Hawrylycz MJ, Roberts CJ, Jones AR, Geschwind DH, Lein ES (2012) Transcriptional architecture of the primate neocortex. Neuron 73:1083–1099PubMedCentralPubMedGoogle Scholar
  140. 140.
    Oldham MC, Konopka G, Iwamoto K, Langfelder P, Kato T, Horvath S, Geschwind DH (2008) Functional organization of the transcriptome in human brain. Nat Neurosci 11:1271–1282PubMedCentralPubMedGoogle Scholar
  141. 141.
    Winden KD, Oldham MC, Mirnics K, Ebert PJ, Swan CH, Levitt P, Rubenstein JL, Horvath S, Geschwind DH (2009) The organization of the transcriptional network in specific neuronal classes. Mol Syst Biol 5:291PubMedCentralPubMedGoogle Scholar
  142. 142.
    de Carvalho Myskiw J, Benetti F, Izquierdo I (2013) Behavioral tagging of extinction learning. Proc Natl Acad Sci USA 110:1071–1076PubMedGoogle Scholar
  143. 143.
    Bracko O, Singer T, Aigner S, Knobloch M, Winner B, Ray J, Clemenson GD Jr, Suh H, Couillard-Despres S, Aigner L, Gage FH, Jessberger S (2012) Gene expression profiling of neural stem cells and their neuronal progeny reveals IGF2 as a regulator of adult hippocampal neurogenesis. J Neurosci 32:3376–3387PubMedCentralPubMedGoogle Scholar
  144. 144.
    Bonn S, Zinzen RP, Girardot C, Gustafson EH, Perez-Gonzalez A, Delhomme N, Ghavi-Helm Y, Wilczynski B, Riddell A, Furlong EE (2012) Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development. Nat Genet 44:148–156PubMedGoogle Scholar
  145. 145.
    Tye KM, Deisseroth K (2012) Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci 13:251–266PubMedGoogle Scholar
  146. 146.
    Bondy CA, Lee WH (1993) Patterns of insulin-like growth factor and IGF receptor gene expression in the brain. Functional implications. Ann N Y Acad Sci 692:33–43PubMedGoogle Scholar
  147. 147.
    D’Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G (1996) The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 13:227–255PubMedGoogle Scholar
  148. 148.
    Dechiara TM, Efstratiadis A, Robertson EJ (1990) A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor-II gene disrupted by targeting. Nature 345:78–80PubMedGoogle Scholar
  149. 149.
    DeChiara TM, Robertson EJ, Efstratiadis A (1991) Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64:849–859PubMedGoogle Scholar
  150. 150.
    Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82PubMedGoogle Scholar
  151. 151.
    Sim FJ, Keyoung HM, Goldman JE, Kim DK, Jung HW, Roy NS, Goldman SA (2006) Neurocytoma is a tumor of adult neuronal progenitor cells. J Neurosci 26:12544–12555PubMedGoogle Scholar
  152. 152.
    Ye P, D’Ercole AJ (2006) Insulin-like growth factor actions during development of neural stem cells and progenitors in the central nervous system. J Neurosci Res 83:1–6PubMedGoogle Scholar
  153. 153.
    Sutter NB, Bustamante CD, Chase K, Gray MM, Zhao K, Zhu L, Padhukasahasram B, Karlins E, Davis S, Jones PG, Quignon P, Johnson GS, Parker HG, Fretwell N, Mosher DS, Lawler DF, Satyaraj E, Nordborg M, Lark KG, Wayne RK, Ostrander EA (2007) A single IGF1 allele is a major determinant of small size in dogs. Science 316:112–115PubMedCentralPubMedGoogle Scholar
  154. 154.
    Alberini CM, Chen DY (2012) Memory enhancement: consolidation, reconsolidation and insulin-like growth factor 2. Trends Neurosci 35:274–283PubMedCentralPubMedGoogle Scholar
  155. 155.
    Bondy C, Werner H, Roberts CT Jr, LeRoith D (1992) Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience 46:909–923PubMedGoogle Scholar
  156. 156.
    Hodge RD, D’Ercole AJ, O’Kusky JR (2004) Insulin-like growth factor-I accelerates the cell cycle by decreasing G1 phase length and increases cell cycle reentry in the embryonic cerebral cortex. J Neurosci 24:10201–10210PubMedGoogle Scholar
  157. 157.
    Drago J, Murphy M, Carroll SM, Harvey RP, Bartlett PF (1991) Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor I. Proc Natl Acad Sci USA 88:2199–2203PubMedGoogle Scholar
  158. 158.
    Hodge RD, D’Ercole AJ, O’Kusky JR (2005) Increased expression of insulin-like growth factor-I (IGF-I) during embryonic development produces neocortical overgrowth with differentially greater effects on specific cytoarchitectonic areas and cortical layers. Brain Res Dev Brain Res 154:227–237PubMedGoogle Scholar
  159. 159.
    Ozdinler PH, Macklis JD (2006) IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9:1371–1381PubMedGoogle Scholar
  160. 160.
    Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Caceres A, Pfenninger KH, Quiroga S (2006) IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci 9:993–995PubMedGoogle Scholar
  161. 161.
    Oishi K, Watatani K, Itoh Y, Okano H, Guillemot F, Nakajima K, Gotoh Y (2009) Selective induction of neocortical GABAergic neurons by the PDK1-Akt pathway through activation of Mash1. Proc Natl Acad Sci USA 106:13064–13069PubMedGoogle Scholar
  162. 162.
    Hurtado-Chong A, Yusta-Boyo MJ, Vergano-Vera E, Bulfone A, de Pablo F, Vicario-Abejon C (2009) IGF-I promotes neuronal migration and positioning in the olfactory bulb and the exit of neuroblasts from the subventricular zone. Eur J Neurosci 30:742–755PubMedGoogle Scholar
  163. 163.
    O’Kusky JR, Ye P, D’Ercole AJ (2000) Insulin-like growth factor-I promotes neurogenesis and synaptogenesis in the hippocampal dentate gyrus during postnatal development. J Neurosci 20:8435–8442PubMedGoogle Scholar
  164. 164.
    Torres-Aleman I, Pons S, Arevalo MA (1994) The insulin-like growth factor I system in the rat cerebellum: developmental regulation and role in neuronal survival and differentiation. J Neurosci Res 39:117–126PubMedGoogle Scholar
  165. 165.
    Desai M, Li T, Ross MG (2011) Fetal hypothalamic neuroprogenitor cell culture: preferential differentiation paths induced by leptin and insulin. Endocrinology 152:3192–3201PubMedGoogle Scholar
  166. 166.
    Ayer-le Lievre C, Stahlbom PA, Sara VR (1991) Expression of IGF-I and -II mRNA in the brain and craniofacial region of the rat fetus. Development 111:105–115PubMedGoogle Scholar
  167. 167.
    Konishi Y, Takahashi K, Chui DH, Rosenfeld RG, Himeno M, Tabira T (1994) Insulin-like growth factor II promotes in vitro cholinergic development of mouse septal neurons: comparison with the effects of insulin-like growth factor I. Brain Res 649:53–61PubMedGoogle Scholar
  168. 168.
    Hartnett L, Glynn C, Nolan CM, Grealy M, Byrnes L (2010) Insulin-like growth factor-2 regulates early neural and cardiovascular system development in zebrafish embryos. Int J Dev Biol 54:573–583PubMedGoogle Scholar
  169. 169.
    Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46PubMedGoogle Scholar
  170. 170.
    Cui QL, Zheng WH, Quirion R, Almazan G (2005) Inhibition of Src-like kinases reveals Akt-dependent and -independent pathways in insulin-like growth factor I-mediated oligodendrocyte progenitor survival. J Biol Chem 280:8918–8928PubMedGoogle Scholar
  171. 171.
    Kappeler L, De Magalhaes FC, Dupont J, Leneuve P, Cervera P, Perin L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6:e254PubMedCentralPubMedGoogle Scholar
  172. 172.
    D’ercole AJ, Ye P (2008) Expanding the mind: insulin-like growth factor I and brain development. Endocrinology 149:5958–5962Google Scholar
  173. 173.
    Liu W, Ye P, O’Kusky JR, D’Ercole AJ (2009) Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus. J Neurosci Res 87:2821–2832PubMedGoogle Scholar
  174. 174.
    Ye P, Popken GJ, Kemper A, McCarthy K, Popko B, D’Ercole AJ (2004) Astrocyte-specific overexpression of insulin-like growth factor-I promotes brain overgrowth and glial fibrillary acidic protein expression. J Neurosci Res 78:472–484PubMedGoogle Scholar
  175. 175.
    Mairet-Coello G, Tury A, DiCicco-Bloom E (2009) Insulin-like growth factor-1 promotes G(1)/S cell cycle progression through bidirectional regulation of cyclins and cyclin-dependent kinase inhibitors via the phosphatidylinositol 3-kinase/Akt pathway in developing rat cerebral cortex. J Neurosci 29:775–788PubMedCentralPubMedGoogle Scholar
  176. 176.
    Walter HJ, Berry M, Hill DJ, Logan A (1997) Spatial and temporal changes in the insulin-like growth factor (IGF) axis indicate autocrine/paracrine actions of IGF-I within wounds of the rat brain. Endocrinology 138:3024–3034PubMedGoogle Scholar
  177. 177.
    Carro E, Torres-Aleman I (2004) The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer’s disease. Eur J Pharmacol 490:127–133PubMedGoogle Scholar
  178. 178.
    Brown J, Jones EY, Forbes BE (2009) Interactions of IGF-II with the IGF2R/cation-independent mannose-6-phosphate receptor mechanism and biological outcomes. Vitam Horm 80:699–719PubMedGoogle Scholar
  179. 179.
    Hawkes C, Kar S (2004) The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Res Brain Res Rev 44:117–140PubMedGoogle Scholar
  180. 180.
    Poiraudeau S, Lieberherr M, Kergosie N, Corvol MT (1997) Different mechanisms are involved in intracellular calcium increase by insulin-like growth factors 1 and 2 in articular chondrocytes: voltage-gated calcium channels, and/or phospholipase C coupled to a pertussis-sensitive G-protein. J Cell Biochem 64:414–422PubMedGoogle Scholar
  181. 181.
    Hawkes C, Jhamandas JH, Harris KH, Fu W, MacDonald RG, Kar S (2006) Single transmembrane domain insulin-like growth factor-II/mannose-6-phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. J Neurosci 26:585–596PubMedGoogle Scholar
  182. 182.
    Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM (2011) A critical role for IGF-II in memory consolidation and enhancement. Nature 469:491–497PubMedGoogle Scholar
  183. 183.
    Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts CT Jr, Rosenfeld RG (1997) Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci USA 94:12981–12986PubMedGoogle Scholar
  184. 184.
    Honegger B, Galic M, Kohler K, Wittwer F, Brogiolo W, Hafen E, Stocker H (2008) Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. J Biol 7:10PubMedCentralPubMedGoogle Scholar
  185. 185.
    Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23:824–854PubMedGoogle Scholar
  186. 186.
    Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M, Sorensen PH, Seth A (2012) IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors. Sci Signal 5:ra92PubMedGoogle Scholar
  187. 187.
    Ocrant I, Fay CT, Parmelee JT (1990) Characterization of insulin-like growth factor binding proteins produced in the rat central nervous system. Endocrinology 127:1260–1267PubMedGoogle Scholar
  188. 188.
    Hwa V, Oh Y, Rosenfeld RG (1999) The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev 20:761–787PubMedGoogle Scholar
  189. 189.
    Lee WH, Wang GM, Seaman LB, Vannucci SJ (1996) Coordinate IGF-I and IGFBP5 gene expression in perinatal rat brain after hypoxia-ischemia. J Cereb Blood Flow Metab 16:227–236PubMedGoogle Scholar
  190. 190.
    Hynes MA, Brooks PJ, Van Wyk JJ, Lund PK (1988) Insulin-like growth factor II messenger ribonucleic acids are synthesized in the choroid plexus of the rat brain. Mol Endocrinol 2:47–54PubMedGoogle Scholar
  191. 191.
    Stenvers KL, Zimmermann EM, Gallagher M, Lund PK (1994) Expression of insulin-like growth factor binding protein-4 and -5 mRNAs in adult rat forebrain. J Comp Neurol 339:91–105PubMedGoogle Scholar
  192. 192.
    Zappaterra MW, Lehtinen MK (2012) The cerebrospinal fluid: regulator of neurogenesis, behavior, and beyond. Cell Mol Life Sci 69:2863–2878PubMedGoogle Scholar
  193. 193.
    Carro E, Nunez A, Busiguina S, Torres-Aleman I (2000) Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci 20:2926–2933PubMedGoogle Scholar
  194. 194.
    Tomanek B, Iqbal U, Blasiak B, Abulrob A, Albaghdadi H, Matyas JR, Ponjevic D, Sutherland GR (2012) Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging. Neurol Oncol 14:53–63Google Scholar
  195. 195.
    Anderson MF, Aberg MA, Nilsson M, Eriksson PS (2002) Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 134:115–122PubMedGoogle Scholar
  196. 196.
    Ramsey MM, Adams MM, Ariwodola OJ, Sonntag WE, Weiner JL (2005) Functional characterization of des-IGF-1 action at excitatory synapses in the CA1 region of rat hippocampus. J Neurophysiol 94:247–254PubMedGoogle Scholar
  197. 197.
    Deijen JB, de Boer H, van der Veen EA (1998) Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology 23:45–55PubMedGoogle Scholar
  198. 198.
    Dhamoon MS, Noble JM, Craft S (2009) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 72:292–293; author reply 293–294PubMedGoogle Scholar
  199. 199.
    Gronbladh A, Johansson J, Nostl A, Nyberg F, Hallberg M (2013) GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats. J Endocrinol 216:31–41PubMedGoogle Scholar
  200. 200.
    Castro-Alamancos MA, Torres-Aleman I (1994) Learning of the conditioned eye-blink response is impaired by an antisense insulin-like growth factor I oligonucleotide. Proc Natl Acad Sci USA 91:10203–10207PubMedGoogle Scholar
  201. 201.
    Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon DL (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274:34893–34902PubMedGoogle Scholar
  202. 202.
    Nishijima T, Piriz J, Duflot S, Fernandez AM, Gaitan G, Gomez-Pinedo U, Verdugo JM, Leroy F, Soya H, Nunez A, Torres-Aleman I (2010) Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 67:834–846PubMedGoogle Scholar
  203. 203.
    Cohen E, Dillin A (2008) The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci 9:759–767PubMedCentralPubMedGoogle Scholar
  204. 204.
    Piriz J, Muller A, Trejo JL, Torres-Aleman I (2011) IGF-I and the aging mammalian brain. Exp Gerontol 46:96–99PubMedGoogle Scholar
  205. 205.
    Trejo JL, Llorens-Martin MV, Torres-Aleman I (2008) The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37:402–411PubMedGoogle Scholar
  206. 206.
    Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69:29–38PubMedCentralPubMedGoogle Scholar
  207. 207.
    Endres M, Piriz J, Gertz K, Harms C, Meisel A, Kronenberg G, Torres-Aleman I (2007) Serum insulin-like growth factor I and ischemic brain injury. Brain Res 1185:328–335PubMedGoogle Scholar
  208. 208.
    Arpa J, Sanz-Gallego I, Medina-Baez J, Portela LV, Jardim LB, Torres-Aleman I, Saute JA (2011) Subcutaneous insulin-like growth factor-1 treatment in spinocerebellar ataxias: an open label clinical trial. Mov Disord 26:358–359PubMedGoogle Scholar
  209. 209.
    Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine–threonine protein kinase Akt. Science 275:661–665PubMedGoogle Scholar
  210. 210.
    Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I (2002) Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 8:1390–1397PubMedGoogle Scholar
  211. 211.
    Fernandez AM, Fernandez S, Carrero P, Garcia–Garcia M, Torres-Aleman I (2007) Calcineurin in reactive astrocytes plays a key role in the interplay between proinflammatory and anti-inflammatory signals. J Neurosci 27:8745–8756PubMedGoogle Scholar
  212. 212.
    Schmeisser MJ, Baumann B, Johannsen S, Vindedal GF, Jensen V, Hvalby OC, Sprengel R, Seither J, Maqbool A, Magnutzki A, Lattke M, Oswald F, Boeckers TM, Wirth T (2012) IkappaB kinase/nuclear factor kappaB-dependent insulin-like growth factor 2 (Igf2) expression regulates synapse formation and spine maturation via Igf2 receptor signaling. J Neurosci 32:5688–5703PubMedGoogle Scholar
  213. 213.
    Cline BH, Steinbusch HW, Malin D, Revishchin AV, Pavlova GV, Cespuglio R, Strekalova T (2012) The neuronal insulin sensitizer dicholine succinate reduces stress-induced depressive traits and memory deficit: possible role of insulin-like growth factor 2. BMC Neurosci 13:110PubMedCentralPubMedGoogle Scholar
  214. 214.
    Jung S, Lee Y, Kim G, Son H, Lee DH, Roh GS, Kang SS, Cho GJ, Choi WS, Kim HJ (2012) Decreased expression of extracellular matrix proteins and trophic factors in the amygdala complex of depressed mice after chronic immobilization stress. BMC Neurosci 13:58PubMedCentralPubMedGoogle Scholar
  215. 215.
    Abbott MA, Wells DG, Fallon JR (1999) The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci 19:7300–7308PubMedGoogle Scholar
  216. 216.
    Cao P, Maximov A, Sudhof TC (2011) Activity-dependent IGF-1 exocytosis is controlled by the Ca(2+)-sensor synaptotagmin-10. Cell 145:300–311PubMedCentralPubMedGoogle Scholar
  217. 217.
    Liou JC, Tsai FZ, Ho SY (2003) Potentiation of quantal secretion by insulin-like growth factor-1 at developing motoneurons in xenopus cell culture. J Physiol 553:719–728PubMedGoogle Scholar
  218. 218.
    Xing C, Yin Y, Chang R, Gong X, He X, Xie Z (2007) Effects of insulin-like growth factor 1 on synaptic excitability in cultured rat hippocampal neurons. Exp Neurol 205:222–229PubMedGoogle Scholar
  219. 219.
    Hwang O, Choi HJ (1995) Induction of gene expression of the catecholamine-synthesizing enzymes by insulin-like growth factor-I. J Neurochem 65:1988–1996PubMedGoogle Scholar
  220. 220.
    Blair LA, Marshall J (1997) IGF-1 modulates N and L calcium channels in a PI 3-kinase-dependent manner. Neuron 19:421–429PubMedGoogle Scholar
  221. 221.
    Ster J, Colomer C, Monzo C, Duvoid-Guillou A, Moos F, Alonso G, Hussy N (2005) Insulin-like growth factor-1 inhibits adult supraoptic neurons via complementary modulation of mechanoreceptors and glycine receptors. J Neurosci 25:2267–2276PubMedGoogle Scholar
  222. 222.
    Turrigiano GG (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422–435PubMedCentralPubMedGoogle Scholar
  223. 223.
    Leventhal PS, Randolph AE, Vesbit TE, Schenone A, Windebank A, Feldman EL (1995) Insulin-like growth factor-II as a paracrine growth factor in human neuroblastoma cells. Exp Cell Res 221:179–186PubMedGoogle Scholar
  224. 224.
    Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, Eriksson PS (2003) IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci 24:23–40PubMedGoogle Scholar
  225. 225.
    Bateman JM, McNeill H (2006) Insulin/IGF signalling in neurogenesis. Cell Mol Life Sci 63:1701–1705PubMedGoogle Scholar
  226. 226.
    Rodriguez S, Gaunt TR, Day IN (2007) Molecular genetics of human growth hormone, insulin-like growth factors and their pathways in common disease. Hum Genet 122:1–21PubMedGoogle Scholar
  227. 227.
    Chao W, D’Amore PA (2008) IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev 19:111–120PubMedCentralPubMedGoogle Scholar
  228. 228.
    Scolnick JA, Cui K, Duggan CD, Xuan S, Yuan XB, Efstratiadis A, Ngai J (2008) Role of IGF signaling in olfactory sensory map formation and axon guidance. Neuron 57:847–857PubMedCentralPubMedGoogle Scholar
  229. 229.
    Broughton S, Partridge L (2009) Insulin/IGF-like signalling, the central nervous system and aging. Biochem J 418:1–12PubMedGoogle Scholar
  230. 230.
    Lee E, Son H (2009) Adult hippocampal neurogenesis and related neurotrophic factors. BMB Rep 42:239–244PubMedGoogle Scholar
  231. 231.
    Weber MM, Melmed S, Rosenbloom J, Yamasaki H, Prager D (1992) Rat somatotroph insulin-like growth factor-II (IGF-II) signaling: role of the IGF-I receptor. Endocrinology 131:2147–2153PubMedGoogle Scholar
  232. 232.
    Hixon ML, Paccagnella L, Millham R, Perez-Olle R, Gualberto A (2010) Development of inhibitors of the IGF-IR/PI3K/Akt/mTOR pathway. Rev Recent Clin Trials 5:189–208PubMedGoogle Scholar
  233. 233.
    Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56:140–145PubMedGoogle Scholar
  234. 234.
    Ma DK, Marchetto MC, Guo JU, Ming GL, Gage FH, Song H (2010) Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nat Neurosci 13:1338–1344PubMedCentralPubMedGoogle Scholar
  235. 235.
    Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. Neuromol Med 10:81–98Google Scholar
  236. 236.
    Kempermann G, Fabel K, Ehninger D, Babu H, Leal-Galicia P, Garthe A, Wolf SA (2010) Why and how physical activity promotes experience-induced brain plasticity. Front Neurosci 4:189PubMedCentralPubMedGoogle Scholar
  237. 237.
    Trejo JL, Carro E, Torres-Aleman I (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J Neurosci 21:1628–1634PubMedGoogle Scholar
  238. 238.
    Llorens-Martin M, Torres-Aleman I, Trejo JL (2010) Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour. Mol Cell Neurosci 44:109–117PubMedGoogle Scholar
  239. 239.
    Bruel-Jungerman E, Veyrac A, Dufour F, Horwood J, Laroche S, Davis S (2009) Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS One 4:e7901PubMedCentralPubMedGoogle Scholar
  240. 240.
    Duman CH, Schlesinger L, Terwilliger R, Russell DS, Newton SS, Duman RS (2009) Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise. Behav Brain Res 198:366–371PubMedCentralPubMedGoogle Scholar
  241. 241.
    Aimone JB, Deng W, Gage FH (2010) Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci 14:325–337PubMedCentralPubMedGoogle Scholar
  242. 242.
    Kitamura T, Saitoh Y, Takashima N, Murayama A, Niibori Y, Ageta H, Sekiguchi M, Sugiyama H, Inokuchi K (2009) Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139:814–827PubMedGoogle Scholar
  243. 243.
    Aberg ND, Brywe KG, Isgaard J (2006) Aspects of growth hormone and insulin-like growth factor-I related to neuroprotection, regeneration, and functional plasticity in the adult brain. Sci World J 6:53–80Google Scholar
  244. 244.
    Llorens-Martin M, Torres-Aleman I, Trejo JL (2009) Mechanisms mediating brain plasticity: IGF1 and adult hippocampal neurogenesis. Neuroscientist 15:134–148PubMedGoogle Scholar
  245. 245.
    Ziegler AN, Schneider JS, Qin M, Tyler WA, Pintar JE, Fraidenraich D, Wood TL, Levison SW (2012) Igf-II promotes stemness of neural restricted precursors. Stem Cells 30:1265–1276PubMedGoogle Scholar
  246. 246.
    Rotwein P, Burgess SK, Milbrandt JD, Krause JE (1988) Differential expression of insulin-like growth factor genes in rat central nervous system. Proc Natl Acad Sci USA 85:265–269PubMedGoogle Scholar
  247. 247.
    Valentino KL, Ocrant I, Rosenfeld RG (1990) Developmental expression of insulin-like growth factor-II receptor immunoreactivity in the rat central nervous system. Endocrinology 126:914–920PubMedGoogle Scholar
  248. 248.
    Vescovi AL, Reynolds BA, Fraser DD, Weiss S (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966PubMedGoogle Scholar
  249. 249.
    Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486–498PubMedCentralPubMedGoogle Scholar
  250. 250.
    Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T, Ramos-Mejia V, Rouleau A, Yang J, Bosse M, Lajoie G, Bhatia M (2007) IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature 448:1015–1021PubMedGoogle Scholar
  251. 251.
    Castilla-Cortazar I, Garcia-Fernandez M, Delgado G, Puche JE, Sierra I, Barhoum R, Gonzalez-Baron S (2011) Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats. J Transl Med 9:103PubMedCentralPubMedGoogle Scholar
  252. 252.
    Fernandez C, Tatard VM, Bertrand N, Dahmane N (2010) Differential modulation of sonic-hedgehog-induced cerebellar granule cell precursor proliferation by the IGF signaling network. Dev Neurosci 32:59–70PubMedGoogle Scholar
  253. 253.
    Corcoran RB, Raveh TB, Barakat MT, Lee EY, Scott MP (2008) Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 68:8788–8795PubMedCentralPubMedGoogle Scholar
  254. 254.
    Kita Y, Ago Y, Takano E, Fukada A, Takuma K, Matsuda T (2013) Galantamine increases hippocampal insulin-like growth factor 2 expression via alpha7 nicotinic acetylcholine receptors in mice. Psychopharmacology (Berl) 225:543–551Google Scholar
  255. 255.
    Baxter RC (1991) Insulin-like growth factor (IGF) binding proteins: the role of serum IGFBPs in regulating IGF availability. Acta Paediatr Scand Suppl 372:107–114; discussion 115PubMedGoogle Scholar
  256. 256.
    Oh Y, Nagalla SR, Yamanaka Y, Kim HS, Wilson E, Rosenfeld RG (1996) Synthesis and characterization of insulin-like growth factor-binding protein (IGFBP)-7. Recombinant human mac25 protein specifically binds IGF-I and -II. J Biol Chem 271:30322–30325PubMedGoogle Scholar
  257. 257.
    Yamanaka Y, Wilson EM, Rosenfeld RG, Oh Y (1997) Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. J Biol Chem 272:30729–30734PubMedGoogle Scholar
  258. 258.
    Suzuki H, Igarashi S, Nojima M, Maruyama R, Yamamoto E, Kai M, Akashi H, Watanabe Y, Yamamoto H, Sasaki Y, Itoh F, Imai K, Sugai T, Shen L, Issa JP, Shinomura Y, Tokino T, Toyota M (2010) IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis 31:342–349PubMedGoogle Scholar
  259. 259.
    Jiang B, Kumar SD, Loh WT, Manikandan J, Ling EA, Tay SS, Dheen ST (2008) Global gene expression analysis of cranial neural tubes in embryos of diabetic mice. J Neurosci Res 86:3481–3493PubMedGoogle Scholar
  260. 260.
    Tomimaru Y, Eguchi H, Wada H, Noda T, Murakami M, Kobayashi S, Marubashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M, Nagano H (2010) Insulin-like growth factor-binding protein 7 alters the sensitivity to interferon-based anticancer therapy in hepatocellular carcinoma cells. Br J Cancer 102:1483–1490PubMedCentralPubMedGoogle Scholar
  261. 261.
    Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132:363–374PubMedCentralPubMedGoogle Scholar
  262. 262.
    Csoregh L, Andersson E, Fried G (2009) Transcriptional analysis of estrogen effects in human embryonic neurons and glial cells. Neuroendocrinology 89:171–186PubMedGoogle Scholar
  263. 263.
    Tamura K, Hashimoto K, Suzuki K, Yoshie M, Kutsukake M, Sakurai T (2009) Insulin-like growth factor binding protein-7 (IGFBP7) blocks vascular endothelial cell growth factor (VEGF)-induced angiogenesis in human vascular endothelial cells. Eur J Pharmacol 610:61–67PubMedGoogle Scholar
  264. 264.
    Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ (2004) VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36:827–835PubMedGoogle Scholar
  265. 265.
    Heine VM, Zareno J, Maslam S, Joels M, Lucassen PJ (2005) Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 21:1304–1314PubMedGoogle Scholar
  266. 266.
    Ostrovsky O, Ahmed NT, Argon Y (2009) The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation. Mol Biol Cell 20:1855–1864PubMedCentralPubMedGoogle Scholar
  267. 267.
    Gennigens C, Menetrier-Caux C, Droz JP (2006) Insulin-like growth factor (IGF) family and prostate cancer. Crit Rev Oncol Hematol 58:124–145PubMedGoogle Scholar
  268. 268.
    Brown J, Jones EY, Forbes BE (2009) Keeping IGF-II under control: lessons from the IGF-II-IGF2R crystal structure. Trends Biochem Sci 34:612–619PubMedGoogle Scholar
  269. 269.
    Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928PubMedGoogle Scholar
  270. 270.
    Heidegger I, Pircher A, Klocker H, Massoner P (2011) Targeting the insulin-like growth factor network in cancer therapy. Cancer Biol Ther 11:701–707PubMedGoogle Scholar
  271. 271.
    Pietrzkowski Z, Wernicke D, Porcu P, Jameson BA, Baserga R (1992) Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1. Cancer Res 52:6447–6451PubMedGoogle Scholar
  272. 272.
    Fukunaga K, Kawano T (2003) Akt is a molecular target for signal transduction therapy in brain ischemic insult. J Pharmacol Sci 92:317–327PubMedGoogle Scholar
  273. 273.
    Brazil DP, Yang ZZ, Hemmings BA (2004) Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29:233–242PubMedGoogle Scholar
  274. 274.
    Clemmons DR (1997) Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8:45–62PubMedGoogle Scholar
  275. 275.
    Peltier J, O’Neill A, Schaffer DV (2007) PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol 67:1348–1361PubMedGoogle Scholar
  276. 276.
    Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77PubMedGoogle Scholar
  277. 277.
    Hartmann W, Koch A, Brune H, Waha A, Schuller U, Dani I, Denkhaus D, Langmann W, Bode U, Wiestler OD, Schilling K, Pietsch T (2005) Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. Am J Pathol 166:1153–1162PubMedGoogle Scholar
  278. 278.
    Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A, Zack JA, Kornblum HI, Liu X, Wu H (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294:2186–2189PubMedGoogle Scholar
  279. 279.
    Vincent AM, Feldman EL (2002) Control of cell survival by IGF signaling pathways. Growth Horm IGF Res 12:193–197PubMedGoogle Scholar
  280. 280.
    Mathieu C, Sii-Felice K, Fouchet P, Etienne O, Haton C, Mabondzo A, Boussin FD, Mouthon MA (2008) Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells. Mol Cell Neurosci 38:569–577PubMedGoogle Scholar
  281. 281.
    Segu L, Lecomte MJ, Wolff M, Santamaria J, Hen R, Dumuis A, Berrard S, Bockaert J, Buhot MC, Compan V (2010) Hyperfunction of muscarinic receptor maintains long-term memory in 5-HT4 receptor knock-out mice. PLoS One 5:e9529PubMedCentralPubMedGoogle Scholar
  282. 282.
    Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40:897–903PubMedCentralPubMedGoogle Scholar
  283. 283.
    Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400PubMedGoogle Scholar
  284. 284.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedGoogle Scholar
  285. 285.
    Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedGoogle Scholar
  286. 286.
    Fischer A, Sananbenesi F, Mungenast A, Tsai LH (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617PubMedGoogle Scholar
  287. 287.
    Houston I, Peter CJ, Mitchell A, Straubhaar J, Rogaev E, Akbarian S (2013) Epigenetics in the human brain. Neuropsychopharmacology 38:183–197PubMedGoogle Scholar
  288. 288.
    Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD (2004) Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 279:40545–40559PubMedGoogle Scholar
  289. 289.
    Fontan-Lozano A, Romero-Granados R, Troncoso J, Munera A, Delgado-Garcia JM, Carrion AM (2008) Histone deacetylase inhibitors improve learning consolidation in young and in KA-induced-neurodegeneration and SAMP-8-mutant mice. Mol Cell Neurosci 39:193–201PubMedGoogle Scholar
  290. 290.
    Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 328:753–756PubMedGoogle Scholar
  291. 291.
    Bousiges O, Vasconcelos AP, Neidl R, Cosquer B, Herbeaux K, Panteleeva I, Loeffler JP, Cassel JC, Boutillier AL (2010) Spatial memory consolidation is associated with induction of several lysine-acetyltransferase (histone acetyltransferase) expression levels and H2B/H4 acetylation-dependent transcriptional events in the rat hippocampus. Neuropsychopharmacology 35:2521–2537PubMedGoogle Scholar
  292. 292.
    Sananbenesi F, Fischer A (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem 390:1145–1153PubMedGoogle Scholar
  293. 293.
    Sananbenesi F, Fischer A, Schrick C, Spiess J, Radulovic J (2002) Phosphorylation of hippocampal Erk-1/2, Elk-1, and p90-Rsk-1 during contextual fear conditioning: interactions between Erk-1/2 and Elk-1. Mol Cell Neurosci 21:463–476PubMedGoogle Scholar
  294. 294.
    Kelleher RJ 3rd, Govindarajan A, Jung HY, Kang H, Tonegawa S (2004) Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116:467–479PubMedGoogle Scholar
  295. 295.
    Chwang WB, O’Riordan KJ, Levenson JM, Sweatt JD (2006) ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn Mem 13:322–328PubMedGoogle Scholar
  296. 296.
    Kimura A, Matsubara K, Horikoshi M (2005) A decade of histone acetylation: marking eukaryotic chromosomes with specific codes. J Biochem 138:647–662PubMedGoogle Scholar
  297. 297.
    Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A (2012) Loss of HDAC5 impairs memory function: implications for Alzheimer’s disease. J Alzheimers Dis 33:35–44Google Scholar
  298. 298.
    Bahari-Javan S, Maddalena A, Kerimoglu C, Wittnam J, Held T, Bahr M, Burkhardt S, Delalle I, Kugler S, Fischer A, Sananbenesi F (2012) HDAC1 regulates fear extinction in mice. J Neurosci 32:5062–5073PubMedGoogle Scholar
  299. 299.
    Govindarajan N, Rao P, Burkhardt S, Sananbenesi F, Schluter OM, Bradke F, Lu J, Fischer A (2013) Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer’s disease. EMBO Mol Med 5:52–63PubMedCentralPubMedGoogle Scholar
  300. 300.
    Lattal KM, Barrett RM, Wood MA (2007) Systemic or intrahippocampal delivery of histone deacetylase inhibitors facilitates fear extinction. Behav Neurosci 121:1125–1131PubMedGoogle Scholar
  301. 301.
    Stafford JM, Raybuck JD, Ryabinin AE, Lattal KM (2012) Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction. Biol Psychiatry 72:25–33PubMedCentralPubMedGoogle Scholar
  302. 302.
    Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M (2007) Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem 14:268–276PubMedGoogle Scholar
  303. 303.
    Bredy TW, Barad M (2008) The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear. Learn Mem 15:39–45PubMedGoogle Scholar
  304. 304.
    Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60PubMedCentralPubMedGoogle Scholar
  305. 305.
    Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH (2012) An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483:222–226PubMedCentralPubMedGoogle Scholar
  306. 306.
    McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, Mullican SE, Jones S, Rusche JR, Lazar MA, Wood MA (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31:764–774PubMedCentralPubMedGoogle Scholar
  307. 307.
    Benes FM, Lim B, Matzilevich D, Walsh JP, Subburaju S, Minns M (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci USA 104:10164–10169PubMedGoogle Scholar
  308. 308.
    Sharma RP, Grayson DR, Gavin DP (2008) Histone deactylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the national brain databank microarray collection. Schizophr Res 98:111–117PubMedCentralPubMedGoogle Scholar
  309. 309.
    Quinti L, Chopra V, Rotili D, Valente S, Amore A, Franci G, Meade S, Valenza M, Altucci L, Maxwell MM, Cattaneo E, Hersch S, Mai A, Kazantsev A (2010) Evaluation of histone deacetylases as drug targets in Huntington’s disease models. Study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model. PLoS Curr 2 pii: rrn1172Google Scholar
  310. 310.
    Wang Z, Yang D, Zhang X, Li T, Li J, Tang Y, Le W (2011) Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and hippocampal neurons. PLoS One 6:e19229PubMedCentralPubMedGoogle Scholar
  311. 311.
    Holliday R, Pugh JE (1975) DNA modification mechanisms and gene activity during development. Science 187:226–232PubMedGoogle Scholar
  312. 312.
    Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022PubMedGoogle Scholar
  313. 313.
    Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492PubMedGoogle Scholar
  314. 314.
    Wood TL, O’Donnell SL, Levison SW (1995) Cytokines regulate IGF binding proteins in the CNS. Prog Growth Factor Res 6:181–187PubMedGoogle Scholar
  315. 315.
    Holmin S, Mathiesen T, Langmoen IA, Sandberg Nordqvist AC (2001) Depolarization induces insulin-like growth factor binding protein-2 expression in vivo via NMDA receptor stimulation. Growth Horm IGF Res 11:399–406PubMedGoogle Scholar
  316. 316.
    Itoh M, Ide S, Takashima S, Kudo S, Nomura Y, Segawa M, Kubota T, Mori H, Tanaka S, Horie H, Tanabe Y, Goto Y (2007) Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains. J Neuropathol Exp Neurol 66:117–123PubMedGoogle Scholar
  317. 317.
    Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M (2009) Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA 106:2029–2034PubMedGoogle Scholar
  318. 318.
    Garcia-Segura LM, Rodriguez JR, Torres-Aleman I (1997) Localization of the insulin-like growth factor I receptor in the cerebellum and hypothalamus of adult rats: an electron microscopic study. J Neurocytol 26:479–490PubMedGoogle Scholar
  319. 319.
    Sehat B, Tofigh A, Lin Y, Trocme E, Liljedahl U, Lagergren J, Larsson O (2010) SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal 3:ra10PubMedGoogle Scholar
  320. 320.
    Kelley KM, Oh Y, Gargosky SE, Gucev Z, Matsumoto T, Hwa V, Ng L, Simpson DM, Rosenfeld RG (1996) Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics. Int J Biochem Cell Biol 28:619–637PubMedGoogle Scholar
  321. 321.
    Ruan W, Xu E, Xu F, Ma Y, Deng H, Huang Q, Lv B, Hu H, Lin J, Cui J, Di M, Dong J, Lai M (2007) IGFBP7 plays a potential tumor suppressor role in colorectal carcinogenesis. Cancer Biol Ther 6:354–359PubMedGoogle Scholar
  322. 322.
    Alic N, Hoddinott MP, Vinti G, Partridge L (2011) Lifespan extension by increased expression of the Drosophila homologue of the IGFBP7 tumour suppressor. Aging Cell 10:137–147PubMedCentralPubMedGoogle Scholar
  323. 323.
    Lin J, Lai M, Huang Q, Ma Y, Cui J, Ruan W (2007) Methylation patterns of IGFBP7 in colon cancer cell lines are associated with levels of gene expression. J Pathol 212:83–90PubMedGoogle Scholar
  324. 324.
    Lin J, Lai M, Huang Q, Ruan W, Ma Y, Cui J (2008) Reactivation of IGFBP7 by DNA demethylation inhibits human colon cancer cell growth in vitro. Cancer Biol Ther 7:1896–1900PubMedGoogle Scholar
  325. 325.
    Chen Y, Cui T, Knosel T, Yang L, Zoller K, Petersen I (2011) IGFBP7 is a p53 target gene inactivated in human lung cancer by DNA hypermethylation. Lung Cancer 73:38–44PubMedGoogle Scholar
  326. 326.
    Heesch S, Bartram I, Neumann M, Reins J, Mossner M, Schlee C, Stroux A, Haferlach T, Goekbuget N, Hoelzer D, Hofmann WK, Thiel E, Baldus CD (2011) Expression of IGFBP7 in acute leukemia is regulated by DNA methylation. Cancer Sci 102:253–259PubMedGoogle Scholar
  327. 327.
    Scurr LL, Pupo GM, Becker TM, Lai K, Schrama D, Haferkamp S, Irvine M, Scolyer RA, Mann GJ, Becker JC, Kefford RF, Rizos H (2010) IGFBP7 is not required for B-RAF-induced melanocyte senescence. Cell 141:717–727PubMedGoogle Scholar
  328. 328.
    Miller CA, Sweatt JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53:857–869PubMedGoogle Scholar
  329. 329.
    Miller CA, Gavin CF, White JA, Parrish RR, Honasoge A, Yancey CR, Rivera IM, Rubio MD, Rumbaugh G, Sweatt JD (2010) Cortical DNA methylation maintains remote memory. Nat Neurosci 13:664–666PubMedCentralPubMedGoogle Scholar
  330. 330.
    Zovkic IB, Sweatt JD (2013) Epigenetic mechanisms in learned fear: implications for PTSD. Neuropsychopharmacology 38:77–93PubMedGoogle Scholar
  331. 331.
    Leach PT, Poplawski SG, Kenney JW, Hoffman B, Liebermann DA, Abel T, Gould TJ (2012) Gadd45b knockout mice exhibit selective deficits in hippocampus-dependent long-term memory. Learn Mem 19:319–324PubMedGoogle Scholar
  332. 332.
    Ma DK, Jang M-H, Guo JU, Kitabatake Y, Chang M-l, Pow-anpongkul N, Flavell RA, Lu B, Ming G-l, Song H (2009) Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323:1074–1077PubMedCentralPubMedGoogle Scholar
  333. 333.
    Xu X, Coats JK, Yang CF, Wang A, Ahmed OM, Alvarado M, Izumi T, Shah NM (2012) Modular genetic control of sexually dimorphic behaviors. Cell 148:596–607PubMedCentralPubMedGoogle Scholar
  334. 334.
    Insel TR, Fernald RD (2004) How the brain processes social information: searching for the social brain. Annu Rev Neurosci 27:697–722PubMedGoogle Scholar
  335. 335.
    Kellendonk C, Simpson EH, Kandel ER (2009) Modeling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci 32:347–358PubMedGoogle Scholar
  336. 336.
    Esteller M (2011) Non-coding RNAs in human disease. Nat Rev Genet 12:861–874PubMedGoogle Scholar
  337. 337.
    Schratt G (2009) MicroRNAs at the synapse. Nat Rev Neurosci 10:842–849PubMedGoogle Scholar
  338. 338.
    Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in aging. J Cell Sci 125:7–17PubMedGoogle Scholar
  339. 339.
    O’Carroll D, Schaefer A (2013) General principals of miRNA biogenesis and regulation in the brain. Neuropsychopharmacology 38:39–54PubMedGoogle Scholar
  340. 340.
    Balzer E, Heine C, Jiang Q, Lee VM, Moss EG (2010) LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis in vitro. Development 137:891–900PubMedGoogle Scholar
  341. 341.
    Wilting SM, van Boerdonk RA, Henken FE, Meijer CJ, Diosdado B, Meijer GA, le Sage C, Agami R, Snijders PJ, Steenbergen RD (2010) Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer 9:167PubMedCentralPubMedGoogle Scholar
  342. 342.
    Ge Y, Sun Y, Chen J (2011) IGF-II is regulated by microRNA-125b in skeletal myogenesis. J Cell Biol 192:69–81PubMedGoogle Scholar
  343. 343.
    Griggs EM, Young EJ, Rumbaugh G, Miller CA (2013) MicroRNA-182 regulates amygdala-dependent memory formation. J Neurosci 33:1734–1740PubMedCentralPubMedGoogle Scholar
  344. 344.
    Konopka W, Kiryk A, Novak M, Herwerth M, Parkitna JR, Wawrzyniak M, Kowarsch A, Michaluk P, Dzwonek J, Arnsperger T, Wilczynski G, Merkenschlager M, Theis FJ, Kohr G, Kaczmarek L, Schutz G (2010) MicroRNA loss enhances learning and memory in mice. J Neurosci 30:14835–14842PubMedGoogle Scholar
  345. 345.
    Lin Q, Wei W, Coelho CM, Li X, Baker-Andresen D, Dudley K, Ratnu VS, Boskovic Z, Kobor MS, Sun YE, Bredy TW (2011) The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nat Neurosci 14:1115–1117PubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of Psychiatry and PsychotherapyUniversity Medical Center GöttingenGöttingenGermany
  2. 2.German Center for Neurodegenerative Diseases (DZNE) GöttingenGöttingenGermany

Personalised recommendations