neurogenesis

BrdU (red), a marker of DNA replication, highlights neurogenesis in the subgranular zone of hippocampal dentate gyrus. Fragment of an illustration from Faiz et al., 2005.^[1]

Neurogenesis (birth of neurons) is the process by which neurons are generated. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain.

Adult neurogenesis

Doublecortin expression in the rat dentate gyrus, 21st postnatal day. Oomen et al., 2009.^[2]

New neurons are continually born throughout adulthood in predominantly two regions of the brain:

• The subventricular zone (SVZ) lining the lateral ventricles, where the new cells migrate to the olfactory bulb via the rostral migratory stream
• The subgranular zone (SGZ), part of the dentate gyrus of hippocampus.

Many of the newborn cells die shortly after they are born, but a number of them become functionally integrated into the surrounding brain tissue.

Adult neurogenesis is a recent example of a long-held scientific theory being overturned, with the first evidence of mammalian neurogenesis presented in 1992.^[3] Early neuroanatomists, including Santiago Ramon y Cajal, considered the nervous system fixed and incapable of regeneration. For many years afterward, only a handful of biologists (including Joseph Altman, Shirley Bayer, and Michael Kaplan) considered adult neurogenesis a possibility. In 1983, with the characterization of neurogenesis in birds^[4] and the use of confocal microscopy, the possibility of mammalian neurogenesis became more apparent, but it was not until the early 1990s that hippocampal neurogenesis was demonstrated in non-human primates and humans.^[5][6] More recently, neurogenesis in the cerebellum of adult rabbits has also been characterized.^[7] Further, some authors (particularly Elizabeth Gould) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the neocortex.^[8][9][10] However, others^[11] have questioned the scientific evidence of these findings arguing that the new cells may be of glial origin.

Neurogenesis and learning

The functional relevance of adult neurogenesis is uncertain^[12], but there is some evidence that hippocampal adult neurogenesis is important for learning and memory^{[citation needed]}. Multiple mechanisms for the relationship between increased neurogenesis and improved cognition have been suggested, including computational theories to demonstrate that new neurons increase memory capacity,^[13] reduce interference between memories,^[14] or add information about time to memories.^[15] Experiments aimed at ablating neurogenesis have proven inconclusive, but several studies have proposed neurogenic-dependence in some types of learning.^[16] and others seeing no effect^[17] Studies have demonstrated that the act of learning itself is associated with increased neuronal survival.^[18] However, the overall findings that adult neurogenesis is important for any kind of learning are equivocal.

Neurogenesis and stress

Adult-born neurons appear to have a role in the regulation of stress. Studies have linked neurogenesis to the beneficial actions of specific antidepressants, suggesting a connection between decreased hippocampal neurogenesis and depression.^[19][20] In a subsequent paper, scientists demonstrated that the behavioral benefits of antidepressant administration in mice is reversed when neurogenesis is prevented with x-irradiation techniques.^[21] In fact, new-born neurons are more excitable than older neurons due to a differential expression of GABA receptors.^{[citation needed]} A plausible model, therefore, is that these neurons augment the role of the hippocampus in the negative feedback mechanism of the HPA-axis (physiological stress) and perhaps in inhibiting the amygdala (the region of brain responsible for fearful responses to stimuli).^[vague] This is consistent with numerous findings linking stress-relieving activities (learning, exposure to a new yet benign environment, and exercise) to increased levels of neurogenesis, as well as the observation that animals exposed to physiological stress (cortisol) or psychological stress (e.g. isolation) show markedly decreased levels of new-born neurons.

Some studies have hypothesized that learning and memory are linked to depression, and that neurogenesis may promote neuroplasticity. One study proposes that mood may be regulated, at a base level, by plasticity, and thus not chemistry. Accordingly, the effects of antidepressant treatment would only be secondary to change in plasticity.^[22]

Effect of sleep reduction and stress levels on neurogenesis

One study has linked lack of sleep to a reduction in rodent hippocampal neurogenesis. The proposed mechanism for the observed decrease was increased levels of glucocorticoids. It was shown that two weeks of sleep deprivation acted as a neurogenesis-inhibitor, which was reversed after return of normal sleep and even shifted to a temporary increase in normal cell proliferation.^[23]

Neurogenesis and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has paved the way for the possibility of a cell replacement therapy that could ameliorate clinical symptoms in affected patients.^[24] Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain.^[25][26][27] Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone.^[28] Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors.^[28] Neural stem cells have been identified in the neurogenic brain regions, where neurogenesis is constitutively ongoing, but also in the non-neurogenic zones, such as the midbrain and the striatum, where neurogenesis is not thought to occur under normal physiological conditions.^[24] A detailed understanding of the factors governing adult neural stem cells in vivo may ultimately lead to elegant cell therapies for neurodegenerative disorders such as Parkinson’s disease by mobilizing autologous endogenous neural stem cells to replace degenerated neurons.^[24]

Neurogenesis and Exercise

Scientists have shown that physical activity in the form of voluntary exercise results in an increase in the number of newborn neurons in the hippocampus of aging mice. The same study demonstrates an enhancement in learning of the "runner" (physically active) mice ^[29]. While the association between exercise-mediated neurogenesis and enhancement of learning remains unclear, this study clearly demonstrates the benefits of physical activity and could have strong implications in the fields of aging and/or Alzheimer's disease.

Regulation of neurogenesis

Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched environment have been shown to promote the survival of neurons and successful integration newborn cells into the existing hippocampus.^[30][31][32] Another factor is central nervous system injury since neurogenesis occurs after cerebral ischemia,^[33] epileptic seizures,^[34] and bacterial meningitis.^[35] On the other hand, conditions such as chronic stress and aging can result in a decreased neuronal proliferation.^[36][37][38]

Adult neural stem cells

Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1992, Reynolds and Weiss were the first to isolate neural progenitor and stem cells from the striatal tissue, including the subventricular zone — one of the neurogenic areas — of adult mice brain tissue.^[39] Since then, neural progenitor and stem cells have been isolated from various areas of the adult brain, including non-neurogenic areas, such as the spinal cord, and from various species including human.^[40] Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth.^[41] It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.

Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss.^[39] While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies.^{[vague][citation needed]} In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly, this assay allows discrimination between neural stem and progenitor cells.^[42]

See also

• Neural development
• Neuroplasticity

References

Notes

External links

• Media related to neurogenesis at Wikimedia Commons
• Neurogenesis in adult brain - Fred H. Gage and Henriette van Praag
• "Neurogenesis and Parkinson´s disease"
• Scholarpedia Article on Adult Neurogenesis
• "TRENDS in Neurosciences, 10 October 2001 (Michael S. Kaplan MD, PhD)
• New York Times: Studies Find Brains Grow New Cells
• New Yorker: Rethinking the Brain - How the songs of canaries upset a fundamental principle of science
• The Neurogenesis Experiment - Article series on adult human neurogenesis
• Seed magazine: The Reinvention of the Self - A historical background on the field of neurogenesis and implications of this research
• BBC Radio 4: The Memory Experience - Use it or Lose it
• PBS: Changing Your Mind - Grow Your Own Brain
• New York Times "Play" Magazine - Lobes of Steel, Article on Exercise Promoting Neurogenesis