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Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation

Abstract

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life1,2. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation3 and can account for up to ten per cent of the entire granule cell population4. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning5, environmental enrichment6, exercise6 and chronic treatment with antidepressants7,8,9,10. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions11, as well as some of the behavioural effects of antidepressants8,9,10,12,13, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing14,15.

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Figure 1: Bax ablation in neural stem cells in the adult brain increases hippocampal neurogenesis and neurogenesis-dependent LTP.
Figure 2: Increasing adult hippocampal neurogenesis is sufficient to improve discrimination between similar contexts.
Figure 3: Increasing adult hippocampal neurogenesis does not produce anxiolytic or antidepressant-like behavioural effects.
Figure 4: Mice with more adult-born neurons display increased exploratory behaviour and decreased anxiety-like behaviour in the open field test following a voluntary exercise regimen.

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Acknowledgements

We thank J. Gordon, S. Fusi, C. Kellendonk, H. Scharfman and members of the Hen laboratory for comments on the manuscript and discussions about the project. We thank E. Pavlopoulos for consultation on spatial learning, and M. Drew and C. A. Denny for input on the novel object recognition test. A.S. was supported by a 2009 National Institute of Mental Health Grant (1K99MH86615-01), 2006 and 2008 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Awards, and a 2008 Sackler Institute of Columbia University Award. K.N.S. was supported by a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral Fellows (F31). R.H. was supported by grants from NARSAD, the New York Stem Cell Initiative (NYSTEM) and the National Institutes of Health (R01 MH068542).

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A.S. conceived and designed the experiments, performed the circuitry analysis and behaviour experiments, analysed the data and wrote the manuscript. K.N.S. and A.S.H. contributed to the behavioural testing and circuitry analysis. C.M.O. and M.A.K. performed the electrophysiological experiments. A.D. contributed the Nes-CreERT2 transgenic mouse line used in this study. N.S.B. assisted with focal X-ray irradiation of the mice and performed the active place avoidance experiment in the laboratory of A.A.F. R.H. oversaw the overall execution of the project, contributed to the experimental design and the interpretation of the data, provided financial support and helped to write the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Amar Sahay or René Hen.

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R.H. is a consultant to BrainCells and AstraZeneca.

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Sahay, A., Scobie, K., Hill, A. et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470 (2011). https://doi.org/10.1038/nature09817

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