neurogenesis is the process of generating neurons by neural stem cells ( nsc ) and/or neural progenitor cells ( npc ) .
embryonic neurogenesis in humans starts at approximately 5 to 6 gestational weeks ( gw ) , when neuroblasts proliferate and expand rapidly within the ventricular zone ( vz ) lining the cerebral ventricles . at gw8 , these neuroblasts begin transformation into radial glia , which divide asymmetrically into either daughter radial glia or npcs . post - mitotic immature neurons derived from npcs then exit the vz and migrate extensively to reach their destination , where they further develop into mature neurons and become integrated into local circuits . the embryonic neurogenesis peaks at late embryonic and early fetal periods , and by early postnatal stage it declines significantly . before 1990s , it had long been believed that the adult brain lacks neurogenic potentials .
this view has since been changed and today it is well - recognized that the adult brain can generate new neurons in both physiological and pathological circumstances , though the rate of neurogenesis is much lower than its embryonic counterpart .
in addition , the neurogenic regions in the adult brain are largely limited to the subventricular zone ( svz ) of the lateral ventricles and the subgranular zone ( sgz ) of the dentate gyrus ( dg ) , known as neurogenic niche .
the svz and sgz harbor large numbers of nscs and radial glia , which self - maintain the progenitor pool through the adult life , and generate new neurons upon physiological as well as pathological stimuli .
embryonic neurogenesis is an evolving , dynamic , and spatiotemporally regulated developmental event orchestrated by genetic , epigenetic , and environmental factors .
the ultimate goal of embryonic neurogenesis is to establish future brain structures with dedicated cytoarchitecture and chemicoarchitecture , which lies at the foundation of high brain functions .
taking corticogenesis as an example , it starts with migration of post - mitotic immature neurons out of the vz dorsally to form the first recognizable structure named preplate . within the preplate ,
early born pioneer neurons act as stepping stones to establish primitive connections from the developing thalamus and brainstem by serving as synaptic targets .
the preplate later splits into the marginal zone and the subplate layer , the latter is yet another evolving layer that plays a pivotal role in establishing and refining intracortical , extracortical , and thalamocortical circuitries . around gw 78 , the cortical plate , which eventually develops into layers ii  vi of the cerebral cortex ,
emerges between the subplate ( which dissolves later ) and the marginal zone ( which gives rise to layer i ) .
through such a successive migration , expansion , and maturation of neurons , the cortical laminae are formed in an  inside - out  fashion ( tau and peterson , 2010 ) . in order to reach the outermost layer of the cortex
, post - mitotic neurons need to migrate extensively along processes of radial glia , which serve as scaffolds at this stage but also generate neurons and macroglia ( astrocytes and oligodendrocytes ) around birth .
the majority of cortical projection neurons migrate radially from vz , whereas gabaergic interneurons are generated from the medial ganglionic eminence ( mge ) and migrate tangentially to populate the cerebral cortex . as a critical component of neurogenesis ,
neuronal migration is guided by a diverse range of neurochemical cues such as neural cell adhesion molecule ( ncam ) , reelin , contactin - associated protein - like 2 ( cntnap2 ) , disrupted - in schizophrenia 1 ( disc1 ) , etc .
emerging evidence suggests that dysregulation of many of those molecules plays an important pathogenic role in major neurodevelopmental disorders including autism spectrum disorders ( asd ) , attention deficit hyperactivity disorder ( adhd ) , and schizophrenia ( sz ) ( ernst , 2016 ) .
the dogma that the adult brain lacks neurogenic potential was challenged in the 1990s . when examining postmortem brains from cancer patients who had undergone chemotherapy , several studies found brdu neuroblasts in the adult brain . shortly after these reports , the presence of proliferating neuroblasts in the adult brain was confirmed in various animal species including primates .
furthermore , it was demonstrated that adult neurogenesis takes place not only under physiological conditions but also upon brain injury , and the newly generated neurons could migrate towards injured sites , suggesting that adult neurogenesis functions as an endogenous repair mechanism ( apple et al . , 2017 ) .
these pioneering studies spurred intensive interest in exploring the cellular and molecular mechanisms as well as the function of adult neurogenesis , and significant progress has been made in the past 20 years .
the svz - generated neurons migrate to the striatum and differentiate into striatal interneurons ( in rodents they migrate to the olfactory bulb via the rostral migratory stream , rms ) , whereas the sgz generated neurons migrate to the granule cell layer , where they differentiate into mature granule neurons and integrate into local circuits . since the hippocampus plays a central role in learning and memory , the functional contribution of sgz neurogenesis is of particular interest . utilizing a variety of in vivo approaches including neuroimaging , electrophysiology , and behavioral tests , it has been well demonstrated that sgz neurogenesis plays a pivotal role in learning , memory , and mood regulation ( song et al . , 2012 ) . notwithstanding that the svz and sgz are considered to be the principle neurogenic regions in the adult mammalian brain , recently it has been shown that many other regions including the amygdala , neocortex , substantia nigra , tegmentum , brainstem , and spinal cord , also maintain neurogenic potentials .
a plethora of studies suggest that the molecular machineries regulating embryonic and adult neurogenesis are rather similar ( urban and guillemot , 2014 ; gotz et al . , 2016 ) .
for example , both are regulated by similar neurogenic transcription factors ( tfs ) , including the homeodomain proteins ( e.g. , pax6 , gsx2 and dlx ) , the basic helix - loop - helix ( bhlh ) proneural tfs ( e.g. , ascl1 , neurog2 , and neurod1 ) , and extrinsic signaling molecules ( e.g. , wnt , bmp , and certain growth factors ) .
in addition , embryonic radial glia and adult nscs share common molecular markers , such as gfap , nestin , and sox2 .
the embryonic nscs proliferate rapidly and their progeny , the post - mitotic immature neurons , migrate a great distance to populate the entire brain .
in contrast , the adult nscs within the neurogenic niches acquire quiescent states and remain for a long period of time out of the cell cycle , while their progeny migrate either along restricted routes or in short distances ( e.g. , the svz neurons migrate to the olfactory bulb via rms , while the granule cells in the dg migrate within the granule cell layer ) .
secondly , embryonic nscs have greater differentiation potentials , that is , they can generate a vast diversity of neuronal and glial types , which is in contrast to rather limited neuronal types ( either periglomerular or granule cells ) generated from adult nscs .
the major factor underlying these differences is the distinct extracellular microenvironment in which the embryonic and adult nscs are exposed .
the extracellular milieu of the embryonic brain , which changes rapidly , favors neurogenesis , while in the adult brain it remains in a stable homeostasis and generally favors gliogenesis .
lastly , in terms of function , the adult sgz neurogenesis is unique and clearly sets apart from embryonic neurogenesis .
it becomes clear in recent years that adult - born neurons of the hippocampus is required for experience - dependent memory formation , especially spatial and contextual learning and memory ( petsophonsakul et al .
the biological actions and profiles of these secreted inflammatory cytokines can vary in a context - dependent manner ( e.g. , acute vs. chronic inflammation , developing vs. mature brain , etc . ) , and neuroinflammation as a whole can affect neurogenesis either positively or negatively . because microglia , the primary sources of brain inflammatory cytokines upon activation , are also critically involved in normal embryonic neurogenesis ( see below ) , the effect of neuroinflammation on neurogenesis is more complicated in neurodevelopmental disorders than adult neurological disorders .
embryonic neurogenesis consists of multiple steps of cell development , including npc proliferation , differentiation , migration , and maturation .
these events are principally controlled by genetic programs , but could also be influenced by epigenetic and extracellular factors , which are prone to adverse prenatal environmental challenges .
emerging data indicate that many neurodevelopmental and/or neuropsychiatric disorders , including asd , adhd , sz , and bipolar disorders , etc .
a common characteristic of these disorders is their complex etiological origins , which involve multiple genetic and environmental risk factors linked to neurogenesis . on the genetic side , for example , many risk genes for asd and sz are involved in neural induction , neurogenesis , synaptogenesis , and immune system ( casanova and casanova , 2014 ) . among many environmental risk factors , maternal infection and/or immune challenge ( which are perhaps the most pervasive adverse events during pregnancy ) are increasingly realized to play a major etiological role in both asd and sz .
while asd and sz seem to be two very different disorders in terms of phenotypes , they may share similar etiology and pathophysiology at critical early developmental periods .
for example , several lines of evidence suggest that imbalance between excitatory and inhibitory neurotransmission , which is proposed to underline high incidences of seizure in asd and sz patients , is rooted at aberrant synaptic pruning and/or interneuron development . due to ethical issue ,
it is not possible to study neurogenesis in human fetal tissue ; however , a growing body of postmortem studies suggest that there might be an accelerated neurogenesis in asd . for instance
, neuronal density in the frontal cortex was found to be significantly higher in asd individuals as compared to the controls ( courchesne et al . , 2011 ) , this is consistent with large body of neuroimaging data showing accelerated brain growth in asd infants around 1-year of age ( sacco et al . , 2015 ) .
in addition , it was found that genes involved in proliferation , cell cycle , and apoptosis , were differentially expressed in the prefrontal cortex of young asd subjects ( chow et al . , 2012 ) , suggesting a dysregulated cell growth and cell number control .
strikingly , a recent study demonstrated that neural organoids developed from induced pluripotent stem cells ( ipscs ) of asd patients , exhibited accelerated cell cycles ( mariani et al . , 2015 ) .
nevertheless , when analyzed closely with data from animal studies , together they provide great insight into early neurobiology of asd .
one of the widely used animal models for asd and sz is maternal immune activation ( mia , commonly induced by exposing pregnant animals to bacterial endotoxin lps , or viral mimics such as the double - stranded rna poly i : c ) .
interestingly , altered neuronal proliferation , migration , and differentiation , have been well - replicated in the mia model ( estes and mcallister , 2016 ) .
adult neurogenesis is known to be highly plastic , i.e. , it can be influenced by various physiological stimuli such as physical exercise and behavioral experience .
notably , non - physiological stimuli such as certain medications including antidepressant drugs , also affect adult neurogenesis ( samuels et al . , 2014 ) .
with regard to pathological conditions , either an increase or decrease in neurogenesis has been reported .
increased neurogenesis was reported at early stages of certain neurological disorders , including traumatic brain injury and stroke ( kernie and parent , 2009 ) .
although direct evidence from human studies is limited , available data converge on the idea that in many chronic neurodegenerative disorders such as multiple sclerosis ( ms ) , alzheimer 's disease ( ad ) , parkinson 's disease ( pd ) , and amyotrophic lateral sclerosis ( als ) , etc . , neurogenesis is impaired ( winner and winkler , 2015 ) . in the case of increased neurogenesis , however , the contribution of new neurons to functional recovery is limited due to the fact that the majority of newborn neurons ( ~80% ) die by apoptosis ( kuhn , 2015 ) . the exact mechanisms underlying poor survival of newborn neurons
are not fully understood , but may be principally attributed to challenging extracellular environments of the adult brain , both intrinsically and extrinsically . as mentioned above , the extracellular milieu of the adult brain , which is unfavorable for neurogenesis , could be further modified towards anti - neurogenic during neurological diseases .
neuroinflammation is a complex cellular and molecular response of brain cells to pathological stimuli that aims at maintaining homeostasis and repairing tissue .
since both neuroinflammation and altered neurogenesis are commonly found across cns disorders , studying a causative role of neuroinflammation in dysregulated neurogenesis has gained increasing attention . in certain disorders such as ms , stroke , and traumatic brain injury , the blood - brain barrier ( bbb )
is often compromised enabling systemic inflammatory mediators and/or immune cells to gain access to the brain parenchyma , where they interact with microglia to contribute to overall neuroinflammation . in most cases without clear evidence of bbb damage , neuroinflammation may be largely attributed to activate microglia and astrocytes , although systemically generated cytokines can communicate with the brain through multiple pathways including vagus nerve and circumventricular organs ( mccusker and kelley , 2012 ) . at present , the effect of neuroinflammation on neurogenesis remains controversial ; however , based on studies in neurodegenerative disorders , it appears that in general , chronic neuroinflammation negatively regulates neurogenesis .
much of the work has been focused on the roles of proinflammatory cytokines , such as tumor necrosis factor- ( tnf- ) , interleukin-1 ( il-1 ) , and il-6 , on neurogenesis in neurodegenerative disorders , and their effects appear to vary in different disorders ( discussed below ) .
in addition to inflammatory cytokines , toll - like receptor 4 ( tlr4 ) , which is chiefly responsible for innate immune response and is highly expressed by neuroglia including microglia , is also involved in modulating adult neurogenesis .
however , the mode of actions remains inconclusive due to inconsistent or even contradictory reports .
for example , it was reported that tlr4 deficiency resulted in enhanced dg nsc proliferation and differentiation in mice , while lps treatment led to reduced npc proliferation in wild - type mice ( rolls et al . , 2007 ) .
in contrast , several in vivo ( su et al . , 2005 ) and in vitro ( go et al .
such discrepancies might arise from , at least partially , effects of cytokines released upon tlr4 activation .
although lps is the most potent ligand , tlr4 can also be activated by other endogenous ligands such as atp , fibronectin , etc . , which could be released from damaged neural cells under pathological challenges . in stroke models , it was shown that tlr4 deficient mice exhibited increased number of npcs in the svz but reduced neuroblast migration following ischemia ( moraga et al . , 2014 ) .
( 2015 ) reported that blockage of tlr4 inhibited neurogenesis and worsened functional recovery in rats .
for example , in a mice model of ad , blockage of tlr4 abolished -amyloid oligomers - induced memory impairment in mice ( balducci et al . , 2016 ) .
however , in the developing brain , the mechanisms may be more complex , given the fact that microglia play essential roles in normal brain development .
microglia regulate normal embryonic neurogenesis via a number of mechanisms , including phagocytosis , receptor - mediated bidirectional communication with neurons , and secreted molecules such as nitric oxide ( no ) , cytokines , chemokines , and growth factors ( see below ) .
although it has been long recognized that microglia plays essential roles in modulating neural network maturation via 
synaptic pruning  and controlling neuronal numbers via programmed neuronal death ( pnd ) , the critical involvement of microglia in neurogenesis has emerged only in recent years . in the layer v of early postnatal mice , it was demonstrated that microglia support npcs survival by secreting trophic factors ( ueno et al . , 2013 ) .
seemly paradoxical to such a pro - survival effect , numerous studies reported a pro - death effect of microglia on neurons . in the prenatal mice hippocampus , microglia enhance pnd by cd11b / dap12 integrin signaling - dependent production of reactive oxidative species ( ros ) ( wakselman et al . , 2008 ) . during corticogenesis ,
microglia not only phagocytize apoptotic but also intact immature neurons in the layer v cortex ( cunningham et al . , 2013 ) .
these evidence underscores complex mechanisms by which microglia regulate developing neurogenesis in a highly context - dependent manner ( ueno and yamashita , 2014 ; sato , 2015 ) . following activation by pathological insults , not only do microglia produce a plethora of inflammatory mediators ,
in addition , microglia can be activated by not only the pathogen - associated and danger - associated molecular patterns ( pamps and damps , respectively ) , but also many adverse perinatal insults such as stress , environmental toxins , and certain medications , etc .
thus , the effect of neuroinflammation on embryonic neurogenesis is complicated by the fact that the highly orchestrated , time - sensitive , and context - dependent microglia activities pertinent to normal neurogenesis , are compromised in neurodevelopmental disorders . based on this ,
it likely that neuroinflammation either enhances or suppresses embryonic neurogenesis , depending upon a variety of factors such as the timing , magnitude , and nature of insults .
signs of microglia activation , such as increased cell density and altered morphology , upregulation of proinflammatory and/or anti - inflammatory cytokines , have been reported in postmortem asd patients . as mentioned earlier , several lines of evidence
suggests that neurogenesis may be increased , at least in a subset of asd cases .
a critical question that remains to be determined is whether neuroinflammation plays a causative role in the enhanced neurogenesis in asd .
recently , it was reported that in the cortex of postmortem asd subjects , a gene module regulating m2-like microglia activation was significantly upregulated , which was negatively correlated with a dysregulated gene module involved in neuronal development ( gupta et al . , 2014 ) .
interestingly , we recently reported that rat pups ( on postnatal day 3 ) exposed to lps developed certain asd - like behaviors , which were associated with a m2-like microglia activation and enhanced neurogenesis in both svz and sgz regions ( pang et al . , 2016 ) .
this evidence hints a potential involvement of m-2 like microglial activation in aberrant neurogenesis in asd .
a great effort has been devoted to investigating the role of inflammatory cytokines in regulating neurogenesis . during chronic neuroinflammation ,
as noted in many neurodegenerative disorders , it is thought that the classically activated microglial state and/or multiple proinflammatory cytokines act as suppressors on neurogenesis , although this remains controversial due to inconsistent or even opposite reports , especially from in vivo studies ( fuster - matanzo et al . , 2013 ) .
in vitro studies tend to more consistently report inhibitory and/or detrimental effects of proinflammatory cytokines on npc proliferation and/or survival ; however , their effect on neurogenesis can be either positive or negative , depending on many factors such as species , regions of npcs being isolated , and different experimental settings , etc .
, as discussed in a recent review ( borsini et al . , 2015 ) . among many proinflammatory cytokines , tnf- , il-1 , and il-6 are
for example , at the embryonic stage , il-1 is expressed at relatively high levels and is required for proper hippocampal neurogenesis , as evidence by impairments in hippocampus - mediated memory formation in il-1 receptor knockout mice ( avital et al . , 2003 ) .
in the adult brain , il-1 is greatly downregulated but remains constitutively expressed to support hippocampal neurogenesis .
overexpression of il-1 reduced doublecortin ( dcx ) positive neurons and/or inhibited memory formation ( wu et al . ,
2012 ) , suggesting a dose - dependent relationship between il-1 and neurogenesis . during chronic neuroinflammation , il-1 is markedly upregulated and its effect on neurogenesis becomes suppressive , as demonstrated by many in vivo and in vitro studies .
by contrast , the effect of tnf- on hippocampal neurogenesis appears to be dependent on its receptors , that is , activation of tnfr1 suppresses neurogenesis , whereas tnfr2 increases neurogenesis ( chen and palmer , 2013 ) .
finally , many in vitro studies demonstrated that il-6 promotes npcs towards gliogenesis with a concurrent reduction in neurogenesis .
overexpression of il-6 in the astrocytes significantly reduced neurogenesis in adult mice ( vallires et al . ,
neuroinflammation is associated with production of not only classical proinflammatory mediators , but also anti - inflammatory cytokines and trophic factors .
the most important anti - inflammatory cytokine and trophic factors released by activated microglia include il-4 , il-10 , transforming growth factor- ( tgf- ) , insulin - like growth factor 1 ( igf-1 ) , basic fibroblast growth factor ( bfgf ) , brain - derived neurotrophic factor ( bdnf ) , etc .
those cytokines are mostly associated with pro - neurogenic effect ( belarbi and rosi , 2013 ) .
for example , in vitro , il-10 and il-4 upregulated the surface adhesion molecule lymphocyte function - associated antigen 1 ( lfa-1 ) and chemokine receptors cxcr4 and ccr5 on nscs , suggesting that il-10 and il-4 may promote neuronal migration . il-4
polarized microglia have been shown to encourage neurogenesis , which is mediated at least partially by igf-1 released from microglia ( butovsky et al . , 2006 ) .
thus , pretreatment with anti - inflammatory cytokines such as il-4 and il-10 may provide neuroprotection by enhancing neurogenesis , or facilitate migration of nscs ( endogenous or transplanted nscs ) to the site of damage .
a common feature of neurodegenerative disorders , ad and pd in particular , is chronic neuroinflammation and/or microglia activation , which likely affect adult neurogenesis and contribute to disease development .
initially regarded as an epiphenomenon in neurodegenerative process , neuroinflammation is increasingly realized as an integral component of many neurodegenerative disorders .
a number of reviews have devoted to this topic ( thundyil and lim , 2014 ; calsolaro and edison , 2016 ) so we will only discuss briefly .
there are many potential factors contributing to a chronic neuroinflammatory state in ad and pd , and the dominant hypothesis is that a vicious cycle is formed between glial activation and neuronal death , that is , damps released from degenerated neurons activate glial cells via tlrs , whereas neuroinflammation further promote neurodegeneration .
needless to say , aging itself is a high risk factor for a number of neurodegenerative disorders including ad and pd .
it becomes clear that a chronic inflammatory state , which is present in both the periphery and central nervous system ( cns ) , is a prominent feature of ageing .
as we age , the innate immunity becomes dysregulated , resulting in persistent inflammatory state ( shaw et al . , 2013 ) .
this phenomenon was coined as  inflamaging  by franceschi and colleagues ( franceschi et al . , 2007 ) . it was argued that individuals with healthy ageing are armed with efficient anti - inflammatory network to neutralize the pro - inflammatory state , while those with pathological aging are deficient in such an anti - inflammatory mechanism . in summary
, mounting evidence suggests that neuroinflammation affects both embryonic and adult neurogenesis , contributing to the pathogenesis of numerous neurodevelopmental , neuropsychiatric , and neurological disorders .
however , many questions remain unaddressed . for example , simply put , in the inflamed brain , a diverse range of inflammatory molecules co - exist and potentially interact , and the converging effect on neurogenesis may be different from that of individual cytokines . furthermore , such effect may vary significantly between the embryonic and adult brain . when the precise mechanisms of how neuroinflammation regulates neurogenesis in the context of different diseases are better clarified , it is hopeful that modulating neurogenesis by targeting neuroinflammation may provide a novel therapeutic strategy for those brain disorders .
 embryonic neurogenesis is the process of generating neurons , the functional units of the brain . because of its sensitivity to adverse intrauterine environment such as infection , dysregulation of this process has emerged as a key mechanism underlying many neurodevelopmental disorders such as autism spectrum disorders ( asd ) . 
 adult neurogenesis , although is restricted to a few neurogenic niches , plays pivotal roles in brain plasticity and repair . 
 increasing evidence suggests that impairments in adult neurogenesis are involved in major neurodegenerative disorders such as alzheimer 's disease . a hallmark feature of these brain disorders is neuroinflammation , which can either promote or inhibit neurogenesis depending upon the context of brain microenvironment . 
 in this review paper , we present evidence from both experimental and human studies to show a complex picture of relationship between these two events , and discussed potential factors contributing to different or even opposing actions of neuroinflammation on neurogenesis in neurodevelopmental and neurological disorders . 
Introduction
Neurogenesis during Development and Adulthood: Similarities and Differences
Dysregulation of Neurogenesis in Neurodevelopmental and Neurological Disorders
Neuroinflammation and Neurogenesis: the Role of Microglia
Neuroinflammation and Neurogenesis: the Role of Inflammatory Cytokines
Chronic Neuroinflammation and Neurodegenerative Disorders