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

Nature Neuroscience volume 15, pages 1613–1620 (2012)Cite this article

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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.

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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.

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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.).

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Authors and Affiliations

  1. Department of Neuroscience, Columbia University, New York, New York, USA

    Mazen A Kheirbek & René Hen

  2. Department of Psychiatry, Columbia University, New York, New York, USA

    Mazen A Kheirbek & René Hen

  3. Division of Integrative Neuroscience, The New York State Psychiatric Institute, New York, New York, USA

    Mazen A Kheirbek & René Hen

  4. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

    Kristen C Klemenhagen

  5. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

    Amar Sahay

  6. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA

    Amar Sahay

  7. Harvard Stem Cell Institute, Boston, Massachusetts, USA

    Amar Sahay

  8. Harvard Medical School, Boston, Massachusetts, USA

    Amar Sahay

  9. Department of Pharmacology, Columbia University, New York, New York, USA

    René Hen

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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

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