Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders

Abstract

Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Excessive generalization in PTSD.
Figure 2: Local circuit properties of the dentate gyrus that facilitate pattern separation.
Figure 3: Testing pattern separation with contextual fear discrimination in rodents and humans.
Figure 4: Modulation of pattern separation by adult neurogenesis and its impact on mood.
Figure 5: Targets for stimulating neurogenesis to enhance pattern separation and restrain overgeneralization.

References

  1. 1

    Kessler, R.C. et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 593–602 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    DuPont, R.L. et al. Economic costs of anxiety disorders. Anxiety 2, 167–172 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kessler, R.C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C.B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995).

    Article  CAS  Google Scholar 

  4. 4

    Milad, M.R. & Quirk, G.J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Jovanovic, T. & Ressler, K.J. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am. J. Psychiatry 167, 648–662 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Lissek, S. et al. Elevated fear conditioning to socially relevant unconditioned stimuli in social anxiety disorder. Am. J. Psychiatry 165, 124–132 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Mineka, S. & Zinbarg, R. A contemporary learning theory perspective on the etiology of anxiety disorders: it's not what you thought it was. Am. Psychol. 61, 10–26 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Bouton, M.E., Mineka, S. & Barlow, D.H. A modern learning theory perspective on the etiology of panic disorder. Psychol. Rev. 108, 4–32 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Lissek, S. et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am. J. Psychiatry 167, 47–55 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Wolpe, J. & Rowan, V.C. Panic disorder: a product of classical conditioning. Behav. Res. Ther. 26, 441–450 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Marr, D. Simple memory: a theory for archicortex. Phil. Trans. R. Soc. Lond. B 262, 23–81 (1971).

    Article  CAS  Google Scholar 

  12. 12

    Treves, A., Tashiro, A., Witter, M.E. & Moser, E.I. What is the mammalian dentate gyrus good for? Neuroscience 154, 1155–1172 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Leutgeb, J.K., Leutgeb, S., Moser, M.B. & Moser, E.I. Pattern separation in the dentate gyrus and CA3 of the hippocampus. Science 315, 961–966 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Fenton, A.A. Neuroscience. Where am I? Science 315, 947–949 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Bakker, A., Kirwan, C.B., Miller, M. & Stark, C.E. Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319, 1640–1642 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Gilbert, P.E., Kesner, R.P. & Lee, I. Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1. Hippocampus 11, 626–636 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Peri, T., Ben-Shakhar, G., Orr, S.P. & Shalev, A.Y. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47, 512–519 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Cohen, L.J. et al. Specificity of neuropsychological impairment in obsessive-compulsive disorder: a comparison with social phobic and normal control subjects. J. Neuropsychiatry Clin. Neurosci. 8, 82–85 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Šodić, L., Anticevic, V., Britvic, D. & Ivkosic, N. Short-term memory in Croatian war veterans with posttraumatic stress disorder. Croat. Med. J. 48, 140–145 (2007).

    PubMed  PubMed Central  Google Scholar 

  20. 20

    Gilbertson, M.W. et al. Configural cue performance in identical twins discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal function. Biol. Psychiatry 62, 513–520 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P. & Bremner, J.D. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J. Affect. Disord. 88, 79–86 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Karl, A., Malta, L.S. & Maercker, A. Meta-analytic review of event-related potential studies in post-traumatic stress disorder. Biol. Psychol. 71, 123–147 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Irle, E. et al. Reduced amygdalar and hippocampal size in adults with generalized social phobia. J. Psychiatry Neurosci. 35, 126–131 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Gilbertson, M.W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 5, 1242–1247 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Gilbertson, M.W. et al. Is trauma a causal agent of psychopathologic symptoms in posttraumatic stress disorder? Findings from identical twins discordant for combat exposure. J. Clin. Psychiatry 71, 1324–1330 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Dannlowski, U. et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol. Psychiatry 71, 286–293 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Hayes, J.P. et al. Reduced hippocampal and amygdala activity predicts memory distortions for trauma reminders in combat-related PTSD. J. Psychiatr. Res. 45, 660–669 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Brohawn, K.H., Offringa, R., Pfaff, D.L., Hughes, K.C. & Shin, L.M. The neural correlates of emotional memory in posttraumatic stress disorder. Biol. Psychiatry 68, 1023–1030 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Wang, Z. et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry 67, 296–303 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    O'Reilly, R.C. & McClelland, J.L. Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus 4, 661–682 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Lisman, J. Formation of the non-functional and functional pools of granule cells in the dentate gyrus: role of neurogenesis, LTP and LTD. J. Physiol. (Lond.) 589, 1905–1909 (2011).

    Article  CAS  Google Scholar 

  33. 33

    Buhl, E.H., Halasy, K. & Somogyi, P. Diverse sources of hippocampal unitary inhibitory postsynaptic potentials and the number of synaptic release sites. Nature 368, 823–828 (1994).

    Article  CAS  Google Scholar 

  34. 34

    Patton, P.E. & McNaughton, B. Connection matrix of the hippocampal formation: I. The dentate gyrus. Hippocampus 5, 245–286 (1995).

    Article  CAS  Google Scholar 

  35. 35

    Henze, D.A., Wittner, L. & Buzsáki, G. Single granule cells reliably discharge targets in the hippocampal CA3 network in vivo. Nat. Neurosci. 5, 790–795 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    McNaughton, B.L. & Morris, R.G.M. Hippocampal synaptic enhancement and information-storage within a distributed memory system. Trends Neurosci. 10, 408–415 (1987).

    Article  Google Scholar 

  37. 37

    Kim, J. & Lee, I. Hippocampus is necessary for spatial discrimination using distal cue-configuration. Hippocampus 21, 609–621 (2011).

    Article  Google Scholar 

  38. 38

    Hunsaker, M.R., Rosenberg, J.S. & Kesner, R.P. The role of the dentate gyrus, CA3a,b, and CA3c for detecting spatial and environmental novelty. Hippocampus 18, 1064–1073 (2008).

    Article  Google Scholar 

  39. 39

    Milad, M.R., Rauch, S.L., Pitman, R.K. & Quirk, G.J. Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol. Psychol. 73, 61–71 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    McHugh, T.J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94–99 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Sahay, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Kheirbek, M.A., Tannenholz, L. & Hen, R. NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J. Neurosci. 32, 8696–8702 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Ressler, K.J. et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatry 61, 1136–1144 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Davis, M., Ressler, K., Rothbaum, B.O. & Richardson, R. Effects of D-cycloserine on extinction: translation from preclinical to clinical work. Biol. Psychiatry 60, 369–375 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Alvarez, R.P., Biggs, A., Chen, G., Pine, D.S. & Grillon, C. Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J. Neurosci. 28, 6211–6219 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Huff, N.C. et al. Revealing context-specific conditioned fear memories with full immersion virtual reality. Front. Behav. Neurosci. 5, 75 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Lacy, J.W., Yassa, M.A., Stark, S.M., Muftuler, L.T. & Stark, C.E. Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity. Learn. Mem. 18, 15–18 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Suthana, N., Ekstrom, A., Moshirvaziri, S., Knowlton, B. & Bookheimer, S. Dissociations within human hippocampal subregions during encoding and retrieval of spatial information. Hippocampus 21, 694–701 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Toni, N. et al. Synapse formation on neurons born in the adult hippocampus. Nat. Neurosci. 10, 727–734 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Toni, N. et al. Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429, 184–187 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Ge, S., Yang, C.H., Hsu, K.S., Ming, G.L. & Song, H. A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54, 559–566 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Imayoshi, I. et al. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 11, 1153–1161 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  56. 56

    David, D.J. et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Dranovsky, A. et al. Experience dictates stem cell fate in the adult hippocampus. Neuron 70, 908–923 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Surget, A. et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry 16, 1177–1188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Snyder, J.S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H.A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458–461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K. & Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry 15, 1152–1163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Sahay, A. & Hen, R. Adult hippocampal neurogenesis in depression. Nat. Neurosci. 10, 1110–1115 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    DeCarolis, N.A. & Eisch, A.J. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58, 884–893 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Pittenger, C. & Duman, R.S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88–109 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Boldrini, M. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376–2389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Reif, A. et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 11, 514–522 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Bergmann, O. et al. The age of olfactory bulb neurons in humans. Neuron 74, 634–639 (2012).

    Article  CAS  Google Scholar 

  67. 67

    Sanai, N. et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Aimone, J.B., Deng, W. & Gage, F.H. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Sahay, A., Wilson, D.A. & Hen, R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Clelland, C.D. et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Guo, W. et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat. Med. 17, 559–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Creer, D.J., Romberg, C., Saksida, L.M., van Praag, H. & Bussey, T.J. Running enhances spatial pattern separation in mice. Proc. Natl. Acad. Sci. USA 107, 2367–2372 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Tronel, S. et al. Adult-born neurons are necessary for extended contextual discrimination. Hippocampus 22, 292–298 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Nakashiba, T. et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149, 188–201 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Rolls, E.T. & Kesner, R.P. A computational theory of hippocampal function, and empirical tests of the theory. Prog. Neurobiol. 79, 1–48 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Rolls, E.T. An attractor network in the hippocampus: theory and neurophysiology. Learn. Mem. 14, 714–731 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Freund, T.F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

    Article  CAS  Google Scholar 

  79. 79

    Lacefield, C.O., Itskov, V., Reardon, T., Hen, R. & Gordon, J.A. Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus 22, 106–116 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Singer, B.H. et al. Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proc. Natl. Acad. Sci. USA 108, 5437–5442 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Burghardt, N.S., Park, E.H., Hen, R. & Fenton, A.A. Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus 22, 1795–1808 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Jung, M.W., Wiener, S.I. & McNaughton, B.L. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J. Neurosci. 14, 7347–7356 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Maren, S. & Holt, W.G. Hippocampus and Pavlovian fear conditioning in rats: muscimol infusions into the ventral, but not dorsal, hippocampus impair the acquisition of conditional freezing to an auditory conditional stimulus. Behav. Neurosci. 118, 97–110 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Hunsaker, M.R. & Kesner, R.P. Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear. Neurobiol. Learn. Mem. 89, 61–69 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Czerniawski, J., Ree, F., Chia, C. & Otto, T. Dorsal versus ventral hippocampal contributions to trace and contextual conditioning: differential effects of regionally selective NMDA receptor antagonism on acquisition and expression. Hippocampus 22, 1528–1539 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Wang, S.H., Finnie, P.S., Hardt, O. & Nader, K. Dorsal hippocampus is necessary for novel learning but sufficient for subsequent similar learning. Hippocampus (2012).

  87. 87

    Maren, S. & Fanselow, M.S. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J. Neurosci. 15, 7548–7564 (1995).

    Article  CAS  Google Scholar 

  88. 88

    Adhikari, A., Topiwala, M.A. & Gordon, J.A. Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety. Neuron 65, 257–269 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Bienvenu, T.C., Busti, D., Magill, P.J., Ferraguti, F. & Capogna, M. Cell-type-specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo. Neuron 74, 1059–1074 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Fanselow, M.S. & Dong, H.W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Luo, A.H., Tahsili-Fahadan, P., Wise, R.A., Lupica, C.R. & Aston-Jones, G. Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science 333, 353–357 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Amaral, D.G. & Witter, M.P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Claiborne, B.J., Amaral, D.G. & Cowan, W.M. A light and electron microscopic analysis of the mossy fibers of the rat dentate gyrus. J. Comp. Neurol. 246, 435–458 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Lau, J.Y. et al. BDNF gene polymorphism (Val66Met) predicts amygdala and anterior hippocampus responses to emotional faces in anxious and depressed adolescents. Neuroimage 53, 952–961 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Dolcos, F., LaBar, K.S. & Cabeza, R. Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events. Neuron 42, 855–863 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Banasr, M., Soumier, A., Hery, M., Mocaer, E. & Daszuta, A. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol. Psychiatry 59, 1087–1096 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Stark, S.M., Yassa, M.A. & Stark, C.E. Individual differences in spatial pattern separation performance associated with healthy aging in humans. Learn. Mem. 17, 284–288 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Sierra, A., Encinas, J.M. & Maletic-Savatic, M. Adult human neurogenesis: from microscopy to magnetic resonance imaging. Front. Neurosci. 5, 47 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank L. Drew for comments on the manuscript. The authors are supported by US National Institute of Mental Health grants 1F32MH092101-01A1 and 1K01MH099371-01; a Sackler Institute Award and a NARSAD Young Investigator Award (M.A.K.); US National Institute of Mental Health grant 4R00MH086615-03, the Ellison Medical Foundation New Scholar in Aging and the Whitehall Foundation (A.S.); and NARSAD, the New York Stem Cell Initiative, US National Institutes of Health grant R01 MH068542, and Hope for Depression Research Foundation grants (R.H.).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Amar Sahay or René Hen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kheirbek, M., Klemenhagen, K., Sahay, A. et al. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci 15, 1613–1620 (2012). https://doi.org/10.1038/nn.3262

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing