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