Oitavo Artigo -Surveillance, Phagocytosis, And Inflammation

7/17/2019 Oitavo Artigo -Surveillance, Phagocytosis, And Inflammation

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Review ArticleSurveillance, Phagocytosis, and Inflammation: HowNever-Resting Microglia Influence Adult HippocampalNeurogenesis

Amanda Sierra,1,2,3 Sol Beccari,2,3 Irune Diaz-Aparicio,2,3 Juan M. Encinas,1,2,3

Samuel Comeau,4,5 and Marie-ve Tremblay4,5

Ikerbasque Foundation, Bilbao, SpainAchucarro Basque Center for Neuroscience, Bizkaia Science and echnology Park, Zamudio, Spain Department of Neurosciences, University of the Basque Country, Leioa, Spain Centre de Recherche du CHU de Quebec, Axe Neurosciences, Canada GP C Departement de Medecine Moleculaire, Universite Laval, Canada GV G

Correspondence should be addressed to Amanda Sierra; [email protected] Marie-Eve remblay; [email protected]

Received December ; Accepted February ; Published March

Academic Editor: Carlos Fitzsimons

Copyright Amanda Sierra et al. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Microglia cells are the major orchestrator o the brain inammatory response. As such, they are traditionally studied in variouscontexts o trauma, injury, and disease, where they are well-known or regulating a wide range o physiological processes by theirrelease o proinammatory cytokines, reactive oxygen species, and trophic actors, among other crucial mediators. In the lastew years, however, this classical view o microglia was challenged by a series o discoveries showing their active and positivecontribution to normal brain unctions. In light o these discoveries, surveillant microglia are now emerging as an importanteffector o cellular plasticity in the healthy brain, alongside astrocytes and other types o inammatory cells. Here, we will reviewthe roles o microglia in adult hippocampal neurogenesis and their regulation by inammation during chronic stress, aging,and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their unctionalconsequences or learning and memory.

1. Microglia: The Resident Immune

Cells of the Brain

Microglia were rst described in by the Spanish neu-roanatomist Po del Ro Hortega, a disciple o the renownedSantiago Ramon y Cajal, almost hal a century later thanneurons and astrocytes and just beore oligodendrocytes[]. Tis delayed appearance into the neuroscience arena isstill apparent today, as microglia remain one o the leastunderstood cell types o the brain. raditionally, microgliawere simply considered as brain macrophages controllingthe inammatory response during acute insults andneurode-generative conditions, and only recently was their uniqueorigin revealed. Indeed, microglia were shown to derive rom

primitive myeloid progenitors o the yolk sac that invade

the central nervous system (CNS) during early embryonicdevelopment (reviewed in []). In contrast, circulating mono-cytes and lymphocytes, as well as most tissue macrophages,derive rom hematopoietic stem cells located initially in theoetal liver and later in the bone marrow []. In the adultbrain, the microglial population is maintained exclusively bysel-renewal during normal physiological conditions []. Asa consequence, microglia are the only immune cells whichpermanently reside in the CNSparenchyma, alongside neuraltube-derived neurons, astrocytes, and oligodendrocytes.

Tese past ew years, unprecedented insights were alsoprovided into their extreme dynamism and unctionalbehaviour, in health as much as in disease. Indeed, microglia

Hindawi Publishing CorporationNeural PlasticityVolume 2014, Article ID 610343, 15 pageshttp://dx.doi.org/10.1155/2014/610343
http://dx.doi.org/10.1155/2014/610343http://dx.doi.org/10.1155/2014/610343


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were revealed to be exceptional sensors o their environment,responding on a time scale o minutes to even subtle vari-ations o their milieu, by undergoing concerted changes inmorphology and gene expression [,]. During pathologicalinsults, activated microglia were particularly shown tothicken and retract their processes, extend lopodia, proli-

erate and migrate, release actors and compounds inuenc-ing neuronal survival (such as proinammatory cytokines,trophic actors, reactive oxygen species (ROS), etc.), andphagocytose pathogens, degenerating cells and debris, thusproviding better understanding o their roles in orchestratingthe inammatory response []. Tese abilities as immunecells are also recruited during normal physiological condi-tions, where surveillant microglia urther participate inthe remodeling o neuronal circuits by their phagocyticelimination o synapses and their regulation o glutamater-gic receptors maturation and synaptic transmission, amongother previously unexpected roles [], in addition totheir crucial involvement in the phagocytic elimination onewborn cells in the context o adult neurogenesis [].

Our review will discuss the emerging roles o microgliain adult hippocampal neurogenesis and their regulation byinammation during chronic stress, aging, and neurode-generative diseases, with a particular emphasis on theirunderlying molecular mechanisms and their unctional con-sequences or learning and memory (Figure).

2. A Brief Overview ofAdult Hippocampal Neurogenesis

Adult hippocampal neurogenesis is continuously maintainedby the prolieration o neural stem cells located in thesubgranular zone (SGZ) []. Tese neuroprogenitorshave been named radial glia-like cells (rNSCs), or type cells, since they morphologically and unctionally resemblethe embryonic radial glia. Tey have also been dened asquiescent neuroprogenitors because only a small percentageo the population is actively dividing during normal phys-iological conditions. Te lineage o these cells is requentlytraced by using analogs o the nucleotide thymidine, suchas bromodeoxyuridine (BrdU) which gets incorporated intothe DNA o dividing cells during the S phase and can bedetected by immunouorescence. Alternatively, their lineagecan be traced by labeling with uorescent reporters which are

delivered to dividing cells by retroviral vectors or expressedby specic cell type promoters via inducible transgenic mice(or a review o the methods commonly used to study adultneurogenesis, see []). Te daughter cells o rNSCs, alsocalled type cells or ampliying neuroprogenitors (ANPs),rapidly expand their pool by prolierating beore becomingpostmitotic neuroblasts. Within a month, these neuroblastsdifferentiate and integrate as mature neurons into the hip-pocampal circuitry []. Tey however display unique elec-trophysiological characteristics during several months, beingmore excitable than mature neurons [], and constitute aspecial cell population that is particularly inclined to undergosynaptic remodeling and activity-dependent plasticity [].

Tese unique properties o the newborn neurons andthe neurogenic cascade in general suggested that adulthippocampal neurogenesis could play an important rolein hippocampal-dependent unctions that require exten-sive neuroplasticity such as learning and memory. Indeed,activity-dependent plasticity and learning are long known

or modulating adult neurogenesis in a complex, yet specicmanner, with adult hippocampal neurogenesis being inu-enced by learning tasks which depend on the hippocam-pus [,]. For instance, hippocampal-dependent learningparadigms were ound to regulate the survival o newbornneurons, in a positive manner that depends on the timingbetween their birth andthe phases o learning [, ]. Young(. months old) newborn neurons were also shown tobe preerentially activated during memory recall in a watermaze task, compared to mature neurons, as determined bycolabeling o BrdU with immediate early genes such as c-Fos and Arc, in which expression correlates with neuronalring []. Nonetheless, it has only been in the last ewyears that loss-o-unction and gain-o-unction approacheswith inducible transgenic mice were able to conrm thatadult hippocampal neurogenesis is necessary or synaptictransmission and plasticity, including the induction o long-term potentiation (LP) and long-term depression [], aswell as trace learning in conditioned protocols [], memoryretention in spatial learning tasks [,], and encoding ooverlapping input patterns, that is, pattern separation [].

Adult hippocampal neurogenesis and its unctionalimplications or learning and memory are however inu-enced negatively by a variety o conditions that arecommonlyassociated with microglial activation andinammation in thebrain, such as chronic stress, aging, and neurodegenerativediseases, as we will review herein. Indeed, inammationcaused by irradiation produces a sustained inhibition oneurogenesis, notably by decreasing the prolieration andneuronal differentiation o the progenitors, and thereore,exposure to therapeutic doses o cranial irradiation has beenwidely used or modulating neurogenesis experimentallybeore the development o more specic approaches [].

3. Regulation of Adult HippocampalNeurogenesis by Inflammation

Inammation is a natural bodily response to damage orinection that is generally mediated by proinammatory

cytokines such as interleukin beta (IL-), interleukin (IL-), and tumour necrosis actor alpha (NF), in additionto lipidic mediators such as prostaglandins and leukotrienes.Ofentimes, it is associated with an increased production oROS, as well as nitric oxide (NO). ogether, these proin-ammatory mediators lead to an increase in local bloodow, adhesion, and extravasation o circulating monocytes,neutrophils, and lymphocytes []. In the brain, microglia arethe main orchestrator o the neuroinammatory response,but other resident cell types, including astrocytes, endothelialcells, mast cells, perivascular and meningeal macrophages,and even neurons, can produce proinammatory mediators,though perhaps not to the same extent as microglia [].


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Earlyneuroblasts

Lateneuroblasts

Immatureneurons

GranuleneuronsAstrocytes

Activated granuleneurons

Monocytes

Astrocytes

NeutrophilsStress

Glucocorticoids

Lymphocytes

LPSIrradiation

AgingAD

Fractalkine

Surveillantmicroglia

TNF

IL-1

Proliferation Survival Integration/differentation RecallExhaustion

Inflammatorychallenge

Apoptotic

newborn cell

Enrichedenvironment

Inflammatory microglia

ine

rNSCs ANPs

IGF-1 TGF-

IL-6

F : Te effects o surveillant and inammatory microglia on the adult hippocampal neurogenic cascade. During physiologicalconditions, surveillant microglia effectively phagocytose the excess o apoptotic newborn cells and may release antineurogenic actorssuch as GF. Tis anti-inammatory state is maintained by neuronal (tethered or released) ractalkine. Enriched environment drivesmicroglia towards a phenotype supportive o neurogenesis, via the production o IGF-. In contrast, inammatory challenge triggered byLPS, irradiation, aging, or AD induces the production o proinammatory cytokines such as IL-, NF, and IL- by microglia as well asresident astrocytes and inltrating monocytes, neutrophils, and lymphocytes. Tese cytokines have proound detrimental effects on adultneurogenesis by reducing the prolieration, survival, integration, and differentiation o the newborn neurons and decreasing their recallduring learning and memory paradigms.

In addition, peripheral immune cells invading the CNSduring inammation can urther produce proinammatorymediators, but the respective contribution o microglia versusother cell types in the inammatory response o the brain ispoorly understood.

Te harmul effects o inammation are also widelydetermined by the actual levels o proinammatory media-tors released, rather than the occurrence or absence o aninammatory response in itsel. For instance, NF regulatessynaptic plasticity by potentiating the cell surace expressiono AMPA glutamatergic receptors, thus resulting in a homeo-

static scaling ollowing prolonged blockage o neuronal activ-ity during visual system development []. However, NFalso produces differential effects at higher concentrations,ranging rom an inhibition o long-term potentiation to anenhancement o glutamate-mediated excitotoxicity in vitro[]. Inammation induced by chronic ventricular inusiono bacterial lipopolysaccharides (LPS; a main componento the outer membrane o Gram-negative bacteria), that is,the most widely used method or inducing an inammatorychallenge, also increases ex vivo the hippocampal levels oNFand IL-, thereby impairing novel place recognition,spatial learning, and memory ormation, but all these cog-nitive decits can be restored by pharmacological treatment

with a NF protein synthesis inhibitor, a novel analog othalidomide, ,-dithiothalidomide [].

Te impact o inammation on adult hippocampal neu-rogenesis was originally discovered by Olle Lindvall andTeo Palmers groups in , showing that systemic orintrahippocampal administration o LPS reduces the or-mation o newborn neurons in the adult hippocampus, aneffect that is prevented by indomethacin, a nonsteroidal anti-inammatory drug (NSAID) which inhibits the synthesis oproinammatory prostaglandins [,]. Similarly, inam-mation can determine the increase in neurogenesis that is

driven by seizures, a context in which neurogenesis can beprevented by LPS and increased by the anti-inammatoryantibiotic minocycline []. In these studies, hippocampalprolieration remained unaffected by LPS or minocycline andthus it is likely that inammation targeted the survival onewborn cells [, ], as LPS is known to increase SGZapoptosis []. Inammation also has urther downstreameffects on the neurogenic cascade. For instance, LPS increasesthe number o thin dendritic spines and the expressiono the excitatory synapses marker postsynaptic densityprotein o kDa (PSD) in newborn neurons. LPS inaddition increases the expression o GABA

Areceptors at early

stages o synapse ormation, leading to suggesting a possible


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imbalance o excitatory and inhibitory neurotransmissionin these young neurons []. Finally, LPS also prevents theintegration o newborn neurons into behaviourally relevantnetworks, including most notably their activation duringspatial exploration, as determined by the percentage o BrdUcells colabeled with the immediate early gene Arc [].

Importantly, none o these manipulations is specic tomicroglia and may directly or indirectly affect other braincells involved in the inammatory response o the brain. Forinstance, both LPS and minocycline affect astrocytic unctionin vitro and in vivo []. Furthermore, LPS is knownto drive inltration o monocytes and neutrophils into thebrain parenchyma []. Monocytes and neutrophils producemajor proinammatory mediators and could thereore act onthe neurogenic cascade as well. Te implication o microgliain LPS-induced decrease in neurogenesis is nonethelesssupported in vivo by the negative correlation between thenumber o newborn neurons (BrdU+, NeuN+ cells) andthe number o activated microglia (i.e., expressing ED)[]. ED, also called CD or macrosialin, is a lysosomalprotein which is overexpressed during inammatory chal-lenge. While the location o ED previously suggested itsinvolvementin phagocytosis, itsloss o unction didnot resultin phagocytosis decits and thus, its unction still remainsunknown (reviewed in []). Te number o ED-positivemicroglia also negatively correlates with neurogenesis duringinammation provoked by cranial irradiation []. Whilecorrelation does not involve causation, nor can pinpoint tothe underlying mechanism, these experiments were the rstto reveal a potential role or activated microglia in theregulation o adult hippocampal neurogenesis. More directevidence o microglial mediation in LPS deleterious effectswas obtained romin vitroexperiments, as it was shown thatconditioned media rom LPS-challenged microglia containedIL-, which in turn caused apoptosis o neuroblasts [].Nonetheless, astrocytes can also release IL- when stimulatedwith NF or IL- [] and chronic astrocytic releaseo IL- in transgenic mice reduced prolieration, survival,and differentiation o newborn cells, thus resulting in anet decrease in neurogenesis []. In summary, while thedetrimental impact o inammation on neurogenesis is wellestablished, more work is needed to dene the specic rolesplayed by the various inammatory cells populating thebrain.

4. Inflammation Associated withChronic Stress

Across health and disease, the most prevalent condi-tion that is associated with neuroinammation is chronicstress, which commonly reers to the repeated or sus-tained inability to cope with stressul environmental, social,and psychological constraints. Chronic stress is character-ized by an imbalanced secretion o glucocorticoids by thehypothalamic-pituitary-adrenal (HPA) axis (most notablycortisol in humans and corticosterone in rodents), whichleads to an altered brain remodeling, massive loss o synapses,and compromised cognitive unction []. In particular, an

impairment o spatial learning, working memory, noveltyseeking, and decision making has been associated withchronic stress []. Glucocorticoids are well known ortheir anti-inammatory properties, as they interere withNF-B-mediated cytokine transcription, ultimately delayingwound healing []. Tey are also potent anti-inammatory

mediators in vivo [] and in puried microglia cultures[]. Recently, repeated administration o high doses oglucocorticoids by intraperitoneal injection, to mimic theirrelease by chronic stress, was also shown to induce a losso dendritic spines in the motor cortex, while impairinglearning o a motor task. A transcription-dependent pathwayacting downstream o the glucocorticoid receptor GR wasproposed [,] but the particular cell types involved werenot identied.

Microglia are considered to be a direct target o the gluco-corticoids, as they were shown to express GR during normalphysiological conditionsin vivo[]. In act, transgenic micelacking GR in microglia and macrophages show an increasedproduction o proinammatory mediators (including NFand IL-) and greater neuronal damage in response to anintraparenchymal injection o LPS, compared to wild-typemice []. In contrast, glucocorticoids are considered to beproinammatory in the chronically stressed brain [], whereamong other changes they can promote inammation, oxida-tive stress, neurodegeneration, and microglial activation[].For example, repeated restraint stress induces microglialprolieration and morphological changes, including a hyper-ramication o their processes in the adult hippocampusollowing restraint stress [], but a nearly complete losso processes in the context o social deeat []. Prenatalrestraint stress also causes an increase in the basal levels oNF andIL-, while increasing theproportion o microgliashowing a reactive morphology in the adult hippocampus[]. Similarly, social deeat leads to an enhanced responseto the inammatory challenge induced by intraperitonealinjection o LPS, including an increased production o NFand IL-, and expression o inducible NO synthase (iNOS)by microglia, accompanied by an increased inltration ocirculating monocytes [, ]. Tereore, microglia are astrong candidate or mediating some o the effects o stresson adult neurogenesis, as will be discussed below, in synergywith other types o inammatory cells.

Chronic stress is well known or its negative effects onhippocampal neurogenesis (reviewed in [,]), althoughnot all stress paradigms are equally effective []. Several

stress paradigms can decrease neuroprogenitors prolierationinthe treeshrew []andinmice[, ], although this effectseems to be compensated by an increasedsurvival o newbornneurons [] and whether stress results in a net increaseor decrease in neurogenesis remains controversial (reviewedin [, ]). Te effects o stress on adult neurogenesisseem to be mediated at least partially by glucocorticoids,because mice lacking a single copy o the GR gene showbehavioural symptoms o depression including learned help-lessness, neuroendocrine alterations o the HPA axis, andimpaired neurogenesis []. In parallel, chronic stress isassociated with an increased inammatory response, whichmay inhibit neurogenesis as well. For instance, serum levels


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o IL- and IL- are signicantly increased in depressedpatients []. In mice, restraint stress leads to a widespreadactivation o NF-B in the hippocampus, including at thelevel o neuroprogenitors [] and increased protein levels oIL-[]. In addition to the direct role o glucocorticoids,IL- also seems to mediate some o the effects o mild

chronic stress, because in vivo manipulations that block IL-(either pharmacologically or in null transgenic mice) preventthe anhedonic stress response and the antineurogenic effecto stress[, ]. Moreover, the corticoids and IL- pathwaysmay regulate each other in a bidirectional manner becausethe administration o a GR antagonist can blunt the LPS-induced production o hippocampal IL- in stressed mice[], whereas mice knockout or the IL-receptor (IL-R)ail to display the characteristic elevation o corticosteroneinduced by mild chronic stress []. Another stress-relatedcytokine, IL-, induces depressive phenotypes and preventsthe antidepressant actions o uoxetine when administered tomicein vivo[]. So ar the effects o stress on neurogenesis

via corticosteroids and inammation have been assumed tobe cell autonomous, as neuroprogenitors express both GR[] and IL-R []. Te potential participation o microgliais yet to be determined, but there are some reports o adirect effect o stress on microglial activation. For instance,microglia acutely isolated rom mice subjected to acute stress(by inescapable tail shock) showed a primed response to LPSchallenge by producing higher levels o IL-mRNAex vivo[], and the specic loss o expression o GR in microglialeads to a blunted inammatory response in vitro and to adecreased neuronal damagein vivoin response to LPS [].In stress paradigms, these enhanced responses o microgliato inammatory challenges are similar to their age-relatedpriming which has been associated with and is possiblydue to an increased basal production o proinammatorymediators. However, whether microglia express increasedlevels o IL- and other proinammatory cytokines inresponse to stressul eventsis presently unclear [].It isthuspossible that some o the antineurogenic effects o stress areexerted by means o microglial-dependent inammation, butthis hypothesis remains to be experimentally tested.

5. Inflammation Associated with Aging andNeurodegenerative Diseases

Inammation is also commonly associated with normal

aging and neurodegenerative diseases and, thereore, couldrepresent a putative underlying mechanism that explainstheir decrease in hippocampal neurogenesis. Nonetheless,inammation is also associated with neurological diseases,such as epilepsy or stroke, where neurogenesis is thought tobe increased, although the data rom rodents and humans issomewhat conictive []. Neurogenesis is well known todecline throughout adulthood and normal aging in rodentsandhumans [, ], but the decay is more pronounced andoccurs later in lie in mice than in humans []. Te aging-associated decrease in neurogenesis has been shown to occurmainly as a consequence o exhaustion o the rNSC popula-tion which, afer being recruited and activated, undergo three

rounds o mitosis in average and then terminally differentiateinto astrocytes [, ]. In addition, a reduced mitoticcapacity o the neuroprogenitors could urther contribute todecreasing neurogenesis [], and moreover, an age-relatedincrease in the levels o proinammatory cytokines couldalso hinder neurogenesis in the aging brain. Serum levels

o IL-, IL-, and NF are elevated in elderly patients[, ]. Aged microglia express higher levels o theseproinammatory cytokines and show a greater response toLPS inammatory challenge, that is, a primed response,than their younger counterparts []. Te origin o thislow-grade age-related inammation (inamm-aging [])remains unknown and may be related to both aging anddamage to the surrounding neurons, as well as aging o theimmune systemper se.

At the cellular level, stress to the endoplasmic reticulum(ER) caused by various perturbations, such as nutrient deple-tion, disturbances in calcium or redox status, or increasedlevels o misolded proteins, can induce a cell-autonomousinammatory response to neurons. Stress to the ER, a mul-tiunctional organelle which is involved in protein olding,lipid biosynthesis, and calcium storage triggers a homeostaticresponse mechanism named the unolding protein response(UPR), aiming to clear the unolded proteins in order torestore normal ER homeostasis []. However, i the ERstresscannot be resolved,the UPRalso initiatesinammatoryand apoptotic pathways via activation o the transcriptionactor NF-B which controls the expression o most proin-ammatory cytokines []. In the brain, ER stress is ofeninitiated by the ormation o abnormal protein aggregatesin several neurodegenerative diseases such as Alzheimersdisease (AD), Parkinsons disease (PD), amyotrophic lateralsclerosis (ALS),Huntingtons disease (HD), and prion-relateddisorders []. Tis neurodegeneration-associated ER stressis assumed to occur mostly in neurons, but there aresome examples o microglial protein misolding as well. Forinstance, both microglia and neurons overexpress CHOP(C/EBP homologous protein), a transcription actor whichis activated during ER stress in human patients and mousemodels o ALS []. Inammation has been speculated tobe a main negative contributor to the pathology o ALS[], but a direct microglial involvement in mediating theinammatory response to abnormal protein aggregation inALS and other neurodegenerative conditions remains to betested. Finally, ER stresshas beenlinkedto a variety o inam-matory conditions [,], including chronic stress, diet-

induced obesity, and drug abuse, as well as atherosclerosisand arthritis []. During normal aging, a progressivedecline in expression and activity o key ER molecularchaperones and olding enzymes could also compromise theadaptive response o the UPR, thereby contributing to theage-associated decline in cellular unctions []. Tereore,aging is strongly associated with a chronic ER stress whichleads to increased activation o NF-B []; however, thecontribution o the different brain cell types to inamm-aging is still poorly understood. Te detrimental effects onneurogenesis o increased proinammatory cytokines in theaging brain are not necessarily related to microglia, but alsoto stressed neurons. Furthermore, ER stress may also cause a


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cell-autonomous response in neural stem cells [], althoughits impact on neurogenesis remains to be experimentallydetermined.

In addition, aging is accompanied by an increased levelo mitochondrial oxidative stress, which in turn activatesthe Inammasome [], a group o multimeric proteins

comprising the interleukin converting enzyme (ICE, cas-pase ) which serves to release the active orm o thecytokine []. IL- may act directly on rNSCs (visualisedby labeling with the Sox marker), as they express IL-R in the adult hippocampus []. reatment with IL-decreases hippocampal prolieration in young mice [] andpharmacological inhibition o ICE partially restores the num-ber o newborn neurons in aged mice without signicantlyaffecting their differentiation rate []. ransgenic IL-overexpression results in chronic inammation and deple-tion o doublecortin-labeled neuroblasts, thus mimickingthe aging-associated depletion o neurogenesis []. Teactual mechanism o action o IL- on neurogenesis in

aged mice, including decreased prolieration o rNSCs/ANPsand survival o newborn neurons, remains undetermined.Microglia are a main source o IL-in the aging brain, butthe hypothesis that microglia-derived IL- is responsibleor depleting neurogenesis in the aging brain remains to bedirectly tested.

Te regulation o neurogenesis by IL- in the agingbrain has been urther linked to the activity o anothercytokine, the chemokine ractalkine, or CXCL. Fractalkinehas soluble and membrane-tethered orms and is exclu-sively expressed by neurons, while the ractalkine receptor(CXCR) is expressed in the brain by microglia alone [ ].Tis module orms a uniqueneuron-microglia signalling unit

that controls the extent o microglial inammation in severalneurodegenerative conditions including PD, ALS [], orAD []. In act, CXCR blocking antibodies increasethe production o hippocampal IL- when administeredto young adult rats []. Importantly, chronic treatmentwith ractalkine increases hippocampal prolieration and thenumber o neuroblasts in aged ( months old) but notyoung ( months old) or middle-aged rats ( months old),whereas an antagonists o CXCR has the opposite effectsin young, but not in middle-aged nor old rats []. Sinceractalkine expression is decreased during aging [], areduced neuron-microglia signalling might be releasing thebrake on microglial contribution to inammatory responses,although increased levels o ractalkine were instead reportedin aged rat hippocampus by other studies []. Additionalinsights into the role o ractalkine signalling come romknock-in mice in which the endogenous CXCR locus isreplaced by the uorescent reporter GFP []. Te initial

studies suggested that CX3CR1GFP/GFP (i.e., CX3CR1/)mice haveno signicant differences in brain development andunctions [], but more systematic investigations recentlyrevealed a long list o hippocampal-dependent changes in

young ( months old) CX3CR1GFP/GFP and CX3CR1GFP/+

mice compared to wild-type mice. Tese changes notablyincluded decreased neuroprogenitors prolieration and neu-roblasts number, impaired LP, perormance in contextual

ear conditioning and water maze spatial learning and mem-ory, and, importantly, increased IL- protein levels [].Tesignalling pathway o ractalkine-IL- is unctionally rele-

vant, because IL-R antagonists rescued LP and cognitive

unction in CX3CR1GFP/GFP mice []. In sum, even thoughneuronal ractalkine seems to be sufficient or restraining

the inammatory activity o microglia in young rats, itsdownregulation during aging could activate the microglialinammatory response and thereby subsequently reduce theprolieration o remaining neuroprogenitors.

In AD, inammatory cytokines such as IL- are over-expressed in the microglia associated with the amyloid beta(A) plaques o postmortem samples [] and in transgenicmice modeling the disease []. Te loss o synapses (romhippocampus to rontal cortex) is one o the main patho-logical substrates in this disease, but adult neurogenesis isalso severely reduced in most mouse models o AD, possiblydue to a decreased prolieration o neuroprogenitors and adecreased survival o newborn cells, even though the putative

changes in the neurogenic cascade in postmortem samplesremain controversial (reviewed in []). Tis lack o agree-ment is possibly explained by the act that the vast majorityo AD cases have a late onset over years o age, when littleneurogenesis remains. In contrast, in most transgenic ADmouse models, the Aaccumulation, cognitive decits, andchanges in neurogenesis are already detectable in young ani-mals (- months old). Te study o AD is urther hinderedby the difficulty in comparing the time course and pathologyacross different mouse models. For instance, early treatmentwith minocycline can improve cognition and reduce Aburden in mice expressing the human amyloid precursorprotein (APP) []. In contrast, in mice expressing APP and

a mutated orm o presenilin (PS), which is part o thesecretase pathway that cleaves A, inammation is reducedwithout any detectable changes in A plaques deposition[]. Concomitantly with a decrease in tissue inamma-tory cytokines and number o microglial cells, minocyclinerestores neurogenesis and hippocampus-dependent memorydecits in these APP/PS mice [], indirectly suggestingthat cognitive decay in AD may be at least in part relatedto a detrimental effect o inammation on hippocampalneurogenesis. Direct evidence that neurogenesis is associatedwith the cognitive perormance in AD is still lacking. Furtherresearch is also necessary to determine the neurogenic targetso AD-related inammation. One central open questionor uture therapies aiming at increasing neurogenesis andcognition in AD is whether neuroprogenitors are spared orwhether their age-induced loss becomes accelerated. Rather

than increasing the prolieration and neurogenic output othe ew rNSCs remaining in an old AD brain, it may be morerelevant to develop strategies that prevent the age-related losso neuroprogenitors in presymptomatic patients.

In summary, inammation associated with a wide varietyo experimental models o disease produces strong detri-mental effects on hippocampal neurogenesis. Tese effectson human neurogenesis are however not so well describedand, in vitro, IL- increases the prolieration o hip-pocampal embryonic neuroprogenitors but decreases their


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differentiation into neurons []. Novel methods to assesshippocampal neurogenesis in the living human brain, rommetabolomics o neuroprogenitors to hippocampal bloodbrain volume (reviewed in []), will help to determine thecontribution o inammation to adult neurogenesis in thehealthy and diseased human brain during aging.

6. Normal Physiological Conditions

In the healthy mature brain, microglia are an essential com-ponent o the neurogenic SGZ niche, where they physicallyintermingle with neuroprogenitors, neuroblasts, and new-born neurons []. Here, surveillant microglia effectively andrapidly phagocytose the excess o newborn cells undergoingapoptosis []. Importantly, microglial phagocytosis in theadult SGZ is not disturbed by inammation associated withaging or by LPS challenge, as the phagocytic index (i.e.,

the proportion o apoptotic cells completely enguled bymicroglia) is maintained over % in these conditions [].Nonetheless, the consequences o microglial phagocytosis onadult hippocampalneurogenesis remain elusive.reatmentomice with annexin V, which binds to the phosphatidylserine(PS) receptor and prevents the recognition o PS on thesurace o apoptotic cells, presumably blocking phagocytosis,increases the number o apoptotic cells in the SGZ []. Con-comitantly, annexin V reduces neurogenesis by decreasingthe survival o neuroblasts without affecting neuroprogeni-tors prolieration []. Similar results were obtained in trans-genic mice knock-out or ELMO, a cytoplasm protein whichpromotes the internalization o apoptotic cells, althoughthe effects on neurogenesis were ascribed to a decreasedphagocytic activity o neuroblasts []. Te actual phagocytictarget o the neuroblasts remains undetermined, but thenewborn apoptotic cells in the adult SGZ are exclusivelyphagocytosed by microglia, at least in physiological condi-tions []. Nevertheless, none o the above manipulationshas specically tested the role o microglial phagocytosisin hippocampal-dependent learning and memory and thus,the unctional impact o microglial phagocytosis in adultneurogenic niches during normal physiological conditionsremains to be elucidated.

Microglial phagocytosis o apoptotic cells is activelyanti-inammatory, at least in vitro, and thus it has beenhypothesized that anti-inammatory cytokines produced by

phagocytic microglia may urther regulate neurogenesis [].For instance, transorming growth actor beta (GF), whichis produced by phagocytic microgliain vitro [], inhibitsthe prolieration o SGZ neuroprogenitors []. Microgliaare urther able to produce proneurogenic actors in vitro[]. When primed with cytokines associated with helpercells such as interleukin (IL-) or low doses o intererongamma (IFN), cultured microglia support neurogenesis andoligodendrogenesis through decreased production o NFand increased production o insulin-like growth actor (IGF-) [], an inducer o neuroprogenitor prolieration[]. A list o potential actors produced by microgliaand known to act on neuroprogenitor prolieration can

be ound in able . In addition, recent observations sug-gest that neuroprogenitor cells may not only regulate theirown environment, but also inuence microglial unctions.For instance, vascular endothelial growth actor (VEGF)produced by cultured neuroprecursor cells directly affectsmicroglial prolieration, migration, and phagocytosis [].

More potential actors produced by neuroprogenitors shownto be inuencing microglial activity and unction can beound in able. However, it has to be taken into accountthat most o these observations were obtained in culture andthat urther research is needed in order to elucidate whetherthose actors are also secreted and have the same regulatoryresponsesin vivo.

In addition, microglial capacity to remodel and eliminatesynaptic structures during normal physiological conditionshas suggested that microglia could also control the synap-tic integration o the newborn neurons generated duringadult hippocampal neurogenesis []. Tree main mech-anisms were proposed: () the phagocytic elimination ononapoptotic axon terminals and dendritic spines, () theproteolytic remodeling o the perisynaptic environment,and () the concomitant structural remodeling o dendriticspines [, ]. Indeed, microglial contacts with synapticelements are requently observed in the cortex during normalphysiological conditions, sometimes accompanied by theirengulment and phagocytic elimination [], as in thedeveloping retinogeniculate system []. Microglial cells aredistinctively surrounded by pockets o extracellular space,contrarily to all the other cellular elements [], suggestingthat microglia could remodel the volume and geometryo the extracellular space, and thus the concentration o

various ions, neurotransmitters, and signalling moleculesin the synaptic environment. Whether microglia create thepockets o extracellular space themselves or not remainsunknown, but these pockets could result rom microglialrelease o extracellular proteases such as metalloproteinasesand cathepsins [], which are well known or inuencingthe ormation, structural remodeling, and elimination odendritic spinesin situand also experience-dependent plas-ticityin vivo[,]. More recently, microglial phagocytosiso synaptic components was also observed in the developinghippocampus, in the unique time window o synaptogenesis,a process which is notably regulated by ractalkine-CXCRsignalling []. Tereore, the attractive hypothesis thatmicroglial sculpts the circuitry o newborn cells in the adulthippocampus deserves urther attention.

Lastly, microglia were also involved in increasing adulthippocampal neurogenesis in the enriched environment(EE) experimental paradigm. EE is a paradigm mimick-ing some eatures o the normal living circumstances owild animals, as it gives them access to social interactions,toys, running wheels, and edible treats. EE has long beenknown to enhance neurogenesis by acting on newborncells survival, resulting ultimately in an enlargement othe dentate gyrus []. Functionally, these changes areaccompanied by enhanced spatial learning and memoryormation with the water maze paradigm []. Similarincreases in neurogenesis are obtained by subjecting miceto voluntary running paradigms, although in this case the


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: Summary o actors secreted by microglia and the potential effect they have on neuroprogenitorsin vitro.

Microglia secreted actors Reerence Modulation o neural progenitor cells Reerence

BDNF [] Differentiation []

EGF [] Survival, expansion, prolieration, differentiation []

FGF [] Survival and expansion []

GDNF [] Survival, migration, and differentiation []IGF- [] Prolieration []

IL- [] Reduction in migration []

IL- [] Inhibition o neurogenesis []

IL- [] Differentiation []

IL- [] Differentiation []

N- [] Differentiation []

PDGF [] Expansion and differentiation []

GF [] Inhibition o prolieration []

: Summary o actors secreted by neuroprogenitors and the potential effect they have on microgliain vitro.

NPC secreted actors Reerence Modulation o microglia Reerence

BDNF [] Prolieration and induction o phagocytic activity []

Haptoglobin [] Neuroprotection []

IL- [] Intracellular Ca+ elevation and prolieration []

IL- [] Increase in prolieration []

M-CSF [] Mitogen []

NGF [] Decrease in LPS-induced NO []

GF [] Inhibition o NFsecretion []

NF [] Upregulation o IL- secretion []

VEGF [] Induction o chemotaxis and prolieration []

effect is mediated by increased neuroprogenitor prolieration[]. During inammatory conditions, EE is antiapoptoticand neuroprotective [] and it limits the hippocampalresponse to LPS challenge by decreasing the expression oseveral cytokines and chemokines, includingIL- and NF[]. In act, EE is believed to counteract the inammatoryenvironment and rescue the decreased number o neuroblastsin CX3CR1GFP/GFP mice compared to wild-type mice [].Te effects o EE are independent o the IL- signallingpathway, as it increases neurogenesis in mice that are nullor IL-R []. EE also induces microglial prolieration andexpression o the proneurogenic IGF- [], but the ullphenotype o microglia in EE compared to standard housingand its impact on the neurogenic cascade remains to be

determined.Te mechanisms behind the anti-inammatory actions

o EE are unknown, but they were suggested to involvemicroglial interactions with lymphocytes through anincreased expression o the majorhistocompatibility complexo class II (MHC-II) during EE []. MHC-II is responsibleor presenting the phagocytosed and degraded antigens tothe antibodies expressed on the surace o a subtype o lymphocytes ( helper or CD+ cells), thus initiatingtheir activation and production o antigen-specic antibod-ies. Severe combined immunodecient (SCID) mice lackingeither and B lymphocytes or nude mice lacking only cells have impaired prolieration and neurogenesis in normal

and EE housing compared to wild-type mice [], as wellas impaired perormance in the water maze []. Similarly,antibody-based depletion o helper lymphocytes impairsbasal and exercise-induced prolieration and neurogenesis[]. Furthermore, a genetic study in heterogeneous stockmice, which descend rom eight inbred progenitor strains,has ound a signicant positive correlation between geneticloci associated to hippocampal prolieration and to theproportion o CD+ cells among blood CD+ lymphocytes[]. Additional experiments are needed to ully determinethe possible interactions between microglia and cellsin neurogenesis, because, at least in normal physiologicalconditions, () cell surveillance o the brain parenchymais minimal, () microglia are poor antigen presenting cells,

and () antigen presentation by means o MHC-II amily omolecules is thought to occur outside the brain, that is, in themeninges and choroid plexus []. In act, during voluntaryexercise, there are no signicant changes in cell surveillanceo the hippocampus, nor a direct interaction between cellsand microglia, nor any changes in the gene expression proleo microglia, including that o IGF-, IL-, and NF[].Te number o microglia is also inversely correlated withthe number o hippocampal prolierating cells, rNSCs, andneuroblasts in aged ( months) mice subjected to voluntaryrunning, as well as in vitro cocultures o microglia andneuroprogenitors, which has been interpreted as resultingrom an overall inhibitory effect o microglia on adult


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neurogenesis []. Even though EE is clearly a more com-plex environmental actor than voluntary running, urtherresearch is necessary to disregard nonspecic or indirecteffects o genetic or antibody-based cells depletion onmicroglia and other brain cell populations, including rNSCs.For instance, adoptive transer o helper cells treated with

glatiramer acetate, a synthetic analog o myelin basic protein(MBP) approved or the treatment o multiple sclerosis, pro-duces a bystander effect on resident astrocytes and microgliaby increasingtheir expression o anti-inammatory cytokinessuch as GF[]. Alternatively, it has been suggested that cells may mediate an indirect effect on adult hippocampalneurogenesis by increasing the production o brain-derivedneurotrophic actor (BDNF) [], which is involved in theproneurogenic actions o EE []. Whether BDNF cancounteract the detrimental effects o cell depletion on neu-rogenesisremains unknown. Overall, the roles o microglia inEE and running-induced neurogenesis are unclear and haveto be addressed with more precise experimental designs. Insummary, surveillant microglia are part o the physical nichesurrounding the neural stem cells and newborn neurons othe mature hippocampus, where they continuously phagocy-tose the excess o newborn cells. Microglia were also linked tothe proneurogenic and anti-inammatory effects o voluntaryrunning and EE, but direct evidence is missing. Te overallcontribution o microglia to neurogenesis and learning andmemory in normal physiological conditions remains largelyunexplored at this early stage in the eld.

7. Conclusion

In light o these observations, microglia are now emergingas important effector cells during normal brain developmentand unctions, including adult hippocampal neurogenesis.Microglia can exert a positive or negative inuence onthe prolieration, survival, or differentiation o newborncells, depending on the inammatory context. For instance,microglia can compromise the neurogenic cascade duringchronic stress, aging, and neurodegenerative diseases, bytheir release o proinammatory cytokines such as IL-,IL-, and NF. A reduced ractalkine signalling betweenneurons and microglia could also be involved during normalaging. However, microglia are not necessarily the only celltype implicated because astrocytes, endothelial cells, mastcells, perivascular and meningeal macrophages, and to a

lesser extent neurons and invading peripheral immune cellscould urther contribute by releasing proinammatory medi-ators.

Additionally, microglia were shown to phagocytose theexcess o newborn neurons undergoing apoptosis in thehippocampal neurogenic niche during normal physiologicalconditions, while a similar role in the synaptic integrationo newborn cells was also proposed in light o their capacityto phagocytose synaptic elements. Lastly, microglial interac-tions with cells, leading to the release o anti-inammatorycytokines, neurotrophic actors, and other proneurogenicmediators (notably during EE and voluntary running), couldcounteract the detrimental effects o inammation on adult

hippocampal neurogenesis and their unctional implicationsor learning and memory.

However, urther research is necessary to assess the rela-tive contribution o microglia versus other types o residentand inltrating inammatory cells and to determine thenature o the effector cytokines and other inammatory

mediators involved, as well as their cellular andmolecular tar-gets in the neurogenic cascade. Such research will undoubt-edly help to develop novel strategies aiming at protecting theneurogenic potential and ultimately its essential contributionto learning and memory.

Abbreviations

AD: Alzheimers disease

ANPs: Ampliying neuroprogenitorsAPP: Amyloid precursor proteinA: Amyloid betaBDNF: Brain-derived neurotrophic actorBrdU: -Bromo--DeoxyuridineCXCL: FractalkineCXCR: Fractalkine receptorEAE: Experimental acute encephalomyelitisEE: Enriched environmentEGF: Epidermal growth actorFGFb: Basic broblast growth actorGDNF: Glial cell line-derived neurotrophic actorGFAP: Glial brillary acidic proteinGR: Glucocorticoid receptorHPA: Hypothalamic-pituitary-adrenal axisICE: Interleukin converting enzymeIL-: Interleukin betaIL-R: Interleukin beta receptorIL-: Interleukin IL-: Interleukin IL-: Interleukin IL-: Interleukin IFN: Intereron gammaIGF-: Insulin-like growth actor iNOS: Inducible nitric oxide synthaseLPS: Bacterial lipopolysaccharidesLP: Long term potentiationM-CSF: Macrophage colony-stimulating actorMBP: Myelin basic protein

MHC-II: Major histocompatibility complex class IIMOG: Myelin oligodendrocyte glycoproteinNF-B: Nuclear actor

kappa-light-chain-enhancer o activated Bcells

NGF: Nerve growth actorNO: Nitric oxideNSAID: Nonsteroidal anti-inammatory drugN-: Neurotrophin-PDGF: Platelet-derived growth actorPS: PhosphatidylserinePS: Presenilin ROS: Radical oxygen species


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SCID: Severe combined immunodeciencySGZ: Subgranular zoneGF: ransorming growth actor betaNF: umor necrosis actor alphaVEGF: Vascular endothelial growth actor.

Conflict of InterestsTe authors declare that there is no conict o interestsregarding the publication o this paper.

Acknowledgments

Tis work was supported by grants rom the Spanish Min-istry o Economy and Competitiveness to Amanda Sierra(BFU-) and Juan M. Encinas (SAF-),rom Basque Government (Saiotek S-PC UN) and Iker-basquestart-up unds to Juan M. Encinas andAmanda Sierra,and rom Te Banting Research Foundation, the Scottish Rite

Charitable Foundation o Canada, and start-up unds romUniversite Laval and Centre de recherche du CHU de Quebecto Marie-Eve remblay.

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