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Molecular mechanisms in the regulation of adult neurogenesis during stress

Key Points

  • There is reciprocal regulation between adult neurogenesis and stress: adult neurogenesis can affect the stress response, and stress can modulate levels of adult neurogenesis.

  • One potential mechanism by which adult neurogenesis could regulate the stress response is through the neurogenesis-dependent modulation of perception of novel events, which would then influence whether events are perceived as stressful.

  • Many pathways that affect adult neurogenesis are also modulated by stress, including the cytokine, neurotrophic factor and morphogen signalling pathways. However, glucocorticoid hormones are undoubtedly the most important group of molecules in this context.

  • The glucocorticoid receptor signalling pathway can be modulated through several mechanisms, both upstream and downstream of the glucocorticoid receptor; all of these mechanisms can potentially modulate the effects of stress on neurogenesis.

  • Glucocorticoid receptor signalling pathways may be modified during stress through crosstalk with other stress-regulated pathways, indicating that the dynamics of the regulation of adult neurogenesis by stress are highly complex.

Abstract

Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.

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Figure 1: Theory of contextual emotional processing in stress perception.
Figure 2: Expression of glucocorticoid receptors and mineralocorticoid receptors during hippocampal neurogenesis in mice.
Figure 3: Modulation of glucocorticoid and glucocorticoid receptor activity.
Figure 4: Potential crosstalk mechanisms relevant to stress and neurogenesis.

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Acknowledgements

C.M.P. and P.A.Z. are supported by the National Institute of Health Research Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust and King's College London, and by the Medical Research Council UK (MR/J002739/1 and MR/L014815/1). M.E. is supported by a Marie Curie Fellowship from the European Commission and a grant from the Lundbeck Foundation. The authors thank S. Thuret and T. Murphy for discussions on this Review.

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Correspondence to Martin Egeland.

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Patricia A. Zunszain and Carmine M. Pariante have received research funding from pharmaceutical companies interested in depression such as Johnson & Johnson, but this Review is unrelated to this funding.

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Glossary

Subgranular zone

(SGZ). A small region on the inner boundaries of the granular layer in the dentate gyrus of rodents. Cell proliferation of precursors to adult neurogenesis of granular neurons occurs in the SGZ.

Cell proliferation

Among the adult neurogenesis stages, this is an often-quantified stage of the process and is a measure of the number of new cells being formed in the subgranular zone that have the potential to become new neurons or glia.

Unpredictable mild stress

A rodent model of depression in which animals are exposed to repeated stressors that are deemed as mild in an order that cannot be predicted to avoid the development of habituation resilience.

Pattern separation

The process of reducing interference among similar inputs using non-overlapping representations.

Overgeneralization

In behaviour, this is the use of a few and/or non-representative experiences to make an inference of a current experience that is incorrect.

Contextual emotional processing

The process of putting a novel experience into an emotional context using the emotional valence of similar previous experiences.

Dorsal dentate gyrus

A region that is thought to be associated with spatial memory processing.

Cell differentiation

A quantifiable stage of adult neurogenesis in which the number of cells fated to become neurons can be measured.

Circadian rhythms

In terms of hormone secretion, these rhythms vary throughout the day and comprise a period in which there is generally a high level of hormone secretion and a period in which a generally lower level of hormone is secreted.

Ultradian rhythms

In terms of hormone secretion, these rhythms vary within circadian rhythms and are composed of roughly hourly pulses of hormone release that result in peaks in hormone levels followed by troughs in which the hormone is broken down.

Subventricular zone

(SVZ). A thin strip composed of several layers on the inner walls of the lateral ventricles of the rodent forebrain. Cell proliferation of precursors to adult neurogenesis of mainly olfactory bulb neurons occurs in the SVZ.

Ventral dentate gyrus

A region that is thought to be associated with emotional memory processing.

Morphogens

A group of signalling molecules that govern tissue development. They classically control morphogenesis through cell proliferation and differentiation.

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Egeland, M., Zunszain, P. & Pariante, C. Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 16, 189–200 (2015). https://doi.org/10.1038/nrn3855

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