Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation
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Open Access
- 3 April 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 472 (7344), 466-470
- https://doi.org/10.1038/nature09817
Abstract
Loss-of-function studies have implicated adult-born hippocampal neurons — as opposed to those present at birth — in learning and memory and in mediating some effects of antidepressants. Experiments using an inducible genetic gain-of-function strategy to augment the survival of adult-born neurons in mice demonstrate a causal link between increased adult hippocampal neurogenesis and enhancement of specific cognitive functions. This raises the possibility that anxiety disorders and memory impairment might be treated by stimulating adult hippocampal neurogenesis. 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.Keywords
This publication has 39 references indexed in Scilit:
- Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adultsHippocampus, 2011
- New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?Nature Reviews Neuroscience, 2010
- Overgeneralization of Conditioned Fear as a Pathogenic Marker of Panic DisorderAmerican Journal of Psychiatry, 2010
- Krüppel-Like Factor 9 Is Necessary for Late-Phase Neuronal Maturation in the Developing Dentate Gyrus and during Adult Hippocampal NeurogenesisJournal of Neuroscience, 2009
- Neurogenesis-Dependent and -Independent Effects of Fluoxetine in an Animal Model of Anxiety/DepressionNeuron, 2009
- TrkB Regulates Hippocampal Neurogenesis and Governs Sensitivity to Antidepressive TreatmentNeuron, 2008
- Dentate Gyrus NMDA Receptors Mediate Rapid Pattern Separation in the Hippocampal NetworkScience, 2007
- A Critical Period for Enhanced Synaptic Plasticity in Newly Generated Neurons of the Adult BrainNeuron, 2007
- Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrusProceedings of the National Academy of Sciences of the United States of America, 2006
- Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune diseaseProceedings of the National Academy of Sciences of the United States of America, 2005