Research Focus
Stress in early life inhibits neurogenesis in adulthood

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Both structure and function of the hippocampus are altered by stress: by increasing levels of corticosteroids, stress causes atrophy of CA3 pyramidal cell dendrites, inhibits adult neurogenesis in the dentate gyrus, and impairs hippocampus-dependent learning. A recent study shows that adverse experience limited to early life, specifically removal of rat pups from their mother for three hours each day, decreases production of new granule neurons in adulthood through a corticosteroid-dependent mechanism. This finding suggests that stress in early life could permanently impair hippocampus-dependent learning and memory and increase susceptibility to depression by inhibiting adult neurogenesis in the hippocampus.

Introduction

Unlike most neurons in the brain, granule cells in the dentate gyrus, part of the hippocampus, continue to be produced during adulthood. Although the specific function of the new granule neurons is not yet clear, their location in the hippocampus suggests that they have a role in learning and memory, and a small number of studies support this idea 1, 2. A growing number of correlations suggest that inhibition of adult neurogenesis in the dentate gyrus might also have a role in depressive illness [3]. First, several different antidepressant treatments increase proliferation of granule cell precursors with a delay paralleling improvement of clinical symptoms 4, 5, 6, 7. Irradiating the rodent hippocampus impairs adult neurogenesis and also prevents antidepressant-induced changes in behavior [8]. Second, stress, acting through corticosteroid stress hormones, inhibits adult neurogenesis in the dentate gyrus 9, 10, 11 and is also linked to depression – that is, stress can trigger depressive episodes, and a large subset of people with depressive illness show corticosteroid dysregulation 3, 12, 13.

Corticosteroids strongly inhibit granule cell precursor proliferation within three hours of corticosterone injection and possibly even sooner 9, 14. Because external stimuli alter corticosteroid levels within a few minutes, environmental changes could cause several fluctuations in the granule cell production rate in a single day. A recent paper by Mirescu et al. [15], however, shows that stressful experience during postnatal development also regulates granule cell precursor proliferation on a completely different timescale. When rat pups were removed from their mothers for three hours each day between postnatal day (P)1 and P14, they showed decreased proliferation of granule cell precursors many weeks later, as adults. In other words, stress in early life can permanently affect neurogenesis.

Section snippets

How does maternal deprivation inhibit neurogenesis?

The maternal deprivation paradigm used by Mirescu et al. [15] might seem fairly mild, because each separation lasts only three hours and pups are kept warm in an incubator with home-cage bedding material and littermates. However, this manipulation is stressful enough to increase corticosteroid levels in the pups even though they are generally ‘stress hyporesponsive’ at this age [16]. In addition to the acute rise in corticosterone levels, this deprivation paradigm has been shown to cause

Concluding remarks

The findings described here show that experiences in early life can permanently alter the sensitivity of adult neurogenesis in the dentate gyrus to stress and/or stress hormones. Further studies will be needed to understand exactly how and where in the HPA axis or hippocampus this change in sensitivity occurs. But wherever it occurs, the resulting inhibition of adult neurogenesis indicates that early life events have a long-lasting effect on the cellular composition of the hippocampus, and

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