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Formation and integration of new neurons in the adult hippocampus

Nature Reviews Neuroscience volume 22, pages 223–236 (2021)Cite this article

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Abstract

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain. Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight recent advances in the field based on novel technologies (including single-cell RNA sequencing, intravital imaging and functional observation of newborn cells in behaving mice) and characterize the distinct developmental steps from stem cell activation to the integration of newborn neurons into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are regulated, discuss findings regarding survival and maturation of adult-born cells and describe how newborn neurons affect brain function. The evidence arguing for (and against) lifelong neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of what is needed to improve our understanding of the mechanisms and functional consequences of adult neurogenesis and how the field may move towards more translational relevance in the context of acute and chronic neural injury and stem cell-based brain repair.

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Fig. 1: Neurogenesis in the adult hippocampus.
Fig. 2: Systemic regulators of adult hippocampal neurogenesis.
Fig. 3: Maturation of adult-born neurons in the hippocampus.
Fig. 4: Circuit function of newborn granule cells in the adult hippocampus.

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Acknowledgements

The authors thank D. C. Lie for comments. The authors’ laboratory is supported by the European Research Council (STEMBAR to S.J.), the Swiss National Science Foundation (BSCGI0_157859 and 310030_196869 to S.J.), the Novartis Foundation (to A.D.-L. and S.J.), the Helmut Horten Foundation (to S.J.), the Betty & David Koetser Foundation (to S.J.), a Forschungskredit of the University of Zurich (to A.D.-L.) and the Zurich Neuroscience Center (to S.J.).

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  1. Laboratory of Neural Plasticity, Brain Research Institute, Faculty of Medicine and Faculty of Science, University of Zurich, Zurich, Switzerland

    Annina Denoth-Lippuner & Sebastian Jessberger

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  1. Annina Denoth-Lippuner
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The authors contributed equally to all aspects of the article.

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Correspondence to Sebastian Jessberger.

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Glossary

Granule cell layer

The granule cell layer consists mainly of excitatory granule cells, the principal neurons of the dentate gyrus.

Thymidine analogues

Analogues of the DNA component thymidine that can be injected in animals and are integrated into replicating DNA strands and detected using antibodies.

Vascular end-feet

Terminals of astrocytic processes at the vascular surface that regulate vascular function.

Asymmetric divisions

Divisions generating daughter cells with different fates or properties.

Symmetric divisions

Divisions generating daughter cells with similar or identical fates or properties.

Heterochronic parabiosis

Cross-circulation of humoral factors via shared blood circulation, most commonly used by connecting the vasculature (and thus blood circulation) of young and aged mice.

Vimentin

A type III intermediate filament protein that is a cytoskeletal component in various cell types.

Intersectional genetics

Approaches that increase the accuracy of genetic access to cells by combining two or more regulatory elements for a single synthetic output.

Genetic mosaicism

The presence of different genotypes in individual cells arising from a single zygote within an individual.

Na+–K+–Cl– transporter NKCC1

A co-transporter that regulates the transport of sodium, potassium and chloride through cellular membranes.

Multiple-synapse boutons

Synapses with two or more postsynaptic terminals on a single presynaptic terminal.

Morris water maze

A behavioural, spatial navigational task, mostly used in laboratory rodents, to study spatial learning and memory.

Behavioural flexibility

Adaptive changes in the behaviour of an animal in response to changes of the external or internal environment.

Memory traces

Units of cognitive information in the brain that may cause structural or biochemical alterations allowing the storage of memory.

Homosynaptic long-term potentiation

Changes in synaptic strength that are specific for postsynaptic targets that are specifically stimulated by presynaptic cells.

Heterosynaptic long-term depression

A reduction in synaptic strength at unactivated synaptic connections that are input nonspecific.

Gradient-index lens

A lens that makes use of a gradient of the refractive index of a material, allowing a lens with a flat surface or that does not have aberrations of traditional spherical lenses.

Lateral entorhinal cortex

Part of the medial temporal lobe; it projects via the lateral perforant path into the dentate gyrus.

Medial entorhinal cortex

Part of the medial temporal lobe; it projects via the medial perforant path into the dentate gyrus.

Spatial transcriptomics

The characterization of mRNA composition in individual cells while maintaining information regarding their spatial position within complex tissues.

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Denoth-Lippuner, A., Jessberger, S. Formation and integration of new neurons in the adult hippocampus. Nat Rev Neurosci 22, 223–236 (2021). https://doi.org/10.1038/s41583-021-00433-z

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