Neurogenesis 740746 225514353 2008-07-14T02:26:09Z 128.248.223.175 /* Neurogenesis and stress */ '''Neurogenesis''' (''birth of [[neuron]]s'') is the process by which neurons are created. Most active during pre-natal development, '''neurogenesis''' is responsible for populating the growing [[brain]]. ==Adult neurogenesis== New neurons are continually born throughout adulthood in predominantly two regions of the brain: * The ''[[subventricular zone]]'' (SVZ) lining the [[ventricular system|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 (biologist)|Michael Kaplan]]) considered adult neurogenesis a possibility. Only recently, with the characterization of neurogenesis in birds [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=6572982] 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 (psychologist)|Elizabeth Gould]]) have suggested that adult neurogenesis may also occur in other areas including primate [[neopallium|neocortex]] (e.g., Shankle et al. 1999, Gould ''et al.'', 1999b; Zhao ''et al.'', 2003), although others, including Rakic (2002), have questioned the [[scientific method|scientific evidence]] of these findings; in the broad sense, they suggest that the new [[cell (biology)|cells]] may be [[glia]]. A recent paper by Ponti, Peretto, and Bonfanti found evidence of neuronal neurogenesis in the cerebellum of adult rabbits.<ref>{{cite journal |author=Ponti G, Peretto B, Bonfanti L |title=Genesis of neuronal and glial progenitors in the cerebellar cortex of peripuberal and adult rabbits |journal=PLoS ONE |year=2008 |volume=3 |issue=6 |pages=e2366 |pmid=18523645}}</ref> ===Neurogenesis and learning=== The function of adult neurogenesis is not certain [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15082323] - 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[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=15986407], reduce interference between memories [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16435309], or add information about [[time]] to memories[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16732202]. Experiments aimed at knocking out neurogenesis have proven inconclusive, with some studies suggesting some types of learning are neurogenesis dependent[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=12440573] and others seeing no effect[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16648847]. 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) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11124987&query_hl=11] and Manev ''et al.'' (2001) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11137860&query_hl=5] have linked neurogenesis to the beneficial actions of certain [[antidepressant]]s, suggesting a connection between decreased hippocampal neurogenesis and [[depression (mood)|depression]]. In a subsequent paper, Santarelli ''et al.'' (2003) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12907793] demonstrated that the behavioural effects of antidepressants in [[mice]] did not occur when neurogenesis was prevented with [[x-ray|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) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15738959] 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.<ref>[http://www.pnas.org/cgi/content/abstract/103/50/19170?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=neurogenesis+sleep&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT 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.</ref> ===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[http://www.ncbi.nlm.nih.gov/pubmed/18045161?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (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 [http://www.ncbi.nlm.nih.gov/pubmed/11121069?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (Fallon et. al., 2000)], [http://www.ncbi.nlm.nih.gov/pubmed/15372495?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (Arias-Carrión et al., 2004)], [http://www.ncbi.nlm.nih.gov/pubmed/17006899?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (Arias-Carrión et al., 2006)]. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone [http://www.ncbi.nlm.nih.gov/pubmed/15195095?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (Höglinger et al., 2004)]. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors [http://www.ncbi.nlm.nih.gov/pubmed/15195095?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (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[http://www.ncbi.nlm.nih.gov/pubmed/18045161?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (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[http://www.ncbi.nlm.nih.gov/pubmed/18045161?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum (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 [[stress (medicine)|chronic stress]] and [[aging]] can result in a decrease of proliferation. The link between [[Stress (medicine)|stress]], [[Clinical depression|depression]], and the [[hippocampus]] is well-documented (e.g., Lee ''et al.'', 2002; Sheline ''et al.'', 1999). ==Adult neural stem cells== Neural [[stem cell]]s (NSCs) are the self-renewing, [[multipotency|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 [[striatum|striatal tissue]], including the subventricular zone – one of the neurogenic areas - of adult mice brain tissue (Reynolds & Weiss, 1992) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1553558&query_hl=5]. 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) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12205667&query_hl=2]. [[Epidermal growth factor]] (EGF) and [[fibroblast growth factor]] (FGF) are [[mitogen]]s 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) [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11144350&query_hl=2] . 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 [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1553558&query_hl=5 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 ([http://www.ncbi.nlm.nih.gov/pubmed/18218818?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Louis et al., 2008]). ==References== {{reflist}} * Aimone JB, Jessberger S, and Gage FH (2007) Adult Neurogenesis. Scholarpedia, p. 8739 * Arias-Carrión et al., (2004) Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigro-striatal lesions. J. Neurosci. Res. 78:16-28[http://www.ncbi.nlm.nih.gov/pubmed/15372495?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] * Arias-Carrión et al., (2006) Neuronal precursors within the adult rat subventricular zone differentiate into dopaminergic neurons following substantia nigra lesion and chromaffin cell transplant. J. Neurosci. Res. 84:1425-1437[http://www.ncbi.nlm.nih.gov/pubmed/17006899?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] * Arias-Carrión O, Freundlieb N, Oertel WH, Höglinger GU (2007) Adult neurogenesis and Parkinson's disease. CNS Neurol Disord Drug Targets. 2007 Nov;6(5):326-35[http://www.ncbi.nlm.nih.gov/pubmed/18045161?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] * 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 * Fallon, JH, Reid, JR, Kinyamu, RM, Opole, IO, Opole, R, Baratta, J, Korc, M, Endo, T, Duong, A, Nguyen, G, Karkehebadhi, M, Patel, S, Twardzik, D, Loughlin, SE (2000) ''In vivo'' induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc. Natl. Acad. Sci. 26(97): 14686-14691. PMID 11121069 * 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 * Höglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, Hirsch EC. (2004) Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci. Jul;7(7):726-35. PMID 15195095 * 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 * Louis SA, Rietze RL, Deleyrolle L, Wagey RE, Thomas TE, Eaves AC, Reynolds BA. (2008). Enumeration of neural stem and progenitor cells in the neural colony forming cell assay. Stem Cells (Epub ahead of print) [http://www.ncbi.nlm.nih.gov/pubmed/18218818?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PMID 18218818] * 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.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11124987&query_hl=4] * 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.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11137860&query_hl=2] * 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1553558&query_hl=5] * 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 * Shankle, WR, Rafii, MS, Landing, BH, and Fallon, JH (1999) Approximate doubling of the numbers of neurons in the postnatal human cortex and in 35 specific cytoarchitectonic areas from birth to 72 months. Pediatric and Developmental Pathology 2:244-259. * 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. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12205667&query_hl=2] * 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. *[http://publishing.royalsociety.org/brain-repair Dedicated issue of ''Philosophical Transactions B'' on Stem Cells and Brain Repair. Some articles are freely available.] ==External links== *[http://www.peterhofmann.com/projekt2.html "Neurogenesis and Parkinson´s disease" (Arias-Carrión O, Freundlieb N, Oertel WH, Höglinger GU., 2007)] *[http://scholarpedia.org/article/Adult_Neurogenesis Scholarpedia Article on Adult Neurogenesis] *[http://ntp.neuroscience.wisc.edu/neuro675/reqreading/EnvironmentComplexity.pdf "TRENDS in Neurosciences, 10 October 2001 (Michael S. Kaplan MD, PhD)] *[http://query.nytimes.com/gst/fullpage.html?res=9C07E4DC1239F934A25750C0A96E958260&sec=health&pagewanted=all New York Times: Studies Find Brains Grow New Cells] *[http://www.michaelspecter.com/ny/2001/2001_07_23_brain.html New Yorker: Rethinking the Brain] - How the songs of canaries upset a fundamental principle of science *[http://www.seedmagazine.com/news/2006/02/the_reinvention_of_the_self.php Seed magazine: The Reinvention of the Self] - A historical background on the field of neurogenesis and implications of this research *[http://www.bbc.co.uk/radio4/memory/understand/useit.shtml BBC Radio 4: The Memory Experience] - Use it or Lose it *[http://www.pbs.org/saf/1101/resources/resources-2.htm PBS: Changing Your Mind] - Grow Your Own Brain *[http://www.nytimes.com/2007/08/19/sports/playmagazine/0819play-brain.html?pagewanted=1&_r=1&ref=playmagazine New York Times "Play" Magazine - Lobes of Steel, Article on Exercise Promoting Neurogenesis] [[Category:Neurobiology]] [[Category:Neurology]] [[Category:Central nervous system]] [[Category:Neuropsychology]] [[Category:Stem cells]] [[es:Neurogénesis]] [[de:Neurogenese]] [[fr:Neurogenèse]] [[nl:Neurogenese]] [[no:Neurogenesis]] [[pl:Neurogeneza]] [[ru:Нейрогенез]]