View source for Adult neurogenesis

{{Short description|Generating of neurons from neural stem cells in adults}}
{{cs1 config|name-list-style=vanc}}
{{Not to be confused with|Neuroregeneration}}
[[File:Proliferating cells in the dentate gyrus (crop).jpg|thumb|240px|[[Bromodeoxyuridine|BrdU]] (red), a marker of [[DNA]] replication, highlights neurogenesis in the [[subgranular zone]] of hippocampal [[dentate gyrus]]. Fragment of an [[:commons:File:Phenotypes of proliferating cells in the Rostral Migratory Stream and Dentate Gyrus.jpg|illustration]] from Faiz et al., 2005.<ref name="pmid15826306">{{cite journal |author1=Faiz M |author2=Acarin L |author3=Castellano B |author4=Gonzalez B |title=Proliferation dynamics of germinative zone cells in the intact and excitotoxically lesioned postnatal rat brain |journal=[[BMC Neuroscience]] |volume=6 |pages=26 |year=2005 |pmid=15826306 |pmc=1087489 |doi=10.1186/1471-2202-6-26 |doi-access=free }}</ref>]]

[[File:Doublecortin expression.png|thumb|right|[[Doublecortin]] expression in the rat [[dentate gyrus]], 21st postnatal day. Oomen et al., 2009.<ref name="dcx">{{cite journal |author1=Oomen CA |author2=Girardi CE |author3=Cahyadi R |display-authors=etal |editor1-last=Baune |editor1-first=Bernhard |title=Opposite effects of early maternal deprivation on neurogenesis in male versus female rats |journal=PLOS ONE |volume=4 |issue=1 |pages=e3675 |year=2009 |pmid=19180242 |pmc=2629844 |doi=10.1371/journal.pone.0003675 |bibcode=2009PLoSO...4.3675O|doi-access=free }}</ref>]]

'''Adult neurogenesis''' is the process in which [[neuron]]s are generated from [[neural stem cell]]s in the adult. This process differs from [[prenatal development|prenatal]] [[neurogenesis]].

In most mammals, new neurons are born throughout adulthood in two regions of the brain:<ref name="pmid25621867">{{cite journal|last1=Ernst|first1=A|last2=Frisén|first2=J|title=Adult neurogenesis in humans- common and unique traits in mammals.|journal=PLOS Biology|date=January 2015|volume=13|issue=1|pages=e1002045|doi=10.1371/journal.pbio.1002045|pmid=25621867|pmc=4306487|doi-access=free}}</ref>
* The [[subgranular zone]] (SGZ), part of the [[dentate gyrus]] of the [[hippocampus]],<ref name="dentate" /><ref>{{cite journal|last1=Vadodaria|first1=Krishna C.|last2=Gage|first2=Fred H.|title=SnapShot: Adult Hippocampal Neurogenesis|journal=Cell|volume=156|issue=5|pages=1114–1114.e1|doi=10.1016/j.cell.2014.02.029|pmid=24581504|year=2014|doi-access=free}}</ref> where neural stem cells give birth to [[granule cell]]s (implicated in memory formation and learning).<ref>{{cite journal |last1=Duan |first1=Xin |last2=Kang |first2=Eunchai |last3=Liu |first3=Cindy Y |last4=Ming |first4=Guo-li |last5=Song |first5=Hongjun |date=February 2008 |title=Development of neural stem cell in the adult brain |url=|journal=Current Opinion in Neurobiology |volume=18 |issue=1 |pages=108–115 |doi=10.1016/j.conb.2008.04.001 |pmid=18514504 |pmc=2464621 |issn=0959-4388}}</ref>
* The [[subventricular zone]] (SVZ) of the [[lateral ventricle]]s, which can be divided into three microdomains: lateral, dorsal and medial.<ref>{{cite journal|last1=Fiorelli|first1=Roberto|last2=Azim|first2=Kasum|last3=Fischer|first3=Bruno|last4=Raineteau|first4=Olivier|date=2015-06-15|title=Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis|journal=Development|volume=142|issue=12|pages=2109–20|doi=10.1242/dev.119966|issn=1477-9129|pmid=26081572|doi-access=free}}</ref> Neural stem cells migrate to the [[olfactory bulb]] through the [[rostral migratory stream]] where they differentiate into [[interneuron]]s participating in the [[olfaction|sense of smell]].  In humans, however, few if any olfactory bulb neurons are generated after birth.<ref name="pmid24561062">{{cite journal |vauthors=Ernst A, Alkass K, Bernard S, Salehpour M, Perl S, Tisdale J, Possnert G, Druid H, Frisén J |title=Neurogenesis in the striatum of the adult human brain |journal=Cell |volume=156 |issue=5 |pages=1072–83 |year=2014 |pmid=24561062 |doi=10.1016/j.cell.2014.01.044 |doi-access=free }}</ref><ref>{{cite journal |last1=Bergmann |first1=O. |last2=Liebel |first2=J. |last3=Bernard |first3=S. |last4=Alkass |first4=K. |last5=Yeung |first5=M.S.Y. |last6=Steier |first6=P. |last7=Kutschera |first7=W. |last8=Johnson |first8=L. |last9=Landen |first9=M. |last10=Druid |first10=H. |last11=Spalding |first11=K.L. |last12=Frisen |first12=J. |title=The age of olfactory bulb neurons in humans |journal=Neuron |date=2012 |volume=74 |issue=4 |pages=634–9 |doi=10.1016/j.neuron.2012.03.030|pmid=22632721 |doi-access=free }}</ref>

More attention has been given to the neurogenesis in the [[dentate gyrus]] than in the [[striatum]].  In [[rodent]]s, many of the newborn dentate gyrus neurons die shortly after they are born,<ref name="dentate">{{cite journal |last1=Dayer |first1=A.G. |last2=Ford |first2=A.A. |last3=Cleaver |first3=K.M. |last4=Yassaee |first4=M. |last5=Cameron |first5=H.A. |title=Short-term and long-term survival of new neurons in the rat dentate gyrus |journal=The Journal of Comparative Neurology |date=2003 |volume=460 |pages=563–572 |doi=10.1002/cne.10675 |pmid=12717714 |issue=4|s2cid=7153599 |url=https://zenodo.org/record/1229143 }}</ref> but a number of them become functionally integrated into the surrounding brain tissue.<ref>{{cite journal|last1=Toni |first1=N. |last2=Teng |first2=E.M. |last3=Bushong |first3=E.A. |last4=Aimone |first4=J.B. |last5=Zhao |first5=C. |last6=Consiglio |first6=A. |last7=van Praag |first7=H. |last8=Martone |first8=M.E. |last9=Ellisman |first9=M.H. |last10=Gage |first10=F.H. |title=Synapse formation on neurons born in the adult hippocampus |journal=Nature Neuroscience |date=2007 |volume=10 |issue=6 |pages=727–734 |doi=10.1038/nn1908 |pmid=17486101|s2cid=6796849 }}</ref><ref>{{cite journal |last1=Vivar |first1=C. |last2=Potter |first2=M.C. |last3=Choi |first3=J. |last4=Lee |first4=J. |last5=Stringer |first5=T.P. |last6=Callawy |first6=E.M. |last7=Gage |first7=F.H. |last8=Suh |first8=H. |last9=van Praag |first9=H. |title=Monosynaptic inputs to new neurons in the dentate gyrus. |journal=Nature Communications |date=2012 |issue=1038 |doi=10.1038/ncomms2101 |pmid=23033083 |pmc=4603575 |volume=3 |pages=1107|bibcode=2012NatCo...3.1107V }}</ref><ref>{{cite journal |last1=Toni |first1=N. |last2=Laplagne |first2=D.A. |last3=Zhao |first3=C. |last4=Lombardi |first4=G. |last5=Ribak |first5=C.E. |last6=Gage |first6=F.H. |last7=Schinder |first7=A.F. |title=Neurons born in the adult dentate gyrus form functional synapses with target cells |journal=Nature Neuroscience |date=2008 |volume=11 |issue=8 |doi=10.1038/nn.2156 |pmid=18622400 |pmc=2572641 |pages=901–7}}</ref>  Adult neurogenesis in rodents is reported to play a role in learning and memory, emotion, stress, depression, response to injury, and other conditions.<ref name=":0">{{cite journal |last1=Cameron |first1=Heather A. |last2=Glover |first2=Lucas R. |date=2015-01-03 |title=Adult Neurogenesis: Beyond Learning and Memory |journal=Annual Review of Psychology |volume=66 |issue=1 |pages=53–81 |doi=10.1146/annurev-psych-010814-015006 |issn=0066-4308 |pmc=5612417 |pmid=25251485}}</ref>

The numbers of neurons born in the human adult hippocampus remains controversial; some studies have reported that in adult humans about 700 new neurons are added in the hippocampus every day,<ref>{{cite journal|last1=Spalding|first1=Kirsty L.|last2=Bergmann|first2=Olaf|last3=Alkass|first3=Kanar|last4=Bernard|first4=Samuel|last5=Salehpour|first5=Mehran|last6=Huttner|first6=Hagen B.|last7=Boström|first7=Emil|last8=Westerlund|first8=Isabelle|last9=Vial|first9=Céline|date=2013-06-06|title=Dynamics of hippocampal neurogenesis in adult humans|journal=Cell|volume=153|issue=6|pages=1219–27|doi=10.1016/j.cell.2013.05.002|issn=1097-4172|pmc=4394608|pmid=23746839}}</ref> while more recent studies show that adult hippocampal neurogenesis does not exist in humans, or, if it does, it is at undetectable levels.<ref>{{cite journal|last1=Sorrells|first1=SF|last2=Paredes|first2=MF|last3=Cebrian-Silla|first3=A|last4=Sandoval|first4=K|last5=Qi|first5=D|last6=Kelley|first6=KW|last7=James|first7=D|last8=Mayer|first8=S|last9=Chang|first9=J|last10=Auguste|first10=KI|last11=Chang|first11=EF|last12=Gutierrez|first12=AJ|last13=Kriegstein|first13=AR|last14=Mathern|first14=GW|last15=Oldham|first15=MC|last16=Huang|first16=EJ|last17=Garcia-Verdugo|first17=JM|last18=Yang|first18=Z|last19=Alvarez-Buylla|first19=A|title=Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.|journal=Nature|date=15 March 2018|volume=555|issue=7696|pages=377–381|doi=10.1038/nature25975|pmid=29513649|pmc=6179355|bibcode=2018Natur.555..377S}}</ref>  Recent evidence shows that adult neurogenesis is essentially extinct in humans.<ref>{{cite journal |last1=Duque |first1=Alvaro |last2=Arellano |first2=Jon I. |last3=Rakic |first3=Pasko |date=January 2022 |title=An assessment of the existence of adult neurogenesis in humans and value of its rodent models for neuropsychiatric diseases |journal=Molecular Psychiatry |volume=27 |issue=1 |pages=377–382 |doi=10.1038/s41380-021-01314-8 |issn=1476-5578 |pmc=8967762 |pmid=34667259}}</ref> The experiments advocating for the presence of adult neurogenesis have focused on how dual antigen retrieval finds that DCX antibodies are staining many cells within the adult human dentate gyrus. This finding is not as clear though as supporters of adult neurogenesis suggest; the dentate gyrus cells stained with DCX have been shown to have a mature morphology, contrasting the idea that novel neurons are being generated within the adult brain.<ref>{{cite journal |vauthors=Sorrells SF, Paredes MF, Zhang Z, Kang G, Pastor-Alonso O, Biagiotti S, Page CE, Sandoval K, Knox A, Connolly A, Huang EJ, Garcia-Verdugo JM, Oldham MC, Yang Z, Alvarez-Buylla A |title=Positive Controls in Adults and Children Support That Very Few, If Any, New Neurons Are Born in the Adult Human Hippocampus |journal=J Neurosci |volume=41 |issue=12 |pages=2554–65 |date=March 2021 |pmid=33762407 |pmc=8018729 |doi=10.1523/JNEUROSCI.0676-20.2020 }}</ref> The role of new neurons in human adult brain function thus remains unclear.

==Mechanism==

===Adult neural stem cells===
{{main| Adult stem cell |Neural stem cell}}
Neural [[stem cell]]s (NSCs) are the self-renewing, [[multipotency|multipotent]] cells that generate the main [[phenotypes]] of the [[nervous system]].

=== Lineage reprogramming (trans-differentiation) ===
Emerging evidence suggests that neural microvascular pericytes, under instruction from resident glial cells, are reprogrammed into interneurons and enrich local neuronal microcircuits.<ref>{{cite journal|last1=Farahani|first1=Ramin M.|last2=Rezaei-Lotfi|first2=Saba|last3=Simonian|first3=Mary|last4=Xaymardan|first4=Munira|last5=Hunter|first5=Neil|date=2019|title=Neural microvascular pericytes contribute to human adult neurogenesis|journal=Journal of Comparative Neurology|language=en|volume=527|issue=4|pages=780–796|doi=10.1002/cne.24565|pmid=30471080|s2cid=53711787|issn=1096-9861}}</ref> This response is amplified by concomitant [[angiogenesis]].

==Model organisms of neurogenesis==
{{Main |Model organism}}

===Planarian===
[[Planarian]] are one of the earliest [[model organism]]s used to study [[Regeneration (biology)|regeneration]] with [[Peter Simon Pallas|Pallas]] as the forefather of planarian studies. Planarian are a classical invertebrate model that in recent decades have been used to examine neurogenesis. The central nervous system of a planarian is simple, though fully formed with two lobes located in the head and two [[ventral nerve cord]]s. This model reproduces asexually producing a complete and fully functioning nervous system after division allowing for consistent examination of neurogenesis.

===Axolotl===
The [[axolotl]] is less commonly used than other vertebrates, but is still a classical model for examining regeneration and neurogenesis. Though the axolotl has made its place in biomedical research in terms of limb regeneration,<ref>{{cite journal|last=Carlson|first=B. M.|date=December 1975|title=The effects of rotation and positional change of stump tissues upon morphogenesis of the regenerating axolotl limb|journal=Developmental Biology|volume=47|issue=2|pages=269–291|issn=0012-1606|pmid=1204936|doi=10.1016/0012-1606(75)90282-1|hdl=1874/15361|hdl-access=free}}</ref><ref>{{cite journal|last1=Kragl|first1=Martin|last2=Knapp|first2=Dunja|last3=Nacu|first3=Eugen|last4=Khattak|first4=Shahryar|last5=Maden|first5=Malcolm|last6=Epperlein|first6=Hans Henning|last7=Tanaka|first7=Elly M.|date=2009-07-02|title=Cells keep a memory of their tissue origin during axolotl limb regeneration|journal=Nature|volume=460|issue=7251|pages=60–65|doi=10.1038/nature08152|issn=1476-4687|pmid=19571878|bibcode=2009Natur.460...60K|s2cid=4316677}}</ref> the model organism has displayed a robust ability to generate new neurons following damage.<ref>{{cite journal|last1=Maden|first1=Malcolm|last2=Manwell|first2=Laurie A.|last3=Ormerod|first3=Brandi K.|date=2013-01-17|title=Proliferation zones in the axolotl brain and regeneration of the telencephalon|journal=Neural Development|volume=8|pages=1|doi=10.1186/1749-8104-8-1|issn=1749-8104|pmc=3554517|pmid=23327114 |doi-access=free }}</ref><ref>{{cite journal|last1=Clarke|first1=J. D.|last2=Alexander|first2=R.|last3=Holder|first3=N.|date=1988-06-17|title=Regeneration of descending axons in the spinal cord of the axolotl|journal=Neuroscience Letters|volume=89|issue=1|pages=1–6|issn=0304-3940|pmid=3399135|doi=10.1016/0304-3940(88)90471-5|s2cid=23650500}}</ref> Axolotls have contributed as a bridge organism between invertebrates and mammals, as the species has the regenerative capacity to undergo complete neurogenesis forming a wide range of neuronal populations not limited to a small niche,<ref>{{cite journal|last1=Amamoto|first1=Ryoji|last2=Huerta|first2=Violeta Gisselle Lopez|last3=Takahashi|first3=Emi|last4=Dai|first4=Guangping|last5=Grant|first5=Aaron K|last6=Fu|first6=Zhanyan|last7=Arlotta|first7=Paola|title=Adult axolotls can regenerate original neuronal diversity in response to brain injury|journal=eLife|volume=5|doi=10.7554/eLife.13998|issn=2050-084X|pmc=4861602|pmid=27156560|year=2016 |doi-access=free }}</ref> yet the complexity and architecture is complex and analogous in many ways to human neural development.

=== Zebrafish ===
[[Zebrafish]] have long been a classical [[Human development (biology)|developmental]] model due to their transparency during [[organogenesis]] and have been utilized heavily in early development neurogenesis.<ref>{{cite journal|last=Zupanc|first=G. K. H.|date=2006-06-01|title=Neurogenesis and neuronal regeneration in the adult fish brain|journal=Journal of Comparative Physiology A|language=en|volume=192|issue=6|pages=649–670|doi=10.1007/s00359-006-0104-y|pmid=16463148|s2cid=24063389|issn=0340-7594}}</ref><ref>{{cite journal|last1=Schmidt|first1=Rebecca|last2=Strähle|first2=Uwe|last3=Scholpp|first3=Steffen|date=2013-02-21|title=Neurogenesis in zebrafish — from embryo to adult|journal=Neural Development|volume=8|pages=3|doi=10.1186/1749-8104-8-3|issn=1749-8104|pmc=3598338|pmid=23433260 |doi-access=free }}</ref> The zebrafish displays a strong neurogenerative capacity capable of regenerating a variety of tissues and complete neuronal diversity (with the exception of [[astrocyte]]s, as they have yet to be identified within the zebrafish brain) with continued neurogenesis through the life span. In recent decades the model has solidified its role in adult regeneration and neurogenesis following damage.<ref>{{cite journal|last1=Hentig|first1=James T.|last2=Byrd-Jacobs|first2=Christine A.|date=2016-08-31|title=Exposure to Zinc Sulfate Results in Differential Effects on Olfactory Sensory Neuron Subtypes in Adult Zebrafish|journal=International Journal of Molecular Sciences|volume=17|issue=9|pages=1445|doi=10.3390/ijms17091445|issn=1422-0067|pmc=5037724|pmid=27589738|doi-access=free}}</ref><ref>{{cite journal|last1=Gorsuch|first1=Ryne A.|last2=Hyde|first2=David R.|date=June 2014|title=Regulation of Müller glial dependent neuronal regeneration in the damaged adult zebrafish retina|journal=Experimental Eye Research|volume=123|pages=131–140|doi=10.1016/j.exer.2013.07.012|issn=1096-0007|pmc=3877724|pmid=23880528}}</ref><ref>{{cite journal |last1=Trimpe |first1=D. M. |last2=Byrd-Jacobs |first2=C. A. |date=2016 |title=Patterns of olfactory bulb neurogenesis in the adult zebrafish are altered following reversible deafferentation |url=|journal=Neuroscience |volume=331 |pages=134–147 | pmid=27343831 | doi=10.1016/j.neuroscience.2016.06.026|pmc=6496944 }}</ref><ref>{{cite journal|last1=Kroehne|first1=Volker|last2=Freudenreich|first2=Dorian|last3=Hans|first3=Stefan|last4=Kaslin|first4=Jan|last5=Brand|first5=Michael|date=November 2011|title=Regeneration of the adult zebrafish brain from neurogenic radial glia-type progenitors|journal=Development|volume=138|issue=22|pages=4831–41|doi=10.1242/dev.072587|issn=1477-9129|pmid=22007133|doi-access=free}}</ref> The zebrafish, like the axolotl, has played a key role as a bridge organism between invertebrates and mammals. The zebrafish is a rapidly developing organism that is relatively inexpensive to maintain, while providing the field ease of genetic manipulation and a complex nervous system.

=== Chick ===
Though avians have been used primarily to study early embryonic development, in recent decades the developing [[Chicken|chick]] has played a critical role in the examination of neurogenesis and regeneration as the young chick is capable of neuronal-turnover at a young age, but loses the neurogenerative capacity into adulthood.<ref>{{cite journal|last=Fischer|first=Andy J.|date=March 2005|title=Neural regeneration in the chick retina|journal=Progress in Retinal and Eye Research|volume=24|issue=2|pages=161–182|doi=10.1016/j.preteyeres.2004.07.003|issn=1350-9462|pmid=15610972|s2cid=43652371}}</ref> The loss of neuroregenerative ability over maturation has allowed investigators to further examine genetic regulators of neurogenesis.

=== Rodents ===
{{Further|Animal testing on rodents}}
[[Rodent]]s, mice and rats, have been the most prominent model organism since the discovery of modern neurons by [[Santiago Ramón y Cajal|Santiago Ramon y Cajal]]. Rodents have a very similar architecture and a complex nervous system with very little regenerative capacity similar to that found in humans. For that reason, rodents have been heavily used in [[Pre-clinical development|pre-clinical testing]]. Rodents display a wide range of neural circuits responsible for complex behaviors making them ideal for studies of dendritic pruning and axonal shearing.<ref>{{cite journal|last1=Jones|first1=Theresa A.|last2=Schallert|first2=Timothy|date=1992-05-22|title=Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage|journal=Brain Research|volume=581|issue=1|pages=156–160|doi=10.1016/0006-8993(92)90356-E|pmid=1498666|s2cid=34248397}}</ref> While the organism makes for a strong human analog, the model has its limitations not found in the previous models: higher cost of maintenance, lower breeding numbers, and the limited neurogenerative abilities.

To some extent, adult neurogenesis in rodents may be induced by selective disruption of [[Notch signalling]] in [[astrocytes]]:<ref>{{cite journal |last1=Magnusson |first1=Jens |title=A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse |journal=Science |date=2014-10-10 |volume=346 |issue=6206 |pages=237–241 |doi=10.1126/science.346.6206.237 |pmid=25301628 |bibcode=2014Sci...346..237M |s2cid=14534396 |url=https://www.science.org/doi/abs/10.1126/science.346.6206.237|url-access=subscription }}</ref> this produces novel neurons which functionally integrate into the [[striatal]] circuit.<ref>{{cite journal |last1=Dorst |first1=Matthijs |title=Astrocyte-derived neurons provide excitatory input to the adult striatal circuitry |journal=Proceedings of the National Academy of Sciences |date=2021-08-17 |volume=118 |issue=33 |doi=10.1073/pnas.2104119118 |pmc=8379996  |pmid=34389674 |bibcode=2021PNAS..11804119D |doi-access=free }}</ref>

Adult neurogenesis in the subventricular zone and dentate gyrus of rodents generates [[oxidative stress]] and production of [[reactive oxygen species]] that can damage both [[DNA]] and [[lipid]]s.<ref name="Walton2012">{{cite journal |vauthors=Walton NM, Shin R, Tajinda K, Heusner CL, Kogan JH, Miyake S, Chen Q, Tamura K, Matsumoto M |title=Adult neurogenesis transiently generates oxidative stress |journal=PLOS ONE |volume=7 |issue=4 |pages=e35264 |date=2012 |pmid=22558133 |pmc=3340368 |doi=10.1371/journal.pone.0035264 |doi-access=free|bibcode=2012PLoSO...735264W }}</ref> The oxidative stress caused by postnatal neurogenesis may significantly contribute to the reduced [[learning]] and [[memory]] that occurs with increasing age.<ref name = Walton2012/>

=== Octopus ===

A [[cephalopod]] also known as the [[common octopus]], this organism has an intricate nervous system that demonstrates the brain's capacity to produce new cells. In this case and in other taxa when compared,  these organisms adapt to unpredictable environments by using newly formed brain cells.<ref>{{cite journal |vauthors=Di Cosmo A, Bertapelle C, Porcellini A, Polese G |title=Magnitude Assessment of Adult Neurogenesis in the ''Octopus vulgaris'' Brain Using a Flow Cytometry-Based Technique |journal=Front Physiol |volume=9 |pages=1050 |date=2018 |pmid=30116204 |pmc=6082961 |doi=10.3389/fphys.2018.01050 |doi-access=free}}</ref> This is over a short life-span (female about one year) where wild common octopuses focus most of their energy on mating and offspring care.<ref>{{cite book |last1=Di Cosmo |first1=A. |last2=Polese |first2=G. |chapter=Cephalopods meet neuroecology: the role of chemoreception in ''Octopus vulgaris'' reproductive behaviour |editor-first=A. |editor-last=Di Cosmo |editor2-first=W. |editor2-last=Winlow |title=Neuroecology and Neuroethology in Molluscs: The Interface Between Behaviour and Environment |publisher=NOVA Science |date=2014 |isbn=978-1-62948-983-4 |oclc=870272738 |pages=117–132 }}
</ref><ref name="pmid25449183">{{cite journal | vauthors = Polese G, Bertapelle C, Di Cosmo A | title = Role of olfaction in Octopus vulgaris reproduction | journal = Gen. Comp. Endocrinol. | volume = 210 | pages = 55–62 | date = January 2015 | pmid = 25449183 | doi = 10.1016/j.ygcen.2014.10.006 }}</ref> Findings suggest that the octopus vulgaris like other short-lived species have a complex hippocampal proliferation,<ref name="pmid18957357">{{cite journal | vauthors = Amrein I, Lipp HP | title = Adult hippocampal neurogenesis of mammals: evolution and life history | journal = Biol. Lett. | volume = 5 | issue = 1 | pages = 141–4 | date = February 2009 | pmid = 18957357 | pmc = 2657751 | doi = 10.1098/rsbl.2008.0511 }}</ref><ref name="pmid21929629">{{cite journal | vauthors = Amrein I, Isler K, Lipp HP | title = Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage | journal = Eur. J. Neurosci. | volume = 34 | issue = 6 | pages = 978–87 | date = September 2011 | pmid = 21929629 | doi = 10.1111/j.1460-9568.2011.07804.x | s2cid = 36231667 | url = https://www.zora.uzh.ch/id/eprint/54811/1/ComparingAdultHippocampalNeurogenesisInMammalianSpeciesAndOrders.pdf }}</ref> needed for spatial/navigation, and short and long-term memory.<ref>[[Hippocampus]]</ref>{{Circular reference|date=May 2020}}

=== Chickadees ===
{{Further information|Adult neurogenesis in songbirds}}
[[Black-capped chickadees]] are a well-known [[model species]] in the field of neuroscience for their neural mechanisms in [[Bird vocalization|song vocalization]], [[Synaptic plasticity|plasticity]], and memory. Black-capped chickadees are different from other species in the larger group of songbirds because they are characterized by food-caching behaviors. Due to this behavior, chickadees can be described through their remarkable [[spatial memory]]. Seasonal changes in hippocampal densities have been described since 1994<ref name=":1">{{cite journal|last1=Barnea|first1=A.|last2=Nottebohm|first2=F.|date=1994-11-08|title=Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees.|journal=Proceedings of the National Academy of Sciences|volume=91|issue=23|pages=11217–21|doi=10.1073/pnas.91.23.11217|pmid=7972037|pmc=45198|bibcode=1994PNAS...9111217B|issn=0027-8424|doi-access=free}}</ref> where neuronal survival peaks during the fall (October),<ref name=":1" /> measured by [[thymidine]] (see tracking neurogenesis below) labeled cells, weeks after injection.<ref name=":1" /> When compared to non-food caching birds such as the house sparrow, chickadees had significantly more hippocampal neuron recruitment from fall to spring.<ref name=":2">{{cite journal|last1=Hoshooley|first1=Jennifer S.|last2=Sherry|first2=David F.|date=March 2007|title=Greater hippocampal neuronal recruitment in food-storing than in non-food-storing birds|journal=Developmental Neurobiology|volume=67|issue=4|pages=406–414|doi=10.1002/dneu.20316|pmid=17443797|s2cid=15930160|issn=1932-8451|doi-access=free}}</ref> The changes in hippocampal density is directly associated with increased hoarding behavior,<ref name=":2" /> especially during the winter when better spatial memory maximizes their survival.

Over the 2 decades since the initial discovery,<ref name=":1" /> the specific role of chickadee hippocampus in memory has gained wide attention. In an experimental setting, hippocampal lesions affect memory for locations,<ref>{{cite journal|last1=Hampton|first1=Robert R.|last2=Shettleworth|first2=Sara J.|date=1996|title=Hippocampal lesions impair memory for location but not color in passerine birds.|url=|journal=Behavioral Neuroscience|volume=110|issue=4|pages=831–5|doi=10.1037/0735-7044.110.4.831|pmid=8864273|issn=1939-0084}}</ref> validating previous notions for this specific role. Further, experimentally inhibiting neuronal proliferation decreases scores on spatial memory tasks,<ref>{{cite journal|last1=Hall|first1=Zachary J.|last2=Delaney|first2=Shauna|last3=Sherry|first3=David F.|date=2014-04-28|title=Inhibition of cell proliferation in black-capped chickadees suggests a role for neurogenesis in spatial learning|url=|journal=Developmental Neurobiology|volume=74|issue=10|pages=1002–10|doi=10.1002/dneu.22180|pmid=24723376|s2cid=17537082|issn=1932-8451}}</ref> supporting that new neurons hold the same role as pre-existing ones. The specific function of the hippocampus, coupled with seasonal changes in their volume, point towards their temporary advantages for spatial memory consolidation. Taken all together, adult neurogenesis in the hippocampus of black-capped chickadees suggest a selective mechanisms for neuronal survival in direct correlation with seasonal food caching behavior.

Developmentally, [[progenitor cell]]s called [[Radial glial cell|radial glial]] cells are thought to mitigate newly born neurons to their destinations.<ref>{{cite journal|last=Doetsch|first=Fiona|date=2003-10-28|title=The glial identity of neural stem cells|url=|journal=Nature Neuroscience|volume=6|issue=11|pages=1127–34|doi=10.1038/nn1144|pmid=14583753|s2cid=16088822|issn=1097-6256}}</ref> Radial glial cells extend processes from their soma in the avian ventricular zone to the parenchyma of the adult forebrain.<ref name=":3">{{cite journal|last1=Sherry|first1=David F.|last2=Hoshooley|first2=Jennifer S.|date=2010-03-27|title=Seasonal hippocampal plasticity in food-storing birds|url= |journal=Philosophical Transactions of the Royal Society B: Biological Sciences|volume=365|issue=1542|pages=933–943|doi=10.1098/rstb.2009.0220|pmid=20156817|issn=0962-8436|pmc=2830249}}</ref> These new neurons have been observed as early as 3 days after thymidine administration in the HVC<ref>{{cite journal|last1=Kirn|first1=John R.|last2=Fishman|first2=Yon|last3=Sasportas|first3=Kari|last4=Alvarez-Buylla|first4=Arturo|last5=Nottebohm|first5=Fernando|date=1999-08-30|title=Fate of new neurons in adult canary high vocal center during the first 30 days after their formation|journal=The Journal of Comparative Neurology|volume=411|issue=3|pages=487–494|doi=10.1002/(sici)1096-9861(19990830)411:3<487::aid-cne10>3.0.co;2-m|pmid=10413781|s2cid=24242592 |issn=0021-9967}}</ref> and as early as 7 days before reaching the hippocampus.<ref name=":2" /> Avian migration of new neurons are analogous to mammalian species,<ref name=":3" /> providing a future direction in exploring neurogenesis in mammalian species and beyond. However, captivity has been shown to reduce hippocampal volumes when compared to wild counterparts.<ref name=":4">{{cite journal|last1=Tarr|first1=Bernard A.|last2=Rabinowitz|first2=Jeremy S.|last3=Imtiaz|first3=Mubdiul Ali|last4=DeVoogd|first4=Timothy J.|date=December 2009|title=Captivity reduces hippocampal volume but not survival of new cells in a food-storing bird|url= |journal=Developmental Neurobiology|volume=69|issue=14|pages=972–981|doi=10.1002/dneu.20736|pmid=19813245|issn=1932-8451|pmc=4597778}}</ref> Reduced neurogenesis in captive birds may be caused by stress, lack of exercise, diminished social interaction, and limited caching opportunities.<ref name=":4" />

==Tracking neurogenesis==
The creation of new functional [[neuron]]s can be measured in several ways,<ref>{{cite journal |author1=Aimone J. B. |author2=Li Y. |author3=Lee S. W. |author4=Clemenson G. D. |author5=Deng W. |author6=Gage F. H. | year = 2014 | title = Regulation and Function of Adult Neurogenesis: From Genes to Cognition | journal = Physiological Reviews | volume = 94 | issue = 4| pages = 991–1026 | doi=10.1152/physrev.00004.2014|pmid=25287858 |pmc=4280160 }}</ref> summarized in the following sections.

=== DNA labelling ===
Labelled [[DNA]] can trace dividing cell's lineage, and determine the location of its daughter cells. A [[nucleic acid]] analog is inserted into the [[genome]] of a neuron-generating cell (such as a [[neuroglia|glial cell]] or [[neural stem cell]]).<ref name="Ming, Guo-Li 2011">{{cite journal | author = Ming Guo-Li, Song Hongjun | year = 2011 | title = Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions | journal = Neuron | volume = 70 | issue = 4| pages = 687–702 | doi=10.1016/j.neuron.2011.05.001 | pmid=21609825 | pmc=3106107}}</ref> [[Thymine]] analogs (3H) [[thymidine]]<ref name=Altman62/> and [[Bromodeoxyuridine|BrdU]]<ref>{{cite journal |vauthors=Kuhn HG, Cooper-Kuhn CM | year = 2007 | title = Bromodeoxyuridine and the detection of neurogenesis | journal = Curr Pharmaceutical Biotechnol | volume = 8 | issue = 3| pages = 127–131 | doi = 10.2174/138920107780906531 | pmid = 17584085 }}</ref> are commonly used DNA labels, and are used for [[Radioactive tracer|radiolabelling]] and [[immunohistochemistry]] respectively.

=== Fate determination via neuronal lineage markers ===
[[DNA]] labeling can be used in conjunction with [[neuronal lineage marker]]s to determine the [[Cell fate determination|fate]] of new functional [[neuron|brain cells]]. First, incorporated labeled [[nucleotide]]s are used to detect the populations of newly [[Cell division|divided daughter cells]]. Specific cell types are then determined with unique differences in their [[Regulation of gene expression|expression]] of [[protein]]s, which can be used as [[antigen]]s in an [[immunoassay]]. For example, [[NeuN|NeuN/Fox3]] and [[Glial fibrillary acidic protein|GFAP]] are [[antigen]]s commonly used to detect [[neuron]]s, [[neuroglia|glia]], and [[Ependyma|ependymal cells]]. [[Ki-67 (protein)|Ki67]] is the most commonly used antigen to detect [[Cell division|cell proliferation]]. 
Some [[antigen]]s can be used to measure specific [[stem cell]] stages. For example, stem cells requires the [[sox2]] gene to maintain [[pluripotency]] and is used to detect enduring concentrations of stem cells in [[central nervous system|CNS tissue]]. The [[protein]] [[Nestin (protein)|nestin]] is an [[Intermediate filaments|intermediate filament]], which is essential for the radial growth of [[axon]]s, and is therefore used to detect the formation of new [[synapse]]s.

===Cre-Lox recombination===

Some genetic tracing studies utilize [[Cre-Lox recombination|cre-lox recombination]] to bind a [[Promoter (genetics)|promoter]] to a [[reporter gene]], such as [[lac operon|lacZ]] or [[Green fluorescent protein|GFP gene]].<ref name="Ming, Guo-Li 2011"/><ref>{{cite journal |vauthors=Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S, Kageyama R | year = 2008 | title = Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain | journal = Nat Neurosci | volume = 11 | issue = 10| pages = 1153–61 | doi=10.1038/nn.2185| pmid = 18758458 | s2cid = 11627647 }}</ref> This method can be used for long term quantification of cell division and labeling, whereas the previously mentioned procedures are only useful for short-term quantification.

===Viral vectors===

It has recently become more common to use [[Recombinant DNA|recombinant]] viruses to insert the [[Nucleic acid sequence|genetic information]] encoding specific [[Biomarker|markers]] (usually protein [[fluorophore]]s such as [[Green fluorescent protein|GFP]]) that are only [[Gene expression|expressed]] in [[Cell (biology)|cells]] of a certain kind. The marker gene is inserted [[Downstream promoter element|downstream]] of a [[Promoter (genetics)|promoter]], leading to [[Transcription (biology)|transcription]] of that marker only in cells containing the [[Transcription factor|transcription factor(s)]] that bind to that promoter. For example, a recombinant [[plasmid]] may contain the promoter for [[doublecortin]], a protein expressed predominantly by [[neuron]]s, upstream of a sequence coding for [[Green fluorescent protein|GFP]], thereby making infected cells [[Fluorescence|fluoresce]] green upon exposure to light in the blue to ultraviolet range<ref>{{cite journal|last1=Prendergast|first1=Franklyn G.|last2=Mann|first2=Kenneth G.|date=1978-08-22|title=Chemical and physical properties of aequorin and the green fluorescent protein isolated from Aequorea forskalea|journal=Biochemistry|volume=17|issue=17|pages=3448–53|doi=10.1021/bi00610a004|pmid=28749|issn=0006-2960}}</ref> while leaving non [[doublecortin]] expressing cells unaffected, even if they contain the [[plasmid]]. Many cells will contain multiple copies of the plasmid and the fluorophore itself, allowing the fluorescent properties to be transferred along an infected cell's [[Cell lineage|lineage]].

By labeling a cell that gives rise to neurons, such as a [[neural stem cell]]s or neural precursor cells, one can track the creation, proliferation, and even migration of newly created neurons.<ref>{{cite journal|last1=Gonçalves|first1=J. Tiago|last2=Schafer|first2=Simon T.|last3=Gage|first3=Fred H.|title=Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior|journal=Cell|volume=167|issue=4|pages=897–914|doi=10.1016/j.cell.2016.10.021|pmid=27814520|year=2016|doi-access=free}}</ref> It is important to note, however, that while the plasmid is stable for long periods of time, its protein products may have highly variable [[Half-life|half lives]] and their fluorescence may decrease as well as become too diluted to be seen depending on the number of round of replication they have undergone, making this method more useful for tracking self-similar neural precursor or neural stem cells rather than neurons themselves. The insertion of [[Genome|genetic material]] via a [[viral vector]] tends to be sporadic and infrequent relative to the total number of cells in a given region of [[Tissue (biology)|tissue]], making quantification of cell division inaccurate. However, the above method can provide highly accurate data with respect to when a cell was [[cell growth|born]] as well as full cellular [[Morphology (biology)|morphologies]].<ref>{{cite journal |vauthors=Zhao C, Teng EM, ((Summers RG Jr)), Ming GL, Gage FH | year = 2006 | title = Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus | journal = J Neurosci | volume = 26 | issue = 1| pages = 3–11 | doi=10.1523/jneurosci.3648-05.2006| pmid = 16399667 | pmc = 6674324 }}</ref>

== Methods for inhibiting neurogenesis ==
Many studies analyzing the role of adult neurogenesis utilize a method of inhibiting cell proliferation in specific brain regions, mimicking an inhibition of neurogenesis, to observe the effects on behavior.<ref name=":0" />

=== Pharmacological inhibition ===
Pharmacological inhibition is widely used in various studies, as it provides many benefits. It is generally inexpensive as compared to other methods, such as irradiation, can be used on various species, and does not require any invasive procedures or surgeries for the subjects.

However, it does pose certain challenges, as these inhibitors can't be used to inhibit proliferation in specific regions, thus leading to nonspecific effects from other systems being affected. To avoid these effects, more work must be done to determine optimal doses in order to minimize the effects on systems unrelated to neurogenesis.

A common pharmacological inhibitor for adult neurogenesis is methylazoxymethanol acetate (MAM), a chemotherapeutic agent. Other cell division inhibitors commonly used in studies are cytarabine and temozolomide.

=== Pharmacogenetics ===
Another method used to study the effects of adult neurogenesis is using pharmacogenetic models. These models provide different benefits from the pharmacological route, as it allows for more specificity by targeting specific precursors to neurogenesis and specific stem cell promoters. It also allows for temporal specificity with the interaction of certain drugs. This is beneficial in looking specifically at neurogenesis in adulthood, after normal development of other regions in the brain.

The herpes simplex virus thymidine kinase (HSV-TK) has been used in studies in conjunction with antiviral drugs to inhibit adult neurogenesis. It works by targeting stem cells using glial fibrillary acidic proteins and nestin expression. These targeted stem cells undergo cell death instead of cell proliferation when exposed to antiviral drugs.

Cre protein is also commonly used in targeting stem cells that will undergo gene changes upon treatment with tamoxifen.

=== Irradiation ===
Irradiation, the process of exposing parts of something or someone to radiation, is a method that allows for very specific inhibition of adult neurogenesis. It can be targeted to the brain to avoid affecting other systems and having nonspecific effects. It can even be used to target specific brain regions, which is important in determining how adult neurogenesis in different areas of the brain affects behavior.

Irradiation has previously been tested in adult rats, with no significant changes in cognition having been reported. However, neurogenesis in this study was stopped from progressing when the irradiation was specifically directed towards the hippocampus.<ref>{{cite journal |last1=Lensu |first1=S. |last2=Mäkinen |first2=E. |last3=Pekkala |first3=S. |last4=Waselius |first4=T. |last5=Penttonen |first5=M |last6=Nokia |first6=M.S. |last7=Kettunen |first7=H. |last8=Virtanen |first8=A. |last9=Tiirola |first9=M. |date=March 2021 |title=Irradiation of the head reduces adult hippocampal neurogenesis and impairs spatial memory, but leaves overall health intact in rats |url=http://urn.fi/URN:NBN:fi:jyu-202101141087|journal=European Journal of Neuroscience |volume=53 |issue=6 |pages=1885–1904 |doi=10.1111/ejn.15102 |pmid=33382141 |s2cid=229930018 |via=EBSCO}}</ref>

However, irradiation is more expensive than the other methods and also requires large equipment with trained individuals.

== Inhibition of adult neurogenesis in the hippocampus ==
Many studies have observed how inhibiting adult neurogenesis in other mammals, such as rats and mice, affects their behavior.<ref name=":0" /> Inhibition of adult neurogenesis in the hippocampus has been shown to have various effects on learning and memory, conditioning, and investigative behaviors.

Impaired fear conditioning has been seen in studies involving rats with a lack of adult neurogenesis in the hippocampus.<ref>{{cite journal|last1=Shors|first1=Tracey J.|last2=Miesegaes|first2=George|last3=Beylin|first3=Anna|last4=Zhao|first4=Mingrui|last5=Rydel|first5=Tracy|last6=Gould|first6=Elizabeth|title=Neurogenesis in the adult is involved in the formation of trace memories|journal=Nature|volume=410|issue=6826|pages=372–6|doi=10.1038/35066584|pmid=11268214|year=2001|bibcode=2001Natur.410..372S|s2cid=4430850}}</ref> Inhibition of adult neurogenesis in the hippocampus has also been linked to changes in behavior in tasks involving investigation.<ref>{{cite journal|last1=Denny|first1=Christine A.|last2=Burghardt|first2=Nesha S.|last3=Schachter|first3=Daniel M.|last4=Hen|first4=René|last5=Drew|first5=Michael R.|date=2012-05-01|title=4- to 6-week-old adult-born hippocampal neurons influence novelty-evoked exploration and contextual fear conditioning|journal=Hippocampus|language=en|volume=22|issue=5|pages=1188–1201|doi=10.1002/hipo.20964|issn=1098-1063|pmc=3193906|pmid=21739523}}</ref> Rats also show decreased contextualized freezing behaviors in response to contextualized fear and impairment in learning spatial locations when lacking adult neurogenesis.<ref>{{cite journal|title=The Journal of Neurosci|journal=The Journal of Neuroscience|volume=26|issue=34|pages=8767–73|doi=10.1523/JNEUROSCI.1134-06.2006|pmid=16928865|pmc=1808348|year=2006|last1=Plack|first1=C. J.|last2=Oxenham|first2=A. J.|last3=Drga|first3=V.}}</ref><ref>{{cite journal|last1=Drew|first1=Michael R.|last2=Denny|first2=Christine A.|last3=Hen|first3=Rene|title=Arrest of adult hippocampal neurogenesis in mice impairs single- but not multiple-trial contextual fear conditioning.|journal=Behavioral Neuroscience|volume=124|issue=4|pages=446–454|doi=10.1037/a0020081|pmc=2925248|pmid=20695644|year=2010}}</ref>

=== Effects on pattern separation ===
The changes in learning and memory seen in the studies mentioned previously are thought to be related to the role of adult neurogenesis in regulating pattern separation.<ref name=":0" /> Pattern separation is defined as "a process to remove redundancy from similar inputs so that events can be separated from each other and interference can be reduced, and in addition can produce a more orthogonal, sparse, and categorized set of outputs."<ref>{{cite journal|last=Kesner|first=Raymond P.|date=2013-10-01|title=An analysis of the dentate gyrus function|journal=Behavioural Brain Research|series=SI:Medial Temporal Lobe Memory Networks|volume=254|pages=1–7|doi=10.1016/j.bbr.2013.01.012|pmid=23348108|s2cid=5486456}}</ref>

This impairment in pattern separation could explain the impairments seen in other learning and memory tasks. A decreased ability in reducing interference could lead to greater difficulty in forming and retaining new memories,<ref name=":0" /> although it's hard to discriminate between effects of neurogenesis in learning and pattern separation due to limitations in the interpretation of behavioral results.<ref name="França17">{{cite journal|last1=França|first1= Thiago F.A.|last2= Bitencourt|first2= Alexandre M.|last3= Maximilla|first3= Naiana R.|last4= Barros|first4= Daniela M.|last5= Monserrat|first5= Jose M.|date=2017-07-20|title=Hippocampal neurogenesis and pattern separation: a meta-analysis of behavioral data|journal=Hippocampus|series=9|volume=27|issue= 9|pages=937–950|doi=10.1002/hipo.22746|pmid= 28597491|s2cid= 205914396}}</ref>

Studies show that rats with inhibited adult neurogenesis demonstrate difficulty in differentiating and learning contextualized fear conditioning.<ref name=":0" /> Rats with blocked adult neurogenesis also show impaired differential freezing when they are required to differentiate between similar contexts.<ref>{{cite journal|last1=Sahay|first1=Amar|last2=Scobie|first2=Kimberly N.|last3=Hill|first3=Alexis S.|last4=O'Carroll|first4=Colin M.|last5=Kheirbek|first5=Mazen A.|last6=Burghardt|first6=Nesha S.|last7=Fenton|first7=André A.|author-link7=André Fenton|last8=Dranovsky|first8=Alex|last9=Hen|first9=René|year=2011|title=Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation|journal=Nature|volume=472|issue=7344|pages=466–470|bibcode=2011Natur.472..466S|doi=10.1038/nature09817|pmc=3084370|pmid=21460835}}</ref> This also affects their spatial recognition in radial arm maze tests when the arms are closer together rather than when they are further apart.<ref>{{cite journal|last1=Clelland|first1=C. D.|last2=Choi|first2=M.|last3=Romberg|first3=C.|last4=Clemenson|first4=G. D.|last5=Fragniere|first5=A.|last6=Tyers|first6=P.|last7=Jessberger|first7=S.|last8=Saksida|first8=L. M.|author-link8=Lisa Saksida|last9=Barker|first9=R. A.|date=2009-07-10|title=A functional role for adult hippocampal neurogenesis in spatial pattern separation|journal=Science|volume=325|issue=5937|pages=210–3|bibcode=2009Sci...325..210C|doi=10.1126/science.1173215|issn=1095-9203|pmc=2997634|pmid=19590004}}</ref> A meta-analysis of behavioral studies evaluating the effect of neurogenesis in different pattern separation tests has shown a consistent effect of neurogenesis ablation on performance, although there are exceptions in the literature.<ref name="França17"/>

=== Effects on behavioral inhibition ===
Behavioral inhibition is important in rats and other animals in halting whatever they are currently doing in order to reassess a situation in response to a threat or anything else that may require their attention.<ref name=":0" />

Rats with lesioned hippocampi show less behavioral inhibition when exposed to threats, such as cat odor.<ref>{{cite journal|last1=Kheirbek|first1=Mazen A.|last2=Drew|first2=Liam J.|last3=Burghardt|first3=Nesha S.|last4=Costantini|first4=Daniel O.|last5=Tannenholz|first5=Lindsay|last6=Ahmari|first6=Susanne E.|last7=Zeng|first7=Hongkui|last8=Fenton|first8=André A.|last9=Hen|first9=René|date=2013-03-06|title=Differential control of learning and anxiety along the dorsoventral axis of the dentate gyrus|journal=Neuron|volume=77|issue=5|pages=955–968|doi=10.1016/j.neuron.2012.12.038|issn=1097-4199|pmc=3595120|pmid=23473324}}</ref> The disruption of normal cell proliferation and development of the dentate gyrus in developing rats also impairs their freezing response, which is an example of behavior inhibition, when exposed to an unfamiliar adult male rat.<ref>{{cite journal |vauthors=Gould E, Cameron HA | year = 1997 | title = Early NMDA receptor blockade impairs defensive behavior and increases cell proliferation in the dentate gyrus of developing rats | journal = Behav. Neurosci. | volume = 111 | issue = 1| pages = 49–56 | doi=10.1037/0735-7044.111.1.49| pmid = 9109623 }}</ref>

This impairment in behavioral inhibition also ties into the process of learning and memory, as repressing wrong answers or behaviors requires the ability to inhibit that response.<ref name=":0" />

==Implications==

===Role in learning===

The functional relevance of adult neurogenesis is uncertain,<ref>{{cite journal |vauthors=Kempermann G, Wiskott L, Gage FH |title=Functional significance of adult neurogenesis |journal=Current Opinion in Neurobiology  |volume=14 |issue=2 |pages=186–91 |date=April 2004  |pmid=15082323 |doi=10.1016/j.conb.2004.03.001 |s2cid=6241827 }}</ref> but there is some evidence that hippocampal adult neurogenesis is important for [[learning]] and [[memory]].<ref name="G. Neves 2008 65–75">{{cite journal|last1=G. Neves |author2=S.F. Cooke |author3=T.V. Bliss|year=2008|title=Synaptic plasticity, memory and the hippocampus: A neural network approach to causality|journal=Nature Reviews Neuroscience|volume=9|pages=65–75|doi=10.1038/nrn2303|pmid=18094707|first1=G|issue=1|s2cid=33104731 }}</ref> 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,<ref>{{cite journal |author=Becker S |title=A computational principle for hippocampal learning and neurogenesis |journal=Hippocampus |volume=15 |issue=6 |pages=722–38 |year=2005 |pmid=15986407 |doi=10.1002/hipo.20095 |s2cid=1316469 }}</ref> reduce interference between memories,<ref>{{cite journal |vauthors=Wiskott L, Rasch MJ, Kempermann G |title=A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus |journal=Hippocampus |volume=16 |issue=3 |pages=329–43 |year=2006 |pmid=16435309 |doi=10.1002/hipo.20167 |citeseerx=10.1.1.408.8944 |s2cid=788860 }}</ref> or add information about time to memories.<ref>{{cite journal |vauthors=Aimone JB, Wiles J, Gage FH |title=Potential role for adult neurogenesis in the encoding of time in new memories |journal=Nat. Neurosci. |volume=9 |issue=6 |pages=723–7 |date=June 2006 |pmid=16732202 |doi=10.1038/nn1707 |s2cid=10586519 }}</ref> Given that the rate of the neurogenesis does not change substantially during the adulthood, it has been proposed that unique [[episodic memories]] can be created by simply relying on the increased capacity of the young neurons of a particular age to establish stable new [[synapses]] with peers representing the unique features of an event to be memorized <ref>{{cite journal | vauthors = Kovács KA | title = Episodic Memories: How do the Hippocampus and the Entorhinal Ring Attractors Cooperate to Create Them? | journal = Frontiers in Systems Neuroscience | volume = 14 | pages = 68 | date = September 2020 | doi = 10.3389/fnsys.2020.559186 | pmid = 33013334 | pmc = 7511719 | doi-access = free }}</ref> Experiments aimed at ablating neurogenesis have proven inconclusive, but several studies have proposed neurogenic-dependence in some types of learning,<ref>{{cite journal |vauthors=Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E |title=Neurogenesis may relate to some but not all types of hippocampal-dependent learning |journal=Hippocampus |volume=12 |issue=5 |pages=578–84 |year=2002 |pmid=12440573 |doi=10.1002/hipo.10103 |pmc=3289536}}</ref> and others seeing no effect.<ref>{{cite journal  |vauthors=Meshi D, Drew MR, Saxe M, etal |title=Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment |journal=Nat. Neurosci. |volume=9 |issue=6 |pages=729–31 |date=June 2006 |pmid=16648847 |doi=10.1038/nn1696 |s2cid=11043203 }}</ref> Studies have demonstrated that the act of learning itself is associated with increased neuronal survival.<ref>{{harvnb|Gould|Beylin|Tanapat|Reeves|Shors|1999|pp=260–5}}</ref> However, the overall findings that adult neurogenesis is important for any kind of learning are equivocal.

===Alzheimer's disease===

Some studies suggest that decreased hippocampal neurogenesis can lead to development of [[Alzheimer's disease]] (AD).<ref name="Donovan et al, 2006">{{cite journal | pmid = 16432899| year = 2006| last1 = Donovan| first1 = M. H.| title = Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease| journal = The Journal of Comparative Neurology| volume = 495| issue = 1| pages = 70–83| last2 = Yazdani| first2 = U| last3 = Norris| first3 = R. D.| last4 = Games| first4 = D| last5 = German| first5 = D. C.| last6 = Eisch| first6 = A. J.| doi = 10.1002/cne.20840| s2cid = 20559097}}</ref> Yet, others hypothesize that AD patients have increased neurogenesis in the CA1 region of Ammon's horn (the principal region of AD hippocampal pathology) in order to compensate for neuronal loss.<ref name="Jin et al, 2003">{{cite journal | pmid = 14660786| pmc = 314187| year = 2004| last1 = Jin| first1 = K| title = Increased hippocampal neurogenesis in Alzheimer's disease| journal = Proceedings of the National Academy of Sciences| volume = 101| issue = 1| pages = 343–7| last2 = Peel| first2 = A. L.| last3 = Mao| first3 = X. O.| last4 = Xie| first4 = L| last5 = Cottrell| first5 = B. A.| last6 = Henshall| first6 = D. C.| last7 = Greenberg| first7 = D. A.| doi = 10.1073/pnas.2634794100| bibcode = 2004PNAS..101..343J| doi-access = free}}</ref> While the exact nature of the relationship between neurogenesis and Alzheimer's disease is unknown, [[insulin-like growth factor 1]]-stimulated neurogenesis produces major changes in hippocampal plasticity and seems to be involved in Alzheimer's pathology.<ref name="Foster et al, 2011">{{cite journal | pmid = 21602910| pmc = 3092070| year = 2011| last1 = Foster| first1 = P. P.| title = Exercise-induced cognitive plasticity, implications for mild cognitive impairment and Alzheimer's disease| journal = Frontiers in Neurology| volume = 2| pages = 28| last2 = Rosenblatt| first2 = K. P.| last3 = Kuljiš| first3 = R. O.| doi = 10.3389/fneur.2011.00028| doi-access = free}}</ref> [[Allopregnanolone]], a [[neurosteroid]], aids the continued neurogenesis in the brain. Levels of allopregnanolone in the brain decline in [[old age]] and Alzheimer's disease.<ref>{{cite journal  |vauthors=Marx CE, Trost WT, Shampine LJ, etal |title=The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease |journal=Biol. Psychiatry |volume=60 |issue=12 |pages=1287–94 |date=December 2006 |pmid=16997284 |doi=10.1016/j.biopsych.2006.06.017 |s2cid=27813000 }}</ref> Allopregnanolone has been shown through reversing impairment of neurogenesis to reverse the [[cognitive deficit]]s in a [[mouse model]] of Alzheimer's disease.<ref>{{cite journal |vauthors=Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD | year = 2010 | title = Allopregnanolone reverses neuron and cognitive deficits in a mouse model of Alzheimer's disease | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 14| pages = 6498–6503 | doi = 10.1073/pnas.1001422107 | pmc = 2851948 | pmid = 20231471 |bibcode = 2010PNAS..107.6498W | doi-access = free }}</ref> [[Eph receptor]]s and [[ephrin]] signaling have been shown to regulate adult neurogenesis in the [[hippocampus]] and have been studied as potential targets to treat some symptoms of AD.<ref>{{cite journal | pmid = 25193466| year = 2014| last1 = Cissé| first1 = M| title = Eph receptors: New players in Alzheimer's disease pathogenesis| journal = Neurobiology of Disease| volume = 73C| pages = 137–149| last2 = Checler| first2 = F| doi = 10.1016/j.nbd.2014.08.028| s2cid = 28922292}}</ref> Molecules associated with the pathology of AD, including [[ApoE]], [[Photosystem I|PS1]] and [[Amyloid precursor protein|APP]], have also been found to impact adult neurogenesis in the hippocampus.<ref>{{cite journal | pmid = 22192775| pmc = 3261815| year = 2011| last1 = Mu| first1 = Y| title = Adult hippocampal neurogenesis and its role in Alzheimer's disease| journal = Molecular Neurodegeneration| volume = 6| pages = 85| last2 = Gage| first2 = F. H.| doi = 10.1186/1750-1326-6-85| doi-access = free}}</ref>

===Schizophrenia===
Studies suggest that people with [[schizophrenia]] have a reduced hippocampus volume, which is believed to be caused by a reduction of adult neurogenesis.  Correspondingly, this phenomenon might be the underlying cause of many of the symptoms of the disease. Furthermore, several research papers referred to four genes, dystrobrevin binding protein 1 (DTNBP1), neuregulin 1 (NRG1), disrupted in schizophrenia 1 (DISC1), and neuregulin 1 receptor (ERBB4), as being possibly responsible for this deficit in the normal regeneration of neurons.<ref>{{cite journal|last1=LeStrat|first1=Y|title=The role of genes involved in neuroplasticity and neurogenesis in the observation of a gene-environment interaction (GxE) in schizophrenia|journal=Current Molecular Medicine|date=May 2009|volume=9|pages=506–18|doi=10.2174/156652409788167104|pmid=19519407|issue=4}}<!--|access-date=2 December 2014--></ref><ref>{{cite journal|last1=Schreiber|first1=Rudy|last2=Newman-Tancredi|first2=Adrian|journal=Neurobiology of Learning and Memory|date=April 2014|volume=110|pages=72–80|doi=10.1016/j.nlm.2013.12.015|pmid=24423786|title=Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT1A receptor activation|s2cid=28027825}}</ref> Similarities between depression and schizophrenia suggest a possible biological link between the two diseases. However, further research must be done in order to clearly demonstrate this relationship.<ref>{{cite journal|last1=Reif|first1=Andreas|last2=Schmitt|first2=Angelika|last3=Fritzen|first3=Sabrina|last4=Lesch|first4=Klaus-Peter|title=Neurogenesis and schizophrenia: dividing neurons in a divided mind?|journal=European Archives of Psychiatry and Clinical Neuroscience|date=27 Apr 2007|volume=257|issue=5|pages=290–9|doi=10.1007/s00406-007-0733-3|pmid=17468935|s2cid=28750292}}</ref>

===Stress and depression===

Many now believe stress to be the most significant factor for the onset of [[depression (mood)|depression]]. As discussed above, hippocampal cells are sensitive to stress which can lead to decreased neurogenesis. This area is being considered more frequently when examining the causes and treatments of depression. Studies have shown that removing the [[adrenal gland]] in rats caused increased neurogenesis in the [[dentate gyrus]].<ref name="Jacobs, B. L., H. van Praag, F. H. Gage 2000">{{cite journal |author=Jacobs, B. L. |author2=H. van Praag |author3=F. H. Gage |title=Depression and the Birth and Death of Brain Cells |journal=American Scientist |volume=88 |issue=4 |pages=340 |year=2000|bibcode=2000AmSci..88..340J |doi=10.1511/2000.4.340 }}</ref> The adrenal gland is responsible for producing [[cortisol]] in response to a stressor, a substance that when produced in chronic amounts causes the down regulation of [[serotonin]] receptors and suppresses the birth of neurons.<ref>{{cite book | author= Kandel, E. R. | author2= J. H. Schwartz | author3= T. M. Jessell | title = Principles of Neural Science | edition = 5th |date=  2012 | publisher= McGraw Hill | isbn=978-0-07-139011-8 |oclc=814321650}}</ref> It was shown in the same study that administration of corticosterone to normal animals suppressed neurogenesis, the opposite effect.<ref name="Jacobs, B. L., H. van Praag, F. H. Gage 2000"/> The most typical class of antidepressants administered for this disease are [[selective serotonin reuptake inhibitors]] (SSRIs)<ref>{{cite web | author = National Institute of Mental Health | year = 2010 | title = Mental Health Medications | url = http://www.nimh.nih.gov/health/publications/mental-health-medications/nimh-mental-health-medications.pdf }}</ref> and their efficacy may be explained by neurogenesis. In a normal brain, an increase in serotonin causes suppression of the [[corticotropin-releasing hormone]] (CRH) through connection to the hippocampus. It directly acts on the [[paraventricular nucleus]] to decrease CRH release and down regulate norepinephrine functioning in the [[locus coeruleus]].<ref name="Jacobs, B. L., H. van Praag, F. H. Gage 2000"/> Because CRH is being repressed, the decrease in neurogenesis that is associated with elevated levels of it is also being reversed. This allows for the production of more brain cells, in particular at the 5-HT1a receptor in the dentate gyrus of the hippocampus which has been shown to improve symptoms of depression. It normally takes neurons approximately three to six weeks to mature,<ref>{{cite journal |author=Davies-Sala, M. G. |author2=Espósito, M. S. |author3=Piatti, V. C. |author4=Mongiat, L. A. |author5=Trinchero M. F. |author6=Schinder A. F. |title=The Timing for Neuronal Maturation in the Adult Hippocampus Is Modulated by Local Network Activity |journal=The Journal of Neuroscience |volume=31 | issue = 21 |pages=7715–28 |date=25 May 2011 |pmid=21613484 |doi=10.1523/JNEUROSCI.1380-11.2011 |pmc=3701257 }}</ref> which is approximately the same amount of time it takes for SSRIs to take effect. This correlation strengthens the hypothesis that SSRIs act through neurogenesis to decrease the symptoms of depression.  Some neuroscientists have expressed skepticism that neurogenesis is functionally significant, given that a tiny number of nascent neurons are actually integrated into existing neural circuitry. However, a recent study used the irradiation of nascent hippocampal neurons in non-human primates (NHP) to demonstrate that neurogenesis is required for antidepressant efficacy.<ref>{{cite journal | pmc = 3078107 | pmid=21525974 | doi=10.1371/journal.pone.0017600 | volume=6 | issue=4 | title=Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates | year=2011 | journal=PLOS ONE | pages=e17600 |vauthors=Perera TD, Dwork AJ, Keegan KA, Thirumangalakudi L, Lipira CM, Joyce N, Lange C, Higley JD, Rosoklija G, Hen R, Sackeim HA, Coplan JD | bibcode=2011PLoSO...617600P | doi-access=free }}</ref>

Adult-born neurons appear to have a role in the regulation of [[stress (psychological)|stress]].<ref name=schl1>{{harvnb|Schloesser|Manji|Martinowich|2009|pp=553–7}}</ref><ref name=surg1>{{cite journal  |vauthors=Surget A, Tanti A, Leonardo ED, etal |title=Antidepressants recruit new neurons to improve stress response regulation. |journal=Molecular Psychiatry |issue=12 |date=December 2011 |pmid=21537331 |doi=10.1038/mp.2011.48 |volume=16 |pmc=3223314 |pages=1177–88}}</ref> Studies have linked neurogenesis to the beneficial actions of specific [[antidepressant]]s, suggesting a connection between decreased hippocampal neurogenesis and depression.<ref>{{cite journal |vauthors=Malberg JE, Eisch AJ, Nestler EJ, Duman RS |author4-link=Ronald Duman |title=Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus |journal=J. Neurosci. |volume=20 |issue=24 |pages=9104–10 |date=December 2000 |pmid=11124987 |pmc=6773038 |doi= 10.1523/JNEUROSCI.20-24-09104.2000}}</ref><ref>{{cite journal |vauthors=Manev H, Uz T, Smalheiser NR, Manev R |title=Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro |journal=Eur J Pharmacol |volume=411 |issue=1–2 |pages=67–70 |date=January 2001 |pmid=11137860 |doi= 10.1016/S0014-2999(00)00904-3}}</ref> In a pioneer study, scientists demonstrated that the behavioral benefits of antidepressant administration in [[mice]] is reversed when neurogenesis is prevented with [[x-ray|x-irradiation]] techniques.<ref>{{harvnb|Santarelli|Saxe|Gross|2003|pp=805–9}}</ref> In fact, newborn neurons are more excitable than older neurons due to a differential expression of [[Gamma-Aminobutyric acid|GABA]] receptors.<ref>{{cite book|title=Addiction: From Suffering to Solution|last=Bradley|first=Joseph|publisher=Breaux Press |year=2015|isbn=978-0-9854418-0-7 |oclc=1043553735 |pages=173}}</ref> A plausible model, therefore, is that these neurons augment the role of the hippocampus in the negative feedback mechanism of the [[Hypothalamic-pituitary-adrenal axis|HPA-axis]] (physiological stress) and perhaps in inhibiting the [[amygdala]] (the region of brain responsible for fearful responses to stimuli).{{Vague|date=September 2009}} Indeed, suppression of adult neurogenesis can lead to an increased HPA-axis stress response in mildly stressful situations.<ref name="schl1"/> 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 newborn neurons. Under chronic stress conditions, the elevation of newborn neurons by antidepressants improves the hippocampal-dependent control on the stress response; without newborn neurons, antidepressants are unable to restore the regulation of the stress response and recovery becomes impossible.<ref name="surg1"/>

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.<ref>{{cite journal |author=Castrén E |title=Is mood chemistry? |journal=Nature Reviews Neuroscience |volume=6 |issue=3 |pages=241–6 |date=March 2005 |pmid=15738959 |doi=10.1038/nrn1629 |s2cid=34523310 }}</ref> However another study has demonstrated an interaction between antidepressants and plasticity; the antidepressant fluoxetine has been shown to restore plasticity in the adult rat brain.<ref>{{cite journal | doi = 10.1126/science.1150516| pmid = 18420937| title = The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex| journal = Science| volume = 320| issue = 5874| pages = 385–8| year = 2008| last1 = Vetencourt | first1 = J. F. M.| last2 = Sale | first2 = A.| last3 = Viegi | first3 = A.| last4 = Baroncelli | first4 = L.| last5 = De Pasquale | first5 = R.| last6 = f. o'Leary | first6 = O.| last7 = Castren | first7 = E.| last8 = Maffei | first8 = L.| bibcode = 2008Sci...320..385M| s2cid = 39565465| hdl = 11384/85956| hdl-access = free}}</ref> The results of this study imply that instead of being secondary to changes in plasticity, antidepressant therapy could promote it.

==== Major depressive disorder ====
Research indicates that adult hippocampal neurogenesis is inversely related to major depressive disorder (MDD).<ref>{{cite journal|last1=Numakawa|first1=Tadahiro|last2=Odaka|first2=Haruki|last3=Adachi|first3=Naoki|title=Impact of glucocorticoid on neurogenesis|journal=Neural Regeneration Research|volume=12|issue=7|pages=1028–35|doi=10.4103/1673-5374.211174|pmid=28852377|pmc=5558474|year=2017 |doi-access=free }}</ref> Neurogenesis is decreased in the hippocampus of animal models of major depressive disorder, and many treatments for the disorder, including [[antidepressant]] medication and [[electroconvulsive therapy]], increase hippocampal neurogenesis. It has been theorized that decreased hippocampal neurogenesis in individuals with major depressive disorder may be related to the high levels of stress hormones called [[glucocorticoid]]s, which are also associated with the disorder. The hippocampus instructs the [[hypothalamic-pituitary-adrenal axis]] to produce fewer glucocorticoids when glucocorticoid levels are high. A malfunctioning hippocampus, therefore, might explain the chronically high glucocorticoid levels in individuals with major depressive disorder. However, some studies have indicated that hippocampal neurogenesis is not lower in individuals with major depressive disorder and that blood glucocorticoid levels do not change when hippocampal neurogenesis changes, so the associations are still uncertain.

===Parkinson's disease===
[[Parkinson's disease]] is a neurodegenerative disorder characterized by a progressive loss of [[dopaminergic neuron]]s in the [[substantia nigra]]. 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.<ref name=Arias07/> In recent years, scientists 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.<ref>{{cite journal  |vauthors=Fallon J, Reid S, Kinyamu R, etal |title=In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=26 |pages=14686–91 |date=December 2000 |pmid=11121069 |pmc=18979 |doi=10.1073/pnas.97.26.14686 |bibcode = 2000PNAS...9714686F |doi-access=free }}</ref><ref>{{cite journal  |vauthors=Arias-Carrión O, Verdugo-Díaz L, Feria-Velasco A, etal |title=Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions |journal=J Neurosci Res |volume=78 |issue=1 |pages=16–28 |date=October 2004 |pmid=15372495 |doi=10.1002/jnr.20235 |s2cid=6349942 }}</ref><ref>{{cite journal |vauthors=Arias-Carrión O, Hernández-López S, Ibañez-Sandoval O, Bargas J, Hernández-Cruz A, Drucker-Colín R |title=Neuronal precursors within the adult rat subventricular zone differentiate into dopaminergic neurons after substantia nigra lesion and chromaffin cell transplant |journal=J Neurosci Res |volume=84 |issue=7 |pages=1425–37 |date=November 2006 |pmid=17006899 |doi=10.1002/jnr.21068 |s2cid=21995251 }}</ref> Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone.<ref name=Hogl>{{cite journal  |vauthors=Höglinger GU, Rizk P, Muriel MP, etal |title=Dopamine depletion impairs precursor cell proliferation in Parkinson disease |journal=Nat. Neurosci. |volume=7 |issue=7 |pages=726–35 |date=July 2004 |pmid=15195095 |doi=10.1038/nn1265 |s2cid=952173 }}</ref> Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors.<ref name=Hogl/>  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.<ref name=Arias07>{{cite journal |vauthors=Arias-Carrión O, Freundlieb N, Oertel WH, Höglinger GU |title=Adult neurogenesis and Parkinson's disease |journal=CNS Neurol Disord Drug Targets |volume=6 |issue=5 |pages=326–35 |date=October 2007 |pmid=18045161 |doi=10.2174/187152707783220875 |url=http://www.bentham-direct.org/pages/content.php?CNSNDDT/2007/00000006/00000005/0005Z.SGM |archive-url=https://archive.today/20130414092718/http://www.bentham-direct.org/pages/content.php?CNSNDDT/2007/00000006/00000005/0005Z.SGM |url-status=usurped |archive-date=2013-04-14 |url-access=subscription }}</ref> Newer research has shown that there in fact is neurogenesis in the striatum.<ref>[http://www.cell.com/abstract/S0092-8674(14)00137-8 Neurogenesis in the Striatum of the Adult Human Brain]</ref>
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.<ref name=Arias07/>

=== Traumatic brain injury ===
[[Traumatic brain injury|Traumatic brain injuries]] vary in their mechanism of injury, producing a blunt or penetrating trauma resulting in a [[Primary and secondary brain injury|primary and secondary injury]] with [[excitotoxicity]] and relatively wide spread neuronal death. Due to the overwhelming number of traumatic brain injuries as a result of the [[War on Terror]], tremendous amounts of research have been placed towards a better understanding of the pathophysiology of traumatic brain injuries as well as [[Neuroprotection|neuroprotective]] interventions and possible interventions prompting restorative neurogenesis. Hormonal interventions, such as progesterone, estrogen, and allopregnanolone have been examined heavily in recent decades as possible neuroprotective agents following traumatic brain injuries to reduce the inflammation response stunt neuronal death.<ref>{{cite journal|last1=Guo|first1=Qingmin|last2=Sayeed|first2=Iqbal|last3=Baronne|first3=Lon M.|last4=Hoffman|first4=Stuart W.|last5=Guennoun|first5=Rachida|last6=Stein|first6=Donald G.|date=April 2006|title=Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats|journal=Experimental Neurology|volume=198|issue=2|pages=469–478|doi=10.1016/j.expneurol.2005.12.013|issn=0014-4886|pmid=16445913|s2cid=26143265}}</ref><ref>{{cite journal|last1=Petrone|first1=Ashley B.|last2=Gatson|first2=Joshua W.|last3=Simpkins|first3=James W.|last4=Reed|first4=Miranda N.|date=2014-05-25|title=Non-feminizing estrogens: a novel neuroprotective therapy|journal=Molecular and Cellular Endocrinology|volume=389|issue=1–2|pages=40–47|doi=10.1016/j.mce.2013.12.017|issn=1872-8057|pmc=4040321|pmid=24424441}}</ref><ref>{{cite journal|last1=Han|first1=S.|last2=Zhao|first2=B.|last3=Pan|first3=X.|last4=Song|first4=Z.|last5=Liu|first5=J.|last6=Gong|first6=Y.|last7=Wang|first7=M.|date=2015-12-03|title=Estrogen receptor variant ER-α36 is involved in estrogen neuroprotection against oxidative toxicity|journal=Neuroscience|volume=310|pages=224–241|doi=10.1016/j.neuroscience.2015.09.024|issn=1873-7544|pmid=26383254|s2cid=44289364}}</ref><ref>{{cite journal|last1=Singh|first1=Surjit|last2=Hota|first2=Debasish|last3=Prakash|first3=Ajay|last4=Khanduja|first4=Krishan L.|last5=Arora|first5=Sunil K.|last6=Chakrabarti|first6=Amitava|date=January 2010|title=Allopregnanolone, the active metabolite of progesterone protects against neuronal damage in picrotoxin-induced seizure model in mice|journal=Pharmacology Biochemistry and Behavior|volume=94|issue=3|pages=416–422|doi=10.1016/j.pbb.2009.10.003|issn=1873-5177|pmid=19840816|s2cid=45591868}}</ref> In rodents, lacking the regenerative capacity for adult neurogenesis, the activation of stem cells following administration of α7 nicotinic acetylcholine receptor agonist, [[PNU-282,987|PNU-282987]], has been identified in damaged retinas with follow-up work examining activation of neurogenesis in mammals after traumatic brain injury.<ref>{{cite journal|last1=Webster|first1=Mark K.|last2=Cooley-Themm|first2=Cynthia A.|last3=Barnett|first3=Joseph D.|last4=Bach|first4=Harrison B.|last5=Vainner|first5=Jessica M.|last6=Webster|first6=Sarah E.|last7=Linn|first7=Cindy L.|date=2017-03-27|title=Evidence of BrdU-positive retinal neurons after application of an Alpha7 nicotinic acetylcholine receptor agonist|journal=Neuroscience|volume=346|pages=437–446|doi=10.1016/j.neuroscience.2017.01.029|issn=1873-7544|pmc=5341387|pmid=28147247}}</ref> Currently, there is no medical intervention that has passed [[Phases of clinical research|phase-III]] clinical trials for use in the human population.

===Effects of sleep reduction===
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.<ref name=Mirescu06>{{cite journal |vauthors=Mirescu C, Peters JD, Noiman L, Gould E |title=Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=50 |pages=19170–5 |date=December 2006 |pmid=17135354 |pmc=1748194 |doi=10.1073/pnas.0608644103 |bibcode = 2006PNAS..10319170M |doi-access=free }}</ref> More precisely, when levels of corticosterone are elevated, sleep deprivation inhibits this process. Nonetheless, normal levels of neurogenesis after chronic sleep deprivation return after 2 weeks, with a temporary increase of neurogenesis.<ref name=Mirescu06/> While this is recognized, overlooked is the blood glucose demand exhibited during temporary diabetic hypoglycemic states.  The American Diabetes Association amongst many documents the pseudosenilia and agitation found during temporary hypoglycemic states.  Much more clinical documentation is needed to competently demonstrate the link between decreased hematologic glucose and neuronal activity and mood.

On the other hand, short-term sleep deprivation is known to have an antidepressant effect in humans. In animal models, it increases adult neurogenesis and reduces depression-like behavior.<ref>{{cite journal |last1=Kang |first1=E |last2=Wen |first2=Z |last3=Song |first3=H |last4=Christian |first4=KM |last5=Ming |first5=GL |title=Adult Neurogenesis and Psychiatric Disorders. |journal=Cold Spring Harbor Perspectives in Biology |date=1 September 2016 |volume=8 |issue=9 |pages=a019026 |doi=10.1101/cshperspect.a019026 |pmid=26801682 |pmc=5008067}}</ref>

==Factors affecting==

===Changes in old age===
Neurogenesis is substantially reduced in the hippocampus of aged animals, raising the possibility that it may be linked to age-related declines in hippocampal function. For example, the rate of neurogenesis in aged animals is predictive of memory.<ref>{{cite journal|author=Drapeau, E.|author2=Mayo, W.|author3=Aurousseau, C.|author4=Moal, M.L.|author5=Piazza, P.|author6=Abrous, D.N.|title=Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis|journal=PNAS|date=2003|volume=100|issue=24|doi=10.1073/pnas.2334169100 |pages=14385–90|pmid=14614143|pmc=283601|bibcode=2003PNAS..10014385D|doi-access=free}}</ref> However, new born cells in aged animals are functionally integrated.<ref>{{cite journal|author=Marrone, D.F.|author2=Ramirez-Amaya, V.|author3=Barnes, C.A.|title=Neurons generated in senescence maintain capacity for functional integration|journal=Hippocampus|date=2012|volume=22|pages=1134–42|doi=10.1002/hipo.20959|pmid=21695743|issue=5|pmc=3367380}}</ref> Given that neurogenesis occurs throughout life, it might be expected that the hippocampus would steadily increase in size during adulthood, and that therefore the number of granule cells would be increased in aged animals. However, this is not the case, indicating that proliferation is balanced by cell death. Thus, it is not the addition of new neurons into the hippocampus that seems to be linked to hippocampal functions, but rather the rate of turnover of granule cells.<ref>{{cite journal |author=von Bohlen und Halbach O |title=Involvement of BDNF in age-dependent alterations in the hippocampus |journal=Front Aging Neurosci |volume=2 |year=2010 |pmid=20941325 |pmc=2952461 |doi=10.3389/fnagi.2010.00036|doi-access=free }}</ref>

===Effects of exercise===
{{main|Neurobiological effects of physical exercise#Neuroplasticity}}
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 mice and rats.<ref name=Praag99>{{cite journal |vauthors=Praag H, Christie BR, Sejnowski TJ, Gage FH | year = 1999 | title = Running enhances neurogenesis, learning, and long-term potentiation in mice | journal = Proc Natl Acad Sci U S A | volume = 96 | issue = 23| pages = 13427–31 | pmid = 10557337 | doi=10.1073/pnas.96.23.13427 | pmc=23964| bibcode=1999PNAS...9613427V | doi-access = free }}</ref><ref name="ReferenceA"/>  These and other studies have shown that learning in both species can be enhanced by physical exercise.<ref name=Praag99/> Recent research has shown that [[brain-derived neurotrophic factor]] and [[insulin-like growth factor 1]] are key mediators of exercise-induced neurogenesis.<ref name="ReferenceA">{{cite journal |vauthors=Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR | year = 2004 | title = Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo | journal = Neuroscience | volume = 124 | issue = 1| pages = 71–9 | doi = 10.1016/j.neuroscience.2003.09.029 | pmid = 14960340 | s2cid = 2718669 }}</ref><ref name="Trejo et al, 2001">{{cite journal | pmid = 11466439| pmc = 6762673| year = 2001| last1 = Carro| first1 = E| title = Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy| journal = The Journal of Neuroscience| volume = 21| issue = 15| pages = 5678–84| last2 = Trejo| first2 = J. L.| last3 = Busiguina| first3 = S| last4 = Torres-Aleman| first4 = I| doi = 10.1523/JNEUROSCI.21-15-05678.2001}}</ref> Exercise increases the production of BDNF, as well as the NR2B subunit of the NMDA receptor.<ref name="ReferenceA"/> Exercise increases the uptake of IGF-1 from the bloodstream into various brain regions, including the hippocampus. In addition, IGF-1 alters c-fos expression in the hippocampus. When IGF-1 is blocked, exercise no longer induces neurogenesis.<ref name="Trejo et al, 2001" /> Other research demonstrated that exercising mice that did not produce beta-endorphin, a mood-elevating hormone, had no change in neurogenesis. Yet, mice that did produce this hormone, along with exercise, exhibited an increase in newborn cells and their rate of survival.<ref>{{ cite web | title = Adult neurogenesis | work = Brain Briefings | publisher = [[Society for Neuroscience]] | date = June 2007 | url = http://www.sfn.org/index.aspx?pagename=brainbriefings_adult_neurogenesis | access-date = 2011-11-26 }}</ref>
While the association between exercise-mediated neurogenesis and enhancement of learning remains unclear, this study could have strong implications in the fields of aging and/or [[Alzheimer's disease]].

===Effects of cannabinoids===
{{more medical citations needed|section|date=November 2016}}
Some studies have shown that the stimulation of the [[cannabinoid]]s results in the growth of new nerve cells in the hippocampus from both embryonic and adult stem cells. In 2005 a clinical study of rats at the University of Saskatchewan showed regeneration of nerve cells in the hippocampus.<ref name=Jiang05>{{cite journal |title=Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects |author1=Wen Jiang |author2=Yun Zhang |author3=Lan Xiao |author4=Jamie Van Cleemput |author5=Shao-Ping Ji |author6=Guang Bai |author7=Xia Zhang |journal=[[Journal of Clinical Investigation]] |volume=115 |issue=11 |pages=3104–16 |date=2005-11-01 |doi=10.1172/JCI25509 |pmc=1253627 |pmid=16224541}}</ref> Studies have shown that a synthetic drug resembling [[tetrahydrocanabinol|THC]], the main psychoactive ingredient in marijuana, provides some protection against [[brain inflammation]], which might result in better memory at an older age. This is due to receptors in the system that can also influence the production of new neurons.<ref>11-19-2008 [http://www.osu.edu/news/newsitem2227 Ohio State study: Scientists are high on idea that marijuana reduces memory impairment]. OSU.edu</ref>
Nonetheless, a study directed at Rutgers University demonstrated how synchronization of action potentials in the hippocampus of rats was altered after THC administration. Lack of synchronization corresponded with impaired performance in a standard test of memory.<ref>Nov 29, 2006. [http://www.physorg.com/news84048508.html Study: Marijuana may affect neuron firing]. United Press International</ref>
Recent studies indicate that a natural cannabinoid of cannabis, cannabidiol (CBD), increases adult neurogenesis while having no effect on learning. THC however impaired learning and had no effect on neurogenesis.<ref>{{cite journal |last1=Wolf |first1=Susanne A. |last2=Bick-Sander |first2=Anika |last3=Fabel |first3=Klaus |last4=Leal-Galicia |first4=Perla |last5=Tauber |first5=Svantje |last6=Ramirez-Rodriguez |first6=Gerardo |last7=Müller |first7=Anke |last8=Melnik |first8=Andre |last9=Waltinger |first9=Tim P. |last10=Ullrich |first10=Oliver |last11=Kempermann |first11=Gerd |title=Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis |journal=Cell Communication and Signaling |year=2010 |volume=8 |issue=1 |pages=12 |doi=10.1186/1478-811X-8-12 |pmid=20565726 |pmc=2898685 |doi-access=free }}</ref> 
A greater CBD to THC ratio in hair analyses of cannabis users correlates with protection against gray matter reduction in the right hippocampus.<ref>{{cite journal |last1=Demirakca |first1=T. |last2=Sartorius |first2=A. |last3=Ende |first3=G. |last4=Meyer |first4=N. |last5=Welzel |first5=H. |last6=Skopp |first6=G. |last7=Mann |first7=K. |last8=Hermann |first8=D. |doi=10.1016/j.drugalcdep.2010.09.020 |title=Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol |journal=Drug and Alcohol Dependence |volume=114 |issue=2–3 |pages=242–5 |year=2010 |pmid=21050680 }}</ref> CBD has also been observed to attenuate the deficits in prose recall and visuo-spatial associative memory of those currently under the influence of cannabis,<ref>{{cite journal |last1=Wright |first1=M. J. |last2=Vandewater |first2=S. A. |last3=Taffe |first3=M. A. |doi=10.1111/bph.12199 |title=Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ9tetrahydrocannabinol |journal=British Journal of Pharmacology |volume=170 |issue=7 |pages=1365–73 |year=2013 |pmid=23550724 |pmc=3838683}}</ref><ref>{{cite journal |last1=Morgan |first1=C. J. A. |last2=Schafer |first2=G. |last3=Freeman |first3=T. P. |last4=Curran |first4=H. V. |title=Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: Naturalistic study |doi=10.1192/bjp.bp.110.077503 |journal=The British Journal of Psychiatry |volume=197 |issue=4 |pages=285–290 |year=2010 |pmid=20884951 |doi-access=free }}</ref> implying neuroprotective effects against heavy THC exposure. Neurogenesis might play a role in its neuroprotective effects, but further research is required.

A few studies have reported a positive association between THC and hippocampal neurogenesis.<ref name="Biphasic effects of THC in memory a">{{cite journal |last1=Calabrese |first1=Edward J. |last2=Rubio-Casillas |first2=Alberto |title=Biphasic effects of THC in memory and cognition |journal=European Journal of Clinical Investigation |date=May 2018 |volume=48 |issue=5 |pages=e12920 |doi=10.1111/eci.12920 |pmid=29574698 |doi-access=free }}</ref><ref>{{cite journal |last1=Suliman |first1=Noor Azuin |last2=Taib |first2=Che Norma Mat |last3=Moklas |first3=Mohamad Aris Mohd |last4=Basir |first4=Rusliza |title=Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats |journal=Neurotoxicity Research |date=21 September 2017 |volume=33 |issue=2 |pages=402–411 |doi=10.1007/s12640-017-9806-x |pmc=5766723 |pmid=28933048 }}</ref> Some of them hypotethize a biphasic effect,<ref name="Biphasic effects of THC in memory a"/> some of them express that part of the negative effects could be attributable to neuroadaptation due to exposure at a specific period of life, and that it could be reversed.<ref>{{cite journal |last1=Cuccurazzu |first1=Bruna |last2=Zamberletti |first2=Erica |last3=Nazzaro |first3=Cristiano |last4=Prini |first4=Pamela |last5=Trusel |first5=Massimo |last6=Grilli |first6=Mariagrazia |last7=Parolaro |first7=Daniela |last8=Tonini |first8=Raffaella |last9=Rubino |first9=Tiziana |title=Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling |journal=International Journal of Neuropsychopharmacology |date=November 2018 |volume=21 |issue=11 |pages=1014–24 |doi=10.1093/ijnp/pyy057 |pmc=6209859 |pmid=29982505 }}</ref>

==Regulation==
[[File:Summary of the signalling pathways in the neural stem cell microenvironment.jpg|thumb|Summary of the [[signalling pathway]]s in the neural stem cell microenvironment.]]
Many factors may affect the rate of hippocampal neurogenesis. [[Exercise]] and an [[Environmental enrichment (neural)|enriched environment]] have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus.<ref name="pmid15766532">{{cite journal |vauthors=Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS |title=Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice |journal=Cell |volume=120 |issue=5 |pages=701–13 |date=March 2005 |pmid=15766532 |doi=10.1016/j.cell.2005.01.015|s2cid=16756661 |doi-access=free }}</ref><ref>{{cite journal| last1 = Van Praag | first1 = H.| last2 = Shubert | first2 = T.| last3 = Zhao | first3 = C.| last4 = Gage | first4 = F.| title = Exercise enhances learning and hippocampal neurogenesis in aged mice| journal = Journal of Neuroscience| volume = 25| issue = 38| pages = 8680–5| year = 2005| pmid = 16177036| doi = 10.1523/JNEUROSCI.1731-05.2005| pmc = 1360197 }}</ref><ref>{{cite journal| last1 = Van Praag | first1 = H.| last2 = Kempermann | first2 = G.| last3 = Gage | first3 = F.| title = Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus| journal = Nature Neuroscience| volume = 2| issue = 3| pages = 266–270| year = 1999| pmid = 10195220| doi = 10.1038/6368 | s2cid = 7170664}}</ref><ref>{{cite journal |vauthors=Bjørnebekk A, Mathé AA, Brené S |title=The antidepressant effect of running is associated with increased hippocampal cell proliferation |journal=Int J Neuropsychopharmacol |volume=8 |issue=3 |pages=357–68 |date=September 2005 |pmid=15769301 |doi=10.1017/S1461145705005122 |doi-access=free }}</ref> Another factor is [[central nervous system]] injury since neurogenesis occurs after [[cerebral ischemia]],<ref>{{cite journal  |vauthors=Jin K, Wang X, Xie L, etal |title=Evidence for stroke-induced neurogenesis in the human brain |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=35 |pages=13198–202 |date=August 2006 |pmid=16924107 |pmc=1559776 |doi=10.1073/pnas.0603512103 |bibcode = 2006PNAS..10313198J |doi-access=free }}</ref> [[epileptic seizure]]s,<ref>{{cite journal | doi = 10.1002/ana.20699 | author = Parent JM | last2 = Elliott | first2 = RC | last3 = Pleasure | first3 = SJ | last4 = Barbaro | first4 = NM | last5 = Lowenstein | first5 = DH | author-link5 = Daniel H. Lowenstein (physician) | year = 2006 | title = Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy | journal = Annals of Neurology | volume = 59 | issue = 1| pages = 81–91 | pmid = 16261566 | hdl = 2027.42/49280 | s2cid = 9655613 | hdl-access = free }}</ref> and [[bacterial meningitis]].<ref>{{cite journal | doi = 10.1212/WNL.0b013e3181b9c892 |vauthors=Gerber J, Tauber SC, Armbrecht I, Schmidt H, Brück W, Nau R | year = 2009 | title = Increased neuronal proliferation in human bacterial meningitis | journal = Neurology | volume = 73 | issue = 13| pages = 1026–32 | pmid = 19786694 |s2cid=26108905 }}</ref> On the other hand, conditions such as [[stress (medicine)|chronic stress]], viral infection and [[aging]] can result in a decreased neuronal proliferation.<ref>{{cite journal | vauthors = Sharma A, Valadi N, Miller AH, Pearce BD | year = 2002 | title = Adult neurogenesis in the hippocampus is impaired following neonatal viral infection | journal = Neurobiology of Disease | volume = 11 | issue = 2| pages = 246–56 | doi=10.1006/nbdi.2002.0531| pmid = 12505418 | s2cid = 6405590 }}</ref><ref>{{cite journal |vauthors=Lee AL, Ogle WO, Sapolsky RM |title=Stress and depression: possible links to neuron death in the hippocampus |journal=Bipolar Disord. |volume=4 |issue=2 |pages=117–28 |date=April 2002 |pmid=12071509 |doi=10.1034/j.1399-5618.2002.01144.x }}</ref><ref>{{cite journal |vauthors=Sheline YI, Gado MH, Kraemer HC |title=Untreated depression and hippocampal volume loss |journal=Am J Psychiatry |volume=160 |issue=8 |pages=1516–8 |date=August 2003 |pmid=12900317 |doi= 10.1176/appi.ajp.160.8.1516}}</ref><ref name=Jiang05/>
Circulating factors within the blood may reduce neurogenesis. In healthy aging humans, the plasma and cerebrospinal fluid levels of certain chemokines are elevated. In a mouse model, plasma levels of these chemokines correlate with reduced neurogenesis, suggesting that neurogenesis may be modulated by certain global age-dependent systemic changes. These chemokines include [[CCL11]], [[CCL2]] and [[CCL12]], which are highly localized on mouse and human chromosomes, implicating a genetic locus in aging.<ref name="G. Neves 2008 65–75"/> Another study implicated the cytokine, IL-1beta, which is produced by glia. That study found that blocking IL-1 could partially prevent the severe impairment of neurogenesis caused by a viral infection.<ref>{{cite journal | doi=10.1007/s12031-009-9293-5| pmid=19774496| title=Interleukin-1 Mediates Long-Term Hippocampal Dentate Granule Cell Loss Following Postnatal Viral Infection| year=2010| last1=Orr| first1=Anna G.| last2=Sharma| first2=Anup| last3=Binder| first3=Nikolaus B.| last4=Miller| first4=Andrew H.| last5=Pearce| first5=Bradley D.| journal=Journal of Molecular Neuroscience| volume=41| issue=1| pages=89–96| s2cid=2427299}}</ref>

[[Epigenetic Regulation of Neurogenesis|Epigenetic regulation]] also plays a large role in neurogenesis. DNA methylation is critical in the fate-determination of adult neural stem cells in the [[subventricular zone]] for post-natal neurogenesis through the regulation of neuronic genes such as ''Dlx2'', ''Neurog2'', and ''Sp8''. Many [[microRNA]]s such as miR-124 and miR-9 have been shown to influence cortical size and layering during development.<ref>{{cite journal|last=Hu|first=X.L. |author2=Wang, Y. |author3=Shen, Q.|title=Epigenetic control on cell fate choice in neural stem cells|journal=Protein & Cell|year=2012|volume=3|issue=4|pages=278–290|doi=10.1007/s13238-012-2916-6|pmid=22549586|pmc=4729703}}</ref>

[[Ephrin A2|ephrin-A2]] and [[Ephrin A3|ephrin-A3]] have been shown to negatively regulate adult neurogenesis.<ref>{{cite journal |title=Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system |year=2008 |pmc=2438395 |last1=Jiao |first1=J. W. |last2=Feldheim |first2=D. A. |last3=Chen |first3=D. F. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=105 |issue=25 |pages=8778–83 |doi=10.1073/pnas.0708861105 |pmid=18562299 |bibcode=2008PNAS..105.8778J |doi-access=free }}</ref>

==History==
Early neuroanatomists, including [[Santiago Ramón y Cajal]], considered the nervous system fixed and incapable of regeneration.  The first evidence of adult mammalian neurogenesis in the [[cerebral cortex]] was presented by [[Joseph Altman]] in 1962,<ref name=Altman62>{{cite journal |last1=Altman |first1=J. |title=Are new neurons formed in the brains of adult mammals? |journal=Science |volume=135 |pages=1127–8 |year=1962 |pmid=13860748 |bibcode=1962Sci...135.1127A |doi=10.1126/science.135.3509.1127 |issue=3509|s2cid=1606140 }}</ref> followed by a demonstration of adult neurogenesis in the dentate gyrus of the hippocampus in 1963.<ref>{{cite journal |doi=10.1002/ar.1091450409 |last1=Altman |first1=J. |title=Autoradiographic investigation of cell proliferation in the brains of rats and cats |journal=The Anatomical Record |volume=145 |issue=4 |pages=573–591 |year=1963 |pmid=14012334|s2cid=5340726 }}</ref>  In 1969, Joseph Altman discovered and named the [[rostral migratory stream]] as the source of adult generated granule cell neurons in the olfactory bulb.<ref>{{cite journal |last1=Altman |first1=J. |title=Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb |journal=The Journal of Comparative Neurology |volume=137 |issue=4 |pages=433–457 |year=1969 |pmid=5361244 |doi=10.1002/cne.901370404|s2cid=46728071 }}</ref>  Up until the 1980s, the scientific community ignored these findings despite use of the most direct method of demonstrating cell proliferation in the early studies, i.e. 3H-thymidine autoradiography.  By that time, Shirley Bayer<ref>{{cite journal |last1=Bayer |first1=S. A. |last2=Yackel |first2=J. W. |last3=Puri |first3=P. S. |title=Neurons in the rat dentate gyrus granular layer substantially increase during juvenile and adult life |journal=Science |volume=216 |issue=4548 |pages=890–2 |year=1982 |pmid=7079742 |bibcode=1982Sci...216..890B |doi=10.1126/science.7079742}}</ref><ref>{{cite journal |last1=Bayer |first1=S. A. |title=Changes in the total number of dentate granule cells in juvenile and adult rats: a correlated volumetric and 3H-thymidine autoradiographic study |journal=Experimental Brain Research. Experimentelle Hirnforschung. Experimentation Cerebrale |volume=46 |issue=3 |pages=315–323 |year=1982 |pmid=7095040 |doi=10.1007/bf00238626|s2cid=18663323 }}</ref> (and [[Michael Kaplan (biologist)|Michael Kaplan]]) again showed that adult neurogenesis exists in mammals (rats), and Nottebohm showed the same phenomenon in birds<ref>{{cite journal |vauthors=Goldman SA, Nottebohm F |title=Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=80 |issue=8 |pages=2390–4 |date=April 1983 |pmid=6572982 |pmc=393826 |doi=10.1073/pnas.80.8.2390 |bibcode=1983PNAS...80.2390G|doi-access=free }}</ref> sparking renewed interest in the topic.  Studies in the 1990s<ref>{{cite journal |pmid=1553558 |date=Mar 1992 |last1=Reynolds |first1=B. A. |last2=Weiss |first2=S. |title=Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system |volume=255 |issue=5052 |pages=1707–10 |issn=0036-8075 |journal=Science |doi=10.1126/science.1553558 |bibcode=1992Sci...255.1707R}}</ref><ref>{{cite journal |last1=Gage |first1=F. H. |last2=Ray |first2=J. |last3=Fisher |first3=L. J. |title=Isolation, Characterization, and use of Stem Cells from the CNS |journal=Annual Review of Neuroscience |volume=18 |pages=159–92 |year=1995 |pmid=7605059 |doi=10.1146/annurev.ne.18.030195.001111}}</ref> finally put research on adult neurogenesis into a mainstream pursuit.  Also in the early 1990s hippocampal neurogenesis was demonstrated in non-human primates and humans.<ref>{{cite journal |vauthors=Eriksson PS, Perfilieva E, Björk-Eriksson T, etal |title=Neurogenesis in the adult human hippocampus |journal=Nat. Med. |volume=4 |issue=11 |pages=1313–7 |date=November 1998 |pmid=9809557 |doi=10.1038/3305 |doi-access=free }}</ref><ref>{{harvnb|Gould|Reeves|Fallah|Tanapat|Gross|Fuchs|1999|pp=5263–7}}</ref>  More recently, neurogenesis in the cerebellum of adult rabbits has also been characterized.<ref>{{cite journal |last1=Ponti |first1=G. |last2=Peretto |first2=B. |last3=Bonfanti |first3=L. |editor1-last=Reh |editor1-first=Thomas A. |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 |doi=10.1371/journal.pone.0002366 |pmc=2396292 |bibcode=2008PLoSO...3.2366P|doi-access=free }}</ref> Further, some authors (particularly [[Elizabeth Gould (psychologist)|Elizabeth Gould]]) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the [[neopallium|neocortex]].<ref>{{harvnb|Gould|Reeves|Graziano|Gross|1999|pp=548–552}}</ref><ref>{{harvnb|Zhao|Momma|Delfani|2003|pp=7925–30}}</ref><ref>{{harvnb|Shankle|Rafii|Landing|Fallon|1999|pp=244–259}}</ref> However, others<ref name="pmid11826088">{{cite journal |author=Rakic P |title=Adult neurogenesis in mammals: an identity crisis |journal=J. Neurosci. |volume=22 |issue=3 |pages=614–8 |date=February 2002 |pmid=11826088 |pmc=6758501 |doi= 10.1523/JNEUROSCI.22-03-00614.2002}}</ref> have questioned the [[scientific method|scientific evidence]] of these findings, arguing that the new [[cell (biology)|cells]] may be of [[glia|glial origin]]. Recent research has elucidated the regulatory effect of [[GABA]] on neural stem cells. GABA's well-known inhibitory effects across the brain also affect the local circuitry that triggers a stem cell to become dormant. They found that [[diazepam]] (Valium) has a similar effect.<ref>{{cite journal | doi=10.1038/nature11306|pmid = 22842902| pmc=3438284| title=Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision| journal=Nature| volume=489| issue=7414| pages=150–4| year=2012| last1=Song| first1=Juan| last2=Zhong| first2=Chun| last3=Bonaguidi| first3=Michael A.| last4=Sun| first4=Gerald J.| last5=Hsu| first5=Derek| last6=Gu| first6=Yan| last7=Meletis| first7=Konstantinos| last8=Huang| first8=Z. Josh| last9=Ge| first9=Shaoyu| last10=Enikolopov| first10=Grigori| last11=Deisseroth| first11=Karl| last12=Luscher| first12=Bernhard| last13=Christian| first13=Kimberly M.| last14=Ming| first14=Guo-li| last15=Song| first15=Hongjun|bibcode = 2012Natur.489..150S}}</ref>

==See also==
* [[Artificial neural membrane]]
* [[Neural development]]
* [[Neuroplasticity]]
* [[Neurotrophin]]
* [[Neurulation]]
* [[Gliogenesis]]
* [[Adult neurogenesis in songbirds]]

==References==
{{reflist|30em}}
;Notes

{{sfn whitelist|CITEREFSantarelliSaxeGross2003|CITEREFZhaoMommaDelfani2003}}
{{refbegin}}
* {{cite journal |vauthors=Aimone JB, Jessberger S, Gage FH |title=Adult Neurogenesis |date=2007 |journal=Scholarpedia |volume=2 |issue=2 |page=2100 |doi=10.4249/scholarpedia.2100 |doi-access=free|bibcode=2007SchpJ...2.2100A }}
* {{cite journal |vauthors=Gould E, Reeves AJ, Fallah M, Tanapat P, Gross CG, Fuchs E |title=Hippocampal neurogenesis in adult Old World primates |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=9 |pages=5263–7 |date=April 1999 |pmid=10220454 |pmc=21852 |doi= 10.1073/pnas.96.9.5263|bibcode=1999PNAS...96.5263G|doi-access=free }}
* {{cite journal |vauthors=Gould E, Reeves AJ, Graziano MS, Gross CG |title=Neurogenesis in the neocortex of adult primates |journal=Science |volume=286 |issue=5439 |pages=548–52 |date=October 1999 |pmid=10521353 |doi= 10.1126/science.286.5439.548}}
* {{cite journal |vauthors=Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ |title=Learning enhances adult neurogenesis in the hippocampal formation |journal=Nat. Neurosci. |volume=2 |issue=3 |pages=260–5 |date=March 1999 |pmid=10195219 |doi=10.1038/6365 |s2cid=12112156 }}
* {{cite journal |vauthors=Moghadam KS, Chen A, Heathcote RD |title=Establishment of a ventral cell fate in the spinal cord |journal=Dev. Dyn. |volume=227 |issue=4 |pages=552–62 |date=August 2003 |pmid=12889064 |doi=10.1002/dvdy.10340 |s2cid=209599 }}
* {{cite journal |author=Rakic P |title=Neurogenesis in adult primate neocortex: an evaluation of the evidence |journal=Nature Reviews Neuroscience |volume=3 |issue=1 |pages=65–71 |date=January 2002 |pmid=11823806 |doi=10.1038/nrn700 |s2cid=15725675 }}
* {{cite book |last1=Rolls |first1=E.T |last2=Treves |first2=A. |title=Neural Networks and Brain Function |publisher=Oxford University Press |date=1998 |isbn=0-19-852432-3 |oclc=53957833 }}
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{{refend}}

==External links==
* [http://www.wellesley.edu/Biology/Concepts/Html/neurogenesishow.html Concise introduction to neurogenesis] from [[Wellesley College]]
* [https://web.archive.org/web/20180423203940/https://sites.lafayette.edu/neur401-sp10/ Comprehensive website on neurogenesis] from [[Lafayette College]]
* [http://neurondevelopment.org/adult-neurogenesis Early literature on adult neurogenesis]
* [https://web.archive.org/web/20100401052850/http://www.acnp.org/Docs/G5/CH8_109-118.pdf Neurogenesis in adult brain — Fred H. Gage and Henriette van Praag]
* [https://web.archive.org/web/20080514043354/http://www.peterhofmann.com/img/Neurogenesis_CNS_2007.pdf "Neurogenesis and Parkinson´s disease"]
* [http://scholarpedia.org/article/Adult_Neurogenesis Scholarpedia Article on Adult Neurogenesis]
* [https://web.archive.org/web/20060904145025/http://ntp.neuroscience.wisc.edu/neuro675/reqreading/EnvironmentComplexity.pdf  "Trends in Neurosciences, 10 October 2001 (Michael S. Kaplan MD, PhD)]
* [https://query.nytimes.com/gst/fullpage.html?res=9C07E4DC1239F934A25750C0A96E958260&sec=health New York Times: Studies Find Brains Grow New Cells]
* [http://www.michaelspecter.com/2001/07/rethinking-the-brain/ Michael Specter: Rethinking the Brain] {{Webarchive|url=https://web.archive.org/web/20190630113613/http://www.michaelspecter.com/2001/07/rethinking-the-brain/ |date=2019-06-30 }} — How the songs of canaries upset a fundamental principle of science
* [https://web.archive.org/web/20090224102405/http://mwinkelmann.com/category/the-neurogenesis-experiment/ The Neurogenesis Experiment] — Article series on adult human neurogenesis
* [https://web.archive.org/web/20090224053159/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
* [https://www.pbs.org/saf/1101/resources/resources-2.htm PBS: Changing Your Mind] {{Webarchive|url=https://web.archive.org/web/20150924151607/http://www.pbs.org/saf/1101/resources/resources-2.htm |date=2015-09-24 }} — Grow Your Own Brain
* [https://www.nytimes.com/2007/08/19/sports/playmagazine/0819play-brain.html Lobes of Steel: Aerobic exercise appears to promote neurogenesis], New York Times, 19 August 2007.
* {{commons-inline|Category:Neurogenesis|neurogenesis}}

{{Development of nervous system}}
{{Neurotrophinergics}}

[[Category:Neuropsychology]]
[[Category:Stem cells]]
[[Category:Developmental neuroscience]]