Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Integrating new findings and examining clinical applications of pattern separation

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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Circuitry and computational properties of the hippocampus.
Fig. 2: Exponential increase in articles on pattern separation.
Fig. 3: Medial temporal lobe circuitry alterations in disease.
Fig. 4: Behavioral and neural predictions of discrimination performance and pattern separation.

References

  1. 1.

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

    CAS  PubMed  Article  Google Scholar 

  2. 2.

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

    CAS  PubMed  Article  Google Scholar 

  3. 3.

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

    CAS  Article  Google Scholar 

  4. 4.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  11. 11.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

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

    CAS  PubMed  Article  Google Scholar 

  13. 13.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

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

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  22. 22.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  25. 25.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

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

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  55. 55.

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

    PubMed  Article  Google Scholar 

  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).

    Article  Google Scholar 

  57. 57.

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

    CAS  PubMed  Article  Google Scholar 

  58. 58.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

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

    PubMed  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

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

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  88. 88.

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

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  91. 91.

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

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  93. 93.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

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

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

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

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

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

    PubMed  Article  Google Scholar 

  105. 105.

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

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  115. 115.

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

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

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

    Article  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  128. 128.

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

    PubMed  Article  Google Scholar 

  129. 129.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

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

    PubMed  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

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

    PubMed  Article  Google Scholar 

  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).

    PubMed  Article  Google Scholar 

  141. 141.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

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

    CAS  PubMed  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

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

Authors

Corresponding author

Correspondence to Michael A. Yassa.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Leal, S.L., Yassa, M.A. Integrating new findings and examining clinical applications of pattern separation. Nat Neurosci 21, 163–173 (2018). https://doi.org/10.1038/s41593-017-0065-1

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