Neurogenesis

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:

• 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 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., 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.

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.

Very recent 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.^[1]

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.

References

• Aimone JB, Jessberger S, and Gage FH (2007) Adult Neurogenesis. Scholarpedia, p. 8739
• Bjornebekk A, Mathe AA, Brene S. (2005). The antidepressant effect of running is associated with increased hippocampal cell proliferation. Int J Neuropsychopharmacol. Sep;8(3):357-68. PMID 15769301
• Castren E. (2005). Is mood chemistry?. Nat Rev Neurosci. Mar;6(3):241-6. PMID 15738959
• Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. (1998) Neurogenesis in the adult human hippocampus. Nat Med. Nov;4(11):1313-7. PMID 9809557
• Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E. (1999a). Hippocampal neurogenesis in adult Old World primates. Proc Natl Acad Sci U S A. Apr 27;96(9):5263-7. PMID 10220454
• Gould E, Reeves AJ, Graziano MS, Gross CG. (1999b). Neurogenesis in the neocortex of adult primates. Science. Oct 15;286(5439):548-52. PMID 10521353
• Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. (1999c). Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. Mar;2(3):260-5. PMID 10195219
• Lee AL, Ogle WO, Sapolsky RM. (2002). Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. Apr;4(2):117-28. PMID 12071509
• Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000 Dec 15;20(24):9104-10.[15]
• Manev H, Uz T, Smalheiser NR, Manev R. Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol. 2001 Jan 5;411(1-2):67-70.[16]
• Moghadam, K.S., Chen, A and Heathcote, R.D. (2003) Establishment of a ventral cell fate in the spinal cord. Dev. Dyn. 227, 552-562 PMID 12889064
• Rakic P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. (2002). Nat Rev Neurosci. Jan;3(1):65-71. PMID 11823806
• Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992 Mar 27;255(5052):1707-10. PMID 1553558. [17]
• Rolls, E.T & Treves, A. (1998). Neural Networks and Brain Function. Oxford: OUP. ISBN 0-19-852432-3.
• Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. Aug 8;301(5634):805-9. PMID 12907793
• Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003). Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. Jun 24;100(13):7925-30. PMID 12792021
• Sheline YI, Gado MH, Kraemer HC. (2003). Untreated depression and hippocampal volume loss. Am J Psychiatry. Aug;160(8):1516-8. PMID 12900317
• Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res. 2002 Sep 15;69(6):745-9. PMID 12205667. [18]
• Taupin P, Ray J, Fischer WH, Suhr ST, Hakansson K, Grubb A, Gage FH. FGF-2-responsive neural stem cell proliferation requires CCg, a novel autocrine/paracrine cofactor. Neuron. 2000 Nov;28(2):385-97. PMID 11144350.