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

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Adult neurogenesis

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

Many of these newborn cells die shortly after their birth, 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 phenomenon only recently being largely accepted by the scientific community. 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. Only recently, with the characterization of neurogenesis in birds [1] and the use of confocal microscopy, has it become reasonably well-accepted that hippocampal neurogenesis does occur in mammals, including humans (Eriksson et al., 1998; Gould et al., 1999a). Some authors (particularly Elizabeth Gould) have suggested that adult neurogenesis may also occur in other areas including primate neocortex (e.g., Shankle et al. 1999, Gould et al., 1999b; Zhao et al., 2003), although others, including Rakic (2002), have questioned the scientific evidence of these findings; in the broad sense, they suggest that the new cells may be glia. A recent paper by Ponti, Peretto, and Bonfanti found evidence of neuronal neurogenesis in the cerebellum of adult rabbits.[1]

Neurogenesis and learning

The function of adult neurogenesis is not certain [2] - although there is some evidence that hippocampal adult neurogenesis is important for learning and memory. This is perhaps unsurprising given what we know of the hippocampus and its role in learning and memory (several authors, including, for example, Rolls & Treves (1998) have postulated integrated theories for the role of hippocampus in learning and memory). How learning would be affected by neurogenesis is unclear, as several computational theories have recently been suggested, including the idea that new neurons increase memory capacity[3], reduce interference between memories [4], or add information about time to memories[5]. Experiments aimed at knocking out neurogenesis have proven inconclusive, with some studies suggesting some types of learning are neurogenesis dependent[6] and others seeing no effect[7]. Gould et al. (1999c) have demonstrated that the act of learning itself is associated with increased neuronal survival. 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. Malberg et al. (2000) [8] and Manev et al. (2001) [9] have linked neurogenesis to the beneficial actions of certain antidepressants, suggesting a connection between decreased hippocampal neurogenesis and depression. In a subsequent paper, Santarelli et al. (2003) [10] demonstrated that the behavioural effects of antidepressants in mice did not occur when neurogenesis was prevented with x-irradiation techniques. In fact, adult-born neurons are more excitable than older neurons due to a differential expression of GABA receptors. 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). 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 adult-born neurons. Could that well established maxim in psychology that stress begets stress be linked to neurogenesis?

Papers have linked together learning and memory with depression, and have suggested that neurogenesis may promote neuroplasticity. For instance, Castren (2005) [11] has proposed that our mood may be regulated, at a base level, by plasticity, and thus not chemistry; for instance, the effects of antidepressant treatment are only secondary to this.

Sleep reduction and stress levels on neurogenesis

Mirescu, et al. reported that lack of sleep may reduce hippocampian neurogenesis in rats due to increased levels of glucocorticoids. Two weeks of sleep deprivation acted as a neurogenesis-inhibitor which, even though the normal sleep patterns returned after the study, did not reverse the lack of growth of brain cells in the hippocampus of rats.[2]


Neurogenesis and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disorder characterized by a progressive neuronal loss affecting preferentially the dopaminergic neurons of the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has provided the proof of principle that a cell replacement therapy can ameliorate clinical symptoms in affected patients(Arias-Carrión et al., 2007). 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 (Fallon et. al., 2000), (Arias-Carrión et al., 2004), (Arias-Carrión et al., 2006). Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone (Höglinger et al., 2004). Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors (Höglinger et al., 2004). Such stem cells have been identified in so called neurogenic brain areas, where neurogenesis is constitutively ongoing, but also in primarily non-neurogenic areas, such as the midbrain and the striatum, where neurogenesis does not occur under normal physiological conditions(Arias-Carrión et al., 2007). 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(Arias-Carrión et al., 2007).

Regulation of neurogenesis

Many factors may increase or decrease rates of hippocampal neurogenesis. Exercise (e.g., Bjornebekk, Mathe & Brene, 2005) and enriched environment have been shown to promote their survival and successful integration into the existing hippocampus. On the other hand, adverse conditions such as chronic stress and aging can result in a decrease of proliferation. The link between stress, depression, and the hippocampus is well-documented (e.g., Lee et al., 2002; Sheline et al., 1999).

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 (Reynolds & Weiss, 1992) [12]. 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 (Taupin & Gage, 2002) [13]. Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens for neural progenitor and stem cells in vitro, though other factors synthesized by the neural progenitor and stem cells in culture are required for their growth (Taupin et al., 2000) [14] . 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), which was developed by Reynolds and Weiss (1992). While the Neurosphere Assay has been the method of choice for the 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. 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 (Louis et al., 2008).

References

  1. ^ Ponti G, Peretto B, Bonfanti L (2008). "Genesis of neuronal and glial progenitors in the cerebellar cortex of peripuberal and adult rabbits". PLoS ONE 3 (6): e2366. PMID 18523645. 
  2. ^ Mirescu C, Peters JD, Noiman L, Gould E. "Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids." Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19170-5. Epub 2006 Nov 29.
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  • Dedicated issue of Philosophical Transactions B on Stem Cells and Brain Repair. Some articles are freely available.

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