Review Article | Published:

Integrating new findings and examining clinical applications of pattern separation

Nature Neurosciencevolume 21pages163173 (2018) | Download Citation

Abstract

Pattern separation, the ability to independently represent and store similar experiences, is a crucial facet of episodic memory. Growing evidence suggests that the hippocampus possesses unique circuitry that is computationally capable of resolving mnemonic interference by using pattern separation. In this Review, we discuss recent advances in the understanding of this process and evaluate the caveats and limitations of linking across animal and human studies. We summarize clinical and translational studies using methods that are sensitive to pattern separation impairments, an approach that stems from the fact that the hippocampus is a major site of disruption in many brain disorders. We critically evaluate the assumptions that guide fundamental and translational studies in this area. Finally, we suggest guidelines for future research and offer ways to overcome potential interpretational challenges to increase the utility of pattern separation as a construct that can further understanding of both memory processes and brain disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 (1998).

  2. 2.

    Squire, L. R., Stark, C. E. L. & Clark, R. E. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279–306 (2004).

  3. 3.

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

  4. 4.

    Treves, A. & Rolls, E. T. Computational analysis of the role of the hippocampus in memory. Hippocampus 4, 374–391 (1994).

  5. 5.

    McClelland, J. L., McNaughton, B. L. & O’Reilly, R. C. 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, 419–457 (1995).

  6. 6.

    Yassa, M. A. & Stark, C. E. Pattern separation in the hippocampus. Trends Neurosci. 34, 515–525 (2011).

  7. 7.

    Lavenex, P. & Amaral, D. G. Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 10, 420–430 (2000).

  8. 8.

    Anderson, P., Morris, R., Amaral, D., Bliss, T. & O’Keefe, J. The Hippocampus Book (Oxford University Press, Oxford, UK, 2007).

  9. 9.

    Deng, W., Mayford, M. & Gage, F. H. Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice. eLife 2, e00312 (2013).

  10. 10.

    Chavlis, S., Petrantonakis, P. C. & Poirazi, P. Dendrites of dentate gyrus granule cells contribute to pattern separation by controlling sparsity. Hippocampus 27, 89–110 (2017).

  11. 11.

    Scharfman, H. E. The enigmatic mossy cell of the dentate gyrus. Nat. Rev. Neurosci. 17, 562–575 (2016).

  12. 12.

    GoodSmith, D. et al. Spatial representations of granule cells and mossy cells of the dentate gyrus. Neuron 93, 677–690.e5 (2017).

  13. 13.

    Danielson, N. B. et al. Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron 90, 101–112 (2016).

  14. 14.

    McAvoy, K. M. et al. Modulating neuronal competition dynamics in the dentate gyrus to rejuvenate aging memory circuits. Neuron 91, 1356–1373 (2016).

  15. 15.

    Adlaf, E. W. et al. Adult-born neurons modify excitatory synaptic transmission to existing neurons. eLife 6, e19886 (2017).

  16. 16.

    Leutgeb, S., Leutgeb, J. K., Treves, A., Moser, M.-B. & Moser, E. I. Distinct ensemble codes in hippocampal areas CA3 and CA1. Science 305, 1295–1298 (2004).

  17. 17.

    Lee, I., Yoganarasimha, D., Rao, G. & Knierim, J. J. Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3. Nature 430, 456–459 (2004).

  18. 18.

    Vazdarjanova, A. & Guzowski, J. F. Differences in hippocampal neuronal population responses to modifications of an environmental context: evidence for distinct, yet complementary, functions of CA3 and CA1 ensembles. J. Neurosci. 24, 6489–6496 (2004).

  19. 19.

    Guzowski, J. F., Knierim, J. J. & Moser, E. I. Ensemble dynamics of hippocampal regions CA3 and CA1. Neuron 44, 581–584 (2004).

  20. 20.

    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).

  21. 21.

    Stokes, J., Kyle, C. & Ekstrom, A. D. Complementary roles of human hippocampal subfields in differentiation and integration of spatial context. J. Cogn. Neurosci 27, 546–559 (2015).

  22. 22.

    Leutgeb, J. K. et al. Progressive transformation of hippocampal neuronal representations in “morphed” environments. Neuron 48, 345–358 (2005).

  23. 23.

    Duncan, K., Ketz, N., Inati, S. J. & Davachi, L. Evidence for area CA1 as a match/mismatch detector: a high-resolution fMRI study of the human hippocampus. Hippocampus 22, 389–398 (2012).

  24. 24.

    Hasselmo, M. E. & Schnell, E. Laminar selectivity of the cholinergic suppression of synaptic transmission in rat hippocampal region CA1: computational modeling and brain slice physiology. J. Neurosci. 14, 3898–3914 (1994).

  25. 25.

    Kumaran, D. & Maguire, E. A. An unexpected sequence of events: mismatch detection in the human hippocampus. PLoS Biol. 4, e424 (2006).

  26. 26.

    Kumaran, D. & Maguire, E. A. Match mismatch processes underlie human hippocampal responses to associative novelty. J. Neurosci. 27, 8517–8524 (2007).

  27. 27.

    Kumaran, D. & Maguire, E. A. Which computational mechanisms operate in the hippocampus during novelty detection? Hippocampus 17, 735–748 (2007).

  28. 28.

    Lisman, J. E. & Grace, A. A. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 46, 703–713 (2005).

  29. 29.

    Meeter, M., Murre, J. M. J. & Talamini, L. M. Mode shifting between storage and recall based on novelty detection in oscillating hippocampal circuits. Hippocampus 14, 722–741 (2004).

  30. 30.

    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).

  31. 31.

    Neunuebel, J. P. & Knierim, J. J. CA3 retrieves coherent representations from degraded input: direct evidence for CA3 pattern completion and dentate gyrus pattern separation. Neuron 81, 416–427 (2014).

  32. 32.

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

  33. 33.

    Kirwan, C. B. & Stark, C. E. L. Overcoming interference: an fMRI investigation of pattern separation in the medial temporal lobe. Learn. Mem. 14, 625–633 (2007).

  34. 34.

    Stark, S. M., Yassa, Ma, Lacy, J. W. & Stark, C. E. L. A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment. Neuropsychologia 51, 2442–2449 (2013).

  35. 35.

    Yassa, M. A. et al. Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults. Hippocampus 21, 968–979 (2011).

  36. 36.

    Yassa, M. A. et al. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment. Neuroimage 51, 1242–1252 (2010).

  37. 37.

    Toner, C. K., Pirogovsky, E., Kirwan, C. B. & Gilbert, P. E. Visual object pattern separation deficits in nondemented older adults. Learn. Mem. 16, 338–342 (2009).

  38. 38.

    Holden, H. M., Toner, C., Pirogovsky, E., Kirwan, C. B. & Gilbert, P. E. Visual object pattern separation varies in older adults. Learn. Mem. 20, 358–362 (2013).

  39. 39.

    Reagh, Z. M. & Yassa, M. A. Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans. Proc. Natl. Acad. Sci. USA 111, E4264–E4273 (2014).

  40. 40.

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

  41. 41.

    Holden, H. M., Hoebel, C., Loftis, K. & Gilbert, P. E. Spatial pattern separation in cognitively normal young and older adults. Hippocampus 22, 1826–1832 (2012).

  42. 42.

    Holden, H. M. & Gilbert, P. E. Less efficient pattern separation may contribute to age-related spatial memory deficits. Front. Aging Neurosci. 4, 9 (2012).

  43. 43.

    Reagh, Z. M. et al. Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. Hippocampus 24, 303–314 (2014).

  44. 44.

    Gilbert, P. E., Kesner, R. P. & DeCoteau, W. E. Memory for spatial location: role of the hippocampus in mediating spatial pattern separation. J. Neurosci. 18, 804–810 (1998).

  45. 45.

    Oomen, C. A. et al. The touchscreen operant platform for testing working memory and pattern separation in rats and mice. Nat. Protoc. 8, 2006–2021 (2013).

  46. 46.

    McTighe, S. M., Mar, A. C., Romberg, C., Bussey, T. J. & Saksida, L. M. A new touchscreen test of pattern separation: effect of hippocampal lesions. Neuroreport 20, 881–885 (2009).

  47. 47.

    Tolentino, J. C., Pirogovsky, E., Luu, T., Toner, C. K. & Gilbert, P. E. The effect of interference on temporal order memory for random and fixed sequences in nondemented older adults. Learn. Mem. 19, 251–255 (2012).

  48. 48.

    Roberts, J. M., Ly, M., Murray, E. & Yassa, M. A. Temporal discrimination deficits as a function of lag interference in older adults. Hippocampus 24, 1189–1196 (2014).

  49. 49.

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

  50. 50.

    Gilbert, P. E. & Kesner, R. P. The amygdala but not the hippocampus is involved in pattern separation based on reward value. Neurobiol. Learn. Mem. 77, 338–353 (2002).

  51. 51.

    Leal, S. L., Tighe, S. K., Jones, C. K. & Yassa, M. A. Pattern separation of emotional information in hippocampal dentate and CA3. Hippocampus 24, 1146–1155 (2014).

  52. 52.

    Leal, S. L., Tighe, S. K. & Yassa, M. A. Asymmetric effects of emotion on mnemonic interference. Neurobiol. Learn. Mem. 111, 41–48 (2014).

  53. 53.

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

  54. 54.

    Grill-Spector, K., Henson, R. & Martin, A. Repetition and the brain: neural models of stimulus-specific effects. Trends Cogn. Sci. 10, 14–23 (2006).

  55. 55.

    Kumaran, D. & Maguire, E. A. Novelty signals: a window into hippocampal information processing. Trends Cogn. Sci. 13, 47–54 (2009).

  56. 56.

    Kyle, C. T., Stokes, J. D., Lieberman, J. S., Hassan, A. S. & Ekstrom, A. D. Successful retrieval of competing spatial environments in humans involves hippocampal pattern separation mechanisms. eLife 4, 415–445 (2015).

  57. 57.

    Berron, D. et al. Strong evidence for pattern separation in human dentate gyrus. J. Neurosci. 36, 7569–7579 (2016).

  58. 58.

    Baker, S. et al. The human dentate gyrus plays a necessary role in discriminating new memories. Curr. Biol. 26, 2629–2634 (2016).

  59. 59.

    Eichenbaum, H., Sauvage, M., Fortin, N., Komorowski, R. & Lipton, P. Towards a functional organization of episodic memory in the medial temporal lobe. Neurosci. Biobehav. Rev. 36, 1597–1608 (2012).

  60. 60.

    Knierim, J. J. & Neunuebel, J. P. Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics. Neurobiol. Learn. Mem. 129, 38–49 (2016).

  61. 61.

    Knierim, J. J., Neunuebel, J. P. & Deshmukh, S. S. Functional correlates of the lateral and medial entorhinal cortex: objects, path integration and local-global reference frames. Phil. Trans. R. Soc. Lond. B 369, 20130369 (2013).

  62. 62.

    Kent, B. A., Hvoslef-Eide, M., Saksida, L. M. & Bussey, T. J. The representational-hierarchical view of pattern separation: Not just hippocampus, not just space, not just memory? Neurobiol. Learn. Mem. 129, 99–106 (2016).

  63. 63.

    Pidgeon, L. M. & Morcom, A. M. Cortical pattern separation and item-specific memory encoding. Neuropsychologia 85, 256–271 (2016).

  64. 64.

    Reagh, Z. M., Murray, E. A. & Yassa, M. A. Repetition reveals ups and downs of hippocampal, thalamic, and neocortical engagement during mnemonic decisions. Hippocampus 27, 169–183 (2016).

  65. 65.

    Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 150–157 (2001).

  66. 66.

    Ekstrom, A. How and when the fMRI BOLD signal relates to underlying neural activity: the danger in dissociation. Brain Res. Rev. 62, 233–244 (2010).

  67. 67.

    Gong, L., Li, B., Wu, R., Li, A. & Xu, F. Brain-state dependent uncoupling of BOLD and local field potentials in laminar olfactory bulb. Neurosci. Lett. 580, 1–6 (2014).

  68. 68.

    Tyler, C. W., Likova, L. T. & Nicholas, S. C. Analysis of neural-BOLD coupling through four models of the neural metabolic demand. Front. Neurosci. 9, 419 (2015).

  69. 69.

    Craik, F. I. M. & Simon, E. Age differences in memory: the roles of attention and depth of processing. in New Directions in Memory an d Aging (eds. Poon, L. W., Fozard, J., Cermak, L. S., Arenberg, D. & Thompson, L. W.) 95–112 (Psychology Press, New York, 1980).

  70. 70.

    Glisky, E. Changes in cognitive function in human aging. in Brain Aging: Models , Methods, and Mechani sms (ed. Riddle, D.) 1–10 (CRC Press, Boca Raton, FL, USA, 2007).

  71. 71.

    Leal, S. L. & Yassa, M. A. Neurocognitive aging and the hippocampus across species. Trends Neurosci. 38, 800–812 (2015).

  72. 72.

    Wilson, I. A., Gallagher, M., Eichenbaum, H. & Tanila, H. Neurocognitive aging: prior memories hinder new hippocampal encoding. Trends Neurosci. 29, 662–670 (2006).

  73. 73.

    Gallagher, M. et al. Individual differences in neurocognitive aging of the medial temporal lobe. Age 28, 221–233 (2006).

  74. 74.

    Bakker, A. et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74, 467–474 (2012).

  75. 75.

    Wilson, I. A., Ikonen, S., Gallagher, M., Eichenbaum, H. & Tanila, H. Age-associated alterations of hippocampal place cells are subregion specific. J. Neurosci. 25, 6877–6886 (2005).

  76. 76.

    Maurer, A. P. et al. Age-related changes in lateral entorhinal and CA3 neuron allocation predict poor performance on object discrimination. Front. Syst. Neurosci. 11, 49 (2017).

  77. 77.

    Wilson, I. A. et al. Cognitive aging and the hippocampus: how old rats represent new environments. J. Neurosci. 24, 3870–3878 (2004).

  78. 78.

    Kalus, P. et al. Examining the gateway to the limbic system with diffusion tensor imaging: the perforant pathway in dementia. Neuroimage 30, 713–720 (2006).

  79. 79.

    Yassa, M. A., Muftuler, L. T. & Stark, C. E. Ultrahigh-resolution microstructural diffusion tensor imaging reveals perforant path degradation in aged humans in vivo. Proc. Natl. Acad. Sci. USA 107, 12687–12691 (2010).

  80. 80.

    Barnes, C. A., Rao, G. & Houston, F. P. LTP induction threshold change in old rats at the perforant path–granule cell synapse. Neurobiol. Aging 21, 613–620 (2000).

  81. 81.

    Smith, T. D., Adams, M. M., Gallagher, M., Morrison, J. H. & Rapp, P. R. Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats. J. Neurosci. 20, 6587–6593 (2000).

  82. 82.

    Spiegel, A. M., Koh, M. T., Vogt, N. M., Rapp, P. R. & Gallagher, M. Hilar interneuron vulnerability distinguishes aged rats with memory impairment. J. Comp. Neurol. 521, 3508–3523 (2013).

  83. 83.

    Dickerson, B. C. et al. Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65, 404–411 (2005).

  84. 84.

    Small, S. A., Perera, G. M., DeLaPaz, R., Mayeux, R. & Stern, Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Ann. Neurol. 45, 466–472 (1999).

  85. 85.

    West, M. J., Kawas, C. H., Stewart, W. F., Rudow, G. L. & Troncoso, J. C. Hippocampal neurons in pre-clinical Alzheimer’s disease. Neurobiol. Aging 25, 1205–1212 (2004).

  86. 86.

    Rapp, P. R. & Gallagher, M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc. Natl. Acad. Sci. USA 93, 9926–9930 (1996).

  87. 87.

    Van Petten, C. Relationship between hippocampal volume and memory ability in healthy individuals across the lifespan: review and meta-analysis. Neuropsychologia 42, 1394–1413 (2004).

  88. 88.

    Leal, S. L. & Yassa, M. A. Effects of aging on mnemonic discrimination of emotional information. Behav. Neurosci. 128, 539–547 (2014).

  89. 89.

    Leal, S. L., Noche, J. A., Murray, E. A. & Yassa, M. A. Age-related individual variability in memory performance is associated with amygdala-hippocampal circuit function and emotional pattern separation. Neurobiol. Aging 49, 9–19 (2017).

  90. 90.

    Aggleton, J. P. et al. Sparing of the familiarity component of recognition memory in a patient with hippocampal pathology. Neuropsychologia 43, 1810–1823 (2005).

  91. 91.

    Reagh, Z. M. et al. Greater loss of object than spatial mnemonic discrimination in aged adults. Hippocampus 26, 417–422 (2016).

  92. 92.

    Stranahan, A. M., Haberman, R. P. & Gallagher, M. Cognitive decline is associated with reduced reelin expression in the entorhinal cortex of aged rats. Cereb. Cortex 21, 392–400 (2011).

  93. 93.

    Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997).

  94. 94.

    Khan, U. A. et al. Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer’s disease. Nat. Neurosci. 17, 304–311 (2014).

  95. 95.

    Wesnes, K. A., Annas, P., Basun, H., Edgar, C. & Blennow, K. Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E 4 status and cerebrospinal fluid amyloid-β42 levels. Alzheimers Res. Ther. 6, 20 (2014).

  96. 96.

    Marks, S. M., Lockhart, S. N., Baker, S. L. & Jagust, W. J. Tau and β-amyloid are associated with medial temporal lobe structure, function and memory encoding in normal aging. J. Neurosci. 37, 3192–3201 (2017).

  97. 97.

    Vieweg, P., Stangl, M., Howard, L. R. & Wolbers, T. Changes in pattern completion: a key mechanism to explain age-related recognition memory deficits? Cortex 64, 343–351 (2015).

  98. 98.

    Stark, S. M., Stevenson, R., Wu, C., Rutledge, S. & Stark, C. E. L. Stability of age-related deficits in the mnemonic similarity task across task variations. Behav. Neurosci. 129, 257–268 (2015).

  99. 99.

    Becker, S. & Wojtowicz, J. M. A model of hippocampal neurogenesis in memory and mood disorders. Trends Cogn. Sci. 11, 70–76 (2007).

  100. 100.

    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).

  101. 101.

    Kheirbek, M. A., Klemenhagen, K. C., Sahay, A. & Hen, R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat. Neurosci. 15, 1613–1620 (2012).

  102. 102.

    Besnard, A. & Sahay, A. Adult hippocampal neurogenesis, fear generalization and stress. Neuropsychopharmacology 41, 24–44 (2016).

  103. 103.

    Airaksinen, E., Wahlin, A., Forsell, Y. & Larsson, M. Low episodic memory performance as a premorbid marker of depression: evidence from a 3-year follow-up. Acta Psychiatr. Scand. 115, 458–465 (2007).

  104. 104.

    Dere, E., Pause, B. M. & Pietrowsky, R. Emotion and episodic memory in neuropsychiatric disorders. Behav. Brain Res. 215, 162–171 (2010).

  105. 105.

    Stockmeier, C. A. et al. Cellular changes in the postmortem hippocampus in major depression. Biol. Psychiatry 56, 640–650 (2004).

  106. 106.

    Hasler, G., Drevets, W. C., Manji, H. K. & Charney, D. S. Discovering endophenotypes for major depression. Neuropsychopharmacology 29, 1765–1781 (2004).

  107. 107.

    Watanabe, Y., Gould, E. & McEwen, B. S. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 588, 341–345 (1992).

  108. 108.

    Conrad, C. D. What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behav. Cogn. Neurosci. Rev 5, 41–60 (2006).

  109. 109.

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

  110. 110.

    Shelton, D. J. & Kirwan, C. B. A possible negative influence of depression on the ability to overcome memory interference. Behav. Brain Res. 256, 20–26 (2013).

  111. 111.

    Déry, N. et al. Adult hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and depression. Front. Neurosci. 7, 66 (2013).

  112. 112.

    Semenova, A. Higher Depression Scores are Associated with Lower Pattern Separation Performance in Humans. BS thesis, Lund University, Lund, Sweden (2015). .

  113. 113.

    Fujii, T., Saito, D. N., Yanaka, H. T., Kosaka, H. & Okazawa, H. Depressive mood modulates the anterior lateral CA1 and DG/CA3 during a pattern separation task in cognitively intact individuals: a functional MRI study. Hippocampus 24, 214–224 (2014).

  114. 114.

    Leal, S. L., Noche, J. A., Murray, E. A. & Yassa, M. A. Disruption of amygdala-entorhinal-hippocampal network in late-life depression. Hippocampus 27, 464–476 (2017).

  115. 115.

    Balderston, N. L. et al. Effect of anxiety on behavioural pattern separation in humans. Cogn. Emot. 31, 238–248 (2017).

  116. 116.

    McKenna, P., Ornstein, T. & Baddeley, A. D. Schizophrenia. in The Handbook of Memory Disorders (eds. Baddeley, A. D., Kopelman, M. D. & Wilson, B. A.) 413–435 (John Wiley & Sons, Chichester, UK, 2003).

  117. 117.

    Tamminga, C. A., Stan, A. D. & Wagner, A. D. The hippocampal formation in schizophrenia. Am. J. Psychiatry 167, 1178–1193 (2010).

  118. 118.

    Gao, X.-M. et al. Ionotropic glutamate receptors and expression of N-methyl-d-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am. J. Psychiatry 157, 1141–1149 (2000).

  119. 119.

    Li, W. et al. Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia. Am. J. Psychiatry 172, 373–382 (2015).

  120. 120.

    Schobel, S. A. et al. Differential targeting of the CA1 subfield of the hippocampal formation by schizophrenia and related psychotic disorders. Arch. Gen. Psychiatry 66, 938–946 (2009).

  121. 121.

    Das, T., Ivleva, E. I., Wagner, A. D., Stark, C. E. L. & Tamminga, C. A. Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr. Res. 159, 193–197 (2014).

  122. 122.

    Kraguljac, N. V. et al. Mnemonic discrimination deficits in first episode psychosis and a ketamine model suggests dentate gyrus pathology linked to NMDA-receptor hypofunction. Biol. Psychiatry Cogn. Neurosci. Neuroimaging https://doi.org/10.1016/j.bpsc.2017.02.005 (2017).

  123. 123.

    Martinelli, C. & Shergill, S. S. Clarifying the role of pattern separation in schizophrenia: the role of recognition and visual discrimination deficits. Schizophr. Res. 166, 328–333 (2015).

  124. 124.

    White, S. W. et al. Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: understanding anxiety in autism spectrum disorder. Int. J. Dev. Neurosci. 39, 22–36 (2014).

  125. 125.

    South, M. et al. Overactive pattern separation memory associated with negative emotionality in adults diagnosed with autism spectrum disorder. J. Autism Dev. Disord. 45, 3458–3467 (2015).

  126. 126.

    Bolz, L., Heigele, S. & Bischofberger, J. Running improves pattern separation during novel object recognition. Brain Plast. 1, 129–141 (2015).

  127. 127.

    Wu, M. V., Luna, V. M. & Hen, R. Running rescues a fear-based contextual discrimination deficit in aged mice. Front. Syst. Neurosci. 9, 114 (2015).

  128. 128.

    Suwabe, K. et al. Acute moderate exercise improves mnemonic discrimination in young adults. Hippocampus 27, 229–234 (2017).

  129. 129.

    Maass, A. et al. Vascular hippocampal plasticity after aerobic exercise in older adults. Mol. Psychiatry 20, 585–593 (2015).

  130. 130.

    Suwabe, K. et al. Aerobic fitness associates with mnemonic discrimination as a mediator of physical activity effects: evidence for memory flexibility in young adults. Sci. Rep. 7, 5140 (2017).

  131. 131.

    van Praag, H., Kempermann, G. & Gage, F. H. Neural consequences of environmental enrichment. Nat. Rev. Neurosci. 1, 191–198 (2000).

  132. 132.

    Bekinschtein, P., Oomen, C. A., Saksida, L. M. & Bussey, T. J. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin. Cell Dev. Biol. 22, 536–542 (2011).

  133. 133.

    Clemenson, G. D. & Stark, C. E. L. Virtual environmental enrichment through video games improves hippocampal-associated memory. J. Neurosci. 35, 16116–16125 (2015).

  134. 134.

    Borota, D. et al. Post-study caffeine administration enhances memory consolidation in humans. Nat. Neurosci. 17, 201–203 (2014).

  135. 135.

    Bakker, A., Albert, M. S., Krauss, G., Speck, C. L. & Gallagher, M. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance. Neuroimage Clin. 7, 688–698 (2015).

  136. 136.

    Koh, M. T., Haberman, R. P., Foti, S., McCown, T. J. & Gallagher, M. Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment. Neuropsychopharmacology 35, 1016–1025 (2010).

  137. 137.

    Smucny, J., Stevens, K. E. & Tregellas, J. R. The antiepileptic drug levetiracetam improves auditory gating in DBA/2 mice. NPJ Schizophr. 1, 15002 (2015).

  138. 138.

    Sanchez, P. E. et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc. Natl. Acad. Sci. USA 109, E2895–E2903 (2012).

  139. 139.

    Adam Samuels, B., Leonardo, E. D. & Hen, R. Hippocampal subfields and major depressive disorder. Biol. Psychiatry 77, 210–211 (2015).

  140. 140.

    Treadway, M. T. et al. Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Biol. Psychiatry 77, 285–294 (2015).

  141. 141.

    Castrén, E. & Hen, R. Neuronal plasticity and antidepressant actions. Trends Neurosci. 36, 259–267 (2013).

  142. 142.

    Niibori, Y. et al. Suppression of adult neurogenesis impairs population coding of similar contexts in hippocampal CA3 region. Nat. Commun. 3, 1253 (2012).

  143. 143.

    Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013).

  144. 144.

    Manganas, L. N. et al. Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain. Science 318, 980–985 (2007).

  145. 145.

    Amaral, D. G., Ishizuka, N. & Claiborne, B. Neurons, numbers and the hippocampal network. Prog. Brain Res. 83, 1–11 (1990).

  146. 146.

    Ally, B. A., Hussey, E. P., Ko, P. C. & Molitor, R. J. Pattern separation and pattern completion in Alzheimer’s disease: evidence of rapid forgetting in amnestic mild cognitive impairment. Hippocampus 23, 1246–1258 (2013).

Download references

Acknowledgements

We thank M. Tsai, E. Murray and J. Noche for their helpful feedback on earlier versions of this manuscript. We also acknowledge our sources of support. S.L.L. is supported by NIA F32 AG054116. M.A.Y. is supported by NIA R01 AG053555, P50 AG16573 (Alzheimer’s Disease Research Center), NIMH R01 MH102392 and P50 MH096889 (Conte Center at UC Irvine).

Author information

Affiliations

  1. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA

    • Stephanie L. Leal
  2. Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, USA

    • Michael A. Yassa

Authors

  1. Search for Stephanie L. Leal in:

  2. Search for Michael A. Yassa in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael A. Yassa.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41593-017-0065-1