Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus (DG) throughout life 1, 2. Adult-born neurons exhibit heightened synaptic plasticity during their maturation 3 and can account for up to ten percent of the entire granule cell population 4. Moreover, levels of adult hippocampal neurogenesis are elevated by interventions associated with beneficial effects on cognition and mood such as learning 5, environmental enrichment 6, exercise 6 and chronic antidepressant treatment 7–10. Together, these properties of adult neurogenesis suggest that it may be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions 11 and some of the behavioural effects of antidepressants 8–10, 12, 13, it is unknown whether increasing adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons by enhancing their survival improves performance in a specific cognitive task in which an animal must distinguish between two similar contexts. 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, suggestive 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. In contrast, increasing adult hippocampal neurogenesis, on its own, does not produce an anxiolytic or antidepressant-like behavioural response. Together, our findings suggest that strategies designed to specifically increase adult hippocampal neurogenesis, by targeting cell death of adult-born neurons or other means, may have therapeutic potential for reversing impairments in pattern separation such as that seen during normal aging 14, 15.

The development of new treatments for depression is predicated upon identification of neural substrates and mechanisms that underlie its etiology and pathophysiology. The heterogeneity of depression indicates that its origin may lie in dysfunction of multiple brain regions. Here we evaluate adult hippocampal neurogenesis as a candidate mechanism for the etiology of depression and as a substrate for antidepressant action. Current evidence indicates that adult hippocampal neurogenesis may not be a major contributor to the development of depression, but may be required for some of the behavioral effects of antidepressants. We next revisit the functional differentiation of the hippocampus along the septo-temporal axis within the context of adult hippocampal neurogenesis and suggest that neurogenesis in the ventral dentate gyrus may be preferentially involved in regulation of emotion. Finally, we speculate on how increased adult hippocampal neurogenesis may modulate dentate gyrus function to confer the behavioral effects of antidepressants.

Summary Cellular plasticity contributes to the regenerative capacity of plants, invertebrates, teleost fishes, and amphibians. In vertebrates, differentiated cells are known to revert into replicating progenitors, but these cells do not persist as stable stem cells. We now present evidence that differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. Following the ablation of airway stem cells, we observed a surprising increase in the proliferation of committed secretory cells. Subsequent lineage tracing demonstrated that the luminal secretory cells had dedifferentiated into basal stem cells. Dedifferentiated cells were morphologically indistinguishable from stem cells and they functioned as well as their endogenous counterparts to repair epithelial injury. Indeed, single secretory cells clonally dedifferentiated into multipotent stem cells when they were cultured ex vivo without basal stem cells. In contrast, direct contact with a single basal stem cell was sufficient to prevent secretory cell dedifferentiation. In analogy to classical descriptions of amphibian nuclear reprogramming, the propensity of committed cells to dedifferentiate was inversely correlated to their state of maturity. This capacity of committed cells to dedifferentiate into stem cells may play a more general role in the regeneration of many tissues and in multiple disease states, notably cancer.

While adult born neurons in the olfactory bulb (OB) and the dentate gyrus (DG) subregion of the hippocampus have fundamentally different properties, they may have more in common than meets the eye. Here, we propose that new granule cells in the OB and DG may function as modulators of principal neurons to influence pattern separation and that adult neurogenesis constitutes an adaptive mechanism to optimally encode contextual or olfactory information.