Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology

doi:10.1016/j.neubiorev.2008.08.007

Neuroscience & Biobehavioral Reviews

Volume 33, Issue 3, March 2009, Pages 232-252

https://doi.org/10.1016/j.neubiorev.2008.08.007 Get rights and content

Abstract

It is now well established that the mammalian brain has the capacity to produce new neurons into adulthood. One such region that provides the proper milieu to sustain progenitor cells and is permissive to neuronal fate determination is located in the dentate gyrus of the hippocampus. This review will discuss in detail the complex process of adult hippocampal neurogenesis, including proliferation, differentiation, survival, and incorporation into neuronal networks. The regulation of this phenomenon by a number of factors is described, including neurotransmitter systems, growth factors, paracrine signaling molecules, neuropeptides, transcription factors, endogenous psychotropic systems, sex hormones, stress, and others. This review also addresses the functional significance of adult born hippocampal granule cells with regard to hippocampal circuitry dynamics and behavior. Furthermore, the relevance of perturbations in adult hippocampal neurogenesis to the pathophysiology of various disease states, including depression, schizophrenia, epilepsy, and diabetes are examined. Finally, this review discusses the potential of using hippocampal neurogenesis as a therapeutic target for these disorders.

Section snippets

Adult mammalian neurogenesis: historical perspective

“In the adult centres, the nerve paths are something fixed, ended and immutable. Everything may die, nothing may be regenerated.”—Santiago Ramon y Cajal, 1913.

This statement highlights what was one of the central dogmas of neuroscience, that neurogenesis was restricted to prenatal and early postnatal development, and that the adult mammalian brain was unable to facilitate this process. However, in 1912, Ezra Allen provided the first hint of evidence that new neurons could be born in the adult

Neurogenic brain regions

A brain region that supports neurogenesis is classified as neurogenic. Neurogenic implies the presence of immature precursor cells and a microenvironment that is permissive for the production of new neurons. In the adult mammalian brain, there are two neurogenic regions that are generally accepted, the olfactory system and the hippocampus. In the olfactory system, precursor cells reside in the anterior portion of the SVZ in the walls of the lateral ventricles, migrate by ‘chain migration’ along

Neurogenesis: a complex multi-step process

Adult neurogenesis is the production of new neurons in the adult brain. The term comprises a complex process that begins with the proliferation of progenitor cells, followed by commitment to a neuronal phenotype, morphological and physiological maturation with the development of functional neuronal characteristics, and ends with the existence of a new functioning, integrated neuron.

Regulation

Adult hippocampal neurogenesis is bi-directionally regulated by many factors, both intrinsic and extrinsic. They range from neurotrophins, antidepressants, stress, opioids, and seizures, to physical activity, learning, and hormones. Dynamic factors have been shown to affect the different phases of neurogenesis, including expansion (proliferation), differentiation (i.e. neuronal vs. glial), and survival. Therefore, the net effect on neurogenesis often results from different combinations of

Functional role of hippocampal neurogenesis

It has been well established using a variety of different techniques that the newly born cells in the adult hippocampus are electrophysiologically functional and become integrated granule cells (Stanfield and Trice, 1988, Hastings and Gould, 1999, Markakis and Gage, 1999, Carlen et al., 2002, van Praag et al., 2002). However, the role these neurons play in hippocampal function is still unclear and this topic has been the subject of intense research during recent years.

Ablation of adult

Depression

The neurogenic hypothesis postulates that a reduced production of new neurons in the hippocampus relates to the pathogenesis of depression and that successful antidepressant treatment requires an enhancement in hippocampal neurogenesis (Duman et al., 2001). This hypothesis was initially predicated on several lines of evidence. First, there is abundant preclinical evidence that stress suppresses hippocampal neurogenesis (see previous section). Clinically, stressful life events are known to

Concluding remarks

The addition of new neurons to the adult hippocampus can influence its structure and function by multiple possible mechanisms and provides a new mechanism of plasticity that can be used to change the properties of certain neural circuits. Neurogenesis could serve to increase the number of dentate granule cells, provide a reservoir of highly plastic immature neurons, generate multiple cell types, and/or drive the turnover and replacement of mature granule cells (Sahay et al., 2007). There are

Acknowledgments

The authors would like to thank Dr. Georgia Hodes for the critical reading of this manuscript and her expert opinions. This work was supported by NIH grant MH72832 for a National Center for Drug Discovery Group in Mood Disorders established between the University of Pennsylvania and Wyeth Research.

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ReviewAdult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology

Abstract

Section snippets

Adult mammalian neurogenesis: historical perspective

Neurogenic brain regions

Neurogenesis: a complex multi-step process

Regulation

Functional role of hippocampal neurogenesis

Depression

Concluding remarks

Acknowledgments

Mol. Cell. Neurosci.

Brain Res.

Neuroscience

Neuropharmacology

Neurobiol. Dis.

Exp. Neurol.

Neurosci. Lett.

Mol. Cell. Neurosci.

Neuroscience

Brain Res.

Neuroscience

Brain Res.

Neuroscience

Curr. Biol.

J. Biol. Chem.

Biol. Psychiatry

Brain Res.

Cell

Biol. Psychiatry

Cell

Biol. Psychiatry

Exp. Neurol.

Methods Cell Biol.

Exp. Neurol.

Neurosci. Lett.

Mol. Cell. Neurosci.

J. Affect. Disord.

Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus

J. Neurosci.

Corticosterone peak is responsible for stress-induced elevation of glutamate in the hippocampus

Stress

The endocannabinoid system drives neural progenitor proliferation

FASEB J.

In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog

Nature

Potential role for adult neurogenesis in the encoding of time in new memories

Nat. Neurosci.

High-speed imaging reveals neurophysiological links to behavior in an animal model of depression

Science

The cessation of the mitosis in the central nervous system of the albino rat

J. Comp. Neurol.

Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.

Mol. Psychiatry

Autoradiographic investigation of cell proliferation in the brains of rats and cats

Anat. Rec.

Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb

J. Comp. Neurol.

Post-natal origin of microneurones in the rat brain

Nature

Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

J. Comp. Neurol.

Cognitive deficits in depression: possible implications for functional neuropathology

Br. J. Psychiatry

Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus

Eur. J. Neurosci.

Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone

Neuropsychopharmacology

Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis

Eur. J. Neurosci.

Reduced hippocampal neurogenesis and number of hilar neurones in streptozotocin-induced diabetic mice: reversion by antidepressant treatment

Eur. J. Neurosci.

A computational principle for hippocampal learning and neurogenesis

Hippocampus

Chemical characterization of newly generated neurons in the striatum of adult primates

Exp. Brain Res.

Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis

Neuropsychopharmacology

Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures

Proc. Natl. Acad. Sci. U.S.A.

Review
Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology