Adult neurogenesis:a real hope or a delusion?

Adult neurogenesis,the process of creating new neurons,involves the coordinated division,migration,and differentiation of neural stem cells.This process is restricted to neurogenic niches located in two distinct areas of the brain:the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle,where new neurons are generated and then migrate to the olfactory bulb.Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells.Interestingly,recent years have seen tremendous progress in our understanding of adult brain neurogenesis,bridging the knowledge gap between embryonic and adult neurogenesis.Here,we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells.In this notion,we talk about the importance of intra cellular signaling molecules in mobilizing endogenous neural stem cell prolife ration.Based on the current understanding,we can declare that these molecules play a role in targeting neurogenesis in the mature brain.However,to achieve this goal,we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints,which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.

Versatile strategies for adult neurogenesis:avenues to repair the injured brain

Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies.

Microglial activation and adult neurogenesis after brain stroke

The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research.These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle,subgranular zone in the hippocampal dentate gyrus and in the striatum,a component of the basal ganglia,even in humans.In the human hippocampus,neuroblasts are produced even in elderlies.The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules,neurotransmitters and soluble factors released by different sources including glial cells.Microglia,the resident macrophages of the central nervous system,are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions.Following stroke and other acute neural disorders,there is an increase in the numbers of neuroblast production in the neurogenic niches.Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke,depending on the activation level and brain location.In this article,we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia.A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.

Acupuncture: a potent therapeutic tool for inducing adult neurogenesis

Acupuncture has been broadly used as a major therapeutic tool for at least 2,100 years in East Asia. Acupuncture is used for improving the pathological condition of remote organs, such as stomach, liver, brain, etc. by stimulating skin and muscle with fine metal needles through meridians which have been regarded as pathways of Qi within the body （Ernst, 2006）. Physicians in East Asia have tried to treat many kinds of diseases by acupuncture and it was considerably success- ful. Various diseases for which acupuncture is known to be effective, are neurological diseases, including sequelae of stroke, Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, and so on （Nam et al., 2013）.

Features of adult neurogenesis and neurochemical signaling in the Cherry salmon Oncorhynchus masou brain

We investigated the distribution of gamma aminobutyric acid, tyrosine hydroxylase and nitric oxide-producing elements in a cherry salmon Oncorhynchus masou brain at various stages of postnatal ontogenesis by immunohistochemical staining and histochemical staining. The periventricular region cells exhibited the morphology of neurons and glia including radial glia-like cells and contained several neurochemical substances. Heterogeneous populations of tyrosine hydroxylase-, gamma aminobutyric acid-immunoreactive, as well as nicotinamide adenine dinucleotide phosphate diaphorase-positive cells were observed in proliferating cell nuclear antigen-immunoreactive proliferative zones in periventricular area of diencephalon, central grey layer of dorsomedial tegmentum, medulla and spinal cord. Immunolocalization of Pax6 in the cherry salmon brain revealed a neuromeric construction of the brain at various stages of postnatal ontogenesis, and this was confirmed by tyrosine hydroxylase and gamma aminobutyric acid labeling.

The dynamics of adult neurogenesis in human hippocampus

The phenomenon of adult neurogenesis is now an accepted occurrence in mammals and also in humans.At least two discrete places house stem cells for generation of neurons in adult brain. These are olfactory system and the hippocampus. In animals, newly generated neurons have been directly or indirectly demonstrated to generate a significant amount of new neurons to have a functional role. However, the data in humans on the extent of this process is still scanty and such as difficult to comprehend its functional role in humans. This paper explores the available data on as extent of adult hippocampal neurogenesis in humans and makes comparison to animal data.

Proteomic-based evidence for adult neurogenesis in birds and mammals as indicated from cerebrospinal fluid

Adult neurogenesis is the life-long process of neural stem cell proliferation,differentiation into neurons,migration,and incorporation into the existing neuronal circuits.After decades of research,it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny.Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated.Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition.Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood.In this review,we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans(Homo sapiens);mice(Mus musculus);sheep(Ovis aries);chickens(Gallus gallus);and two parrot species,the budgerigar(Melopsittacus undulatus)and cockatiel(Nymphicus hollandicus).We identified up to 911 proteins represented in cerebrospinal fluid,involved in various pathways regulating adult neurogenesis.However,only 196 proteins were common across humans,mice,and birds.Pathway components involved in nervous system development,cell migration,and axonal guidance were commonly evident in all species investigated so far.Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions,cell-adhesion molecules,signals regulating extracellular matrix remodeling,regulation of insulin growth factor signaling,axonal guidance,programmed cell death,immune signaling,and post-translational modifications.Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid.However,the information presently available is still highly fragmentary,and far more questions persist than are answered.Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.

Adult neurogenesis in the four-striped mice(Rhabdomys pumilio)

In this study, we investigated non-captive four-striped mice （Rhabdomys pumilio） for evidence that adult neurogenesis occurs in the adult brain of animal models in natural environment. Ki-67 （a marker for cell proliferation） and doublecortin （a marker for immature neurons） immunos-taining conifrmed that adult neurogenesis occurs in the active sites of subventricular zone of the lateral ventricle with the migratory stream to the olfactory bulb, and the subgranular zone of the dentate gyrus of the hippocampus. No Ki-67 proliferating cells were observed in the striatum substantia nigra, amygdala, cerebral cortex or dorsal vagal complex. Doublecortin-immunore-active cells were observed in the striatum, third ventricle, cerebral cortex, amygdala, olfactory bulb and along the rostral migratory stream but absent in the substantia nigra and dorsal vagal complex. The potential neurogenic sites in the four-striped mouse species could invariably lead to increased neural plasticity.

Adult Neurogenesis (A5)

The ability to generate new neurons in the subventricular zone （SVZ） of the lateral ventricles and the subgranular zone （SGZ） of the hippocampal dentate gyrus provides the adult mammalian brain an important level of plasticity for maintaining cellular homeostasis under physiological conditions, and potentially underlies an injury response under pathological contexts.

Adult neurogenesis and in vivo reprogramming:combining strategies for endogenous brain repair

Functional recovery of the human brain after injury, or slowing of a neurodegenerative disease is the ultimate goal of brain research. Many promising studies have identified key genes involved in the generation of neuroblasts and oligodendrocytes from adult neurogenic niches and determined their involvement in endogenous regeneration after injury. Interestingly,

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

5-Bromo-2'-deoxyuridine labeling:historical perspectives,factors infiuencing the detection,toxicity,and its implications in the neurogenesis

The halopyrimidine 5-bromo-2′-deoxyuridine(BrdU)is an exogenous marker of DNA synthesis.Since the introduction of monoclonal antibodies against BrdU,an increasing number of methodologies have been used for the immunodetection of this synthesized bromine-tagged base analogue into replicating DNA.BrdU labeling is widely used for identifying neuron precursors and following their fate during the embryonic,perinatal,and adult neurogenesis in a variety of vertebrate species including birds,reptiles,and mammals.Due to BrdU toxicity,its incorporation into replicating DNA presents adverse consequences on the generation,survival,and settled patterns of cells.This may lead to false results and misinterpretation in the identification of proliferative neuroblasts.In this review,I will indicate the detrimental effects of this nucleoside during the development of the central nervous system,as well as the reliability of BrdU labeling to detect proliferating neuroblasts.Moreover,it will show factors influencing BrdU immunodetection and the contribution of this nucleoside to the study of prenatal,perinatal,and adult neurogenesis.Human adult neurogenesis will also be discussed.It is my hope that this review serves as a reference for those researchers who focused on detecting cells that are in the synthetic phase of the cell cycle.

Enhancement of endogenous midbrain neurogenesis by microneurotrophin BNN-20 after neural progenitor grafting in a mouse model of nigral degeneration

We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the“weaver”mouse,a model of progressive nigrostriatal degeneration.Here,we extended our investigation in two clinically-relevant ways.First,we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.Second,we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice,at late stages of degeneration.We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells,marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors.In agreement,we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice.However,the graft strongly induced an endogenous neurogenic response throughout the midbrain,which was significantly enhanced by the administration of microneurotrophin BNN-20.Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20.Interestingly,the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.

Transgenic mouse models for studying adult neurogenesis

The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associatedcognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use nenrogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.

No DCX-positive neurogenesis in the cerebral cortex of the adult primate

Whether endogenous neurogenesis occurs in the adult cortex remains controversial.An increasing number of reports suggest that doublecortin(DCX)-positive neurogenesis persists in the adult primate cortex,attracting enormous attention worldwide.In this study,different DCX antibodies were used together with NeuN antibodies in immunohistochemistry and western blot assays using adjacent cortical sections from adult monkeys.Antibody adsorption,antigen binding,primary antibody omission and antibody-free experiments were used to assess specificity of the signals.We found either strong fluorescent signals,medium-weak intensity signals in some cells,weak signals in a few perikarya or near complete lack of labeling in adjacent cortical sections incubated with the various DCX antibodies.The putative DCX-positive cells in the cortex were also positive for NeuN,a specific marker of mature neurons.However,further experiments showed that most of these signals were either the result of antibody cross reactivity,the non-specificity of secondary antibodies or tissue autofluorescence.No confirmed DCX-positive cells were detected in the adult macaque cortex by immunofluorescence.Our findings show that DCX-positive neurogenesis does not occur in the cerebral cortex of adult primates,and that false-positive signals(artefacts)are caused by antibody cross reactivity and autofluorescence.The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Institute of Neuroscience,Beijing,China(approval No.IACUC-AMMS-2014-501).

Is the neocortex a novel reservoir for adult mammalian neurogenesis?

A novel population of cells expressing typical markers of immature neurons, such as doublecortin-positive cells, was recently identified. This population was predominantly located in layer II of the adult cerebral cortex of relatively large mammals. These cells appear to maintain an immature phenotype for a protracted time window, suggesting a lifelong role in cortical plasticity under normal physiological conditions, and possibly under pathological conditions as well. This review discusses recent evidence regarding the detailed features of these unique cells, including their distribution, morphology, fate, temporal and spatial origin, as well as their relevance and possible functions in various physiological and pathological conditions. In addition, we review studies that have produced conflicting results, possibly as a result of discrepancies in the methodology used to detect neurogenesis. In theory, the properties of these cells indicate that they might exert a significant impact on neocortical function, informing potential therapeutic strategies designed to induce endogenous neurogenesis in the treatment of neuropathological diseases.

Neurogenesis in the adult peripheral nervous system

Most researchers believe that neurogenesis in mature mammals is restricted only to the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle in the central nervous system. In the peripheral nervous system, neurogenesis is thought to be active only during prenatal development, with the exception of the olfactory neuroepithelium. However, sensory ganglia in the adult peripheral nervous system have been reported to contain precursor cells that can proliferate in vitro and be induced to differentiate into neurons. The occurrence of insult-induced neurogenesis, which has been reported by several investigators in the brain, is limited to a few recent reports for the peripheral nervous system. These reports suggest that damage to the adult nervous system induces mechanisms similar to those that control the generation of new neurons during prenatal development. Understanding conditions under which neurogenesis can be induced in physiologically non-neurogenic regions in adults is one of the major challenges for developing therapeutic strategies to repair neurological damage. However, the induced neurogenesis in the peripheral nervous system is still largely unexplored. This review presents the history of research on adult neurogenesis in the peripheral nervous system, which dates back more than 100 years and reveals the evidence on the under estimated potential for generation of new neurons in the adult peripheral nervous system.

Adult neurogenesis in the mammalian brain

New neurons are generated throughout life in distinct areas of the mammalian brain. This process, called adult neurogenesis, has challenged previously held concepts about adult brain plasticity and opened novel therapeutic avenues to treat certain neuro-psychiatric diseases. Here, we review the current knowledge regarding the fate and potency of neural stem cells （NSCs）, as well as the mechanisms underlying neuronal differentiation and subsequent integration. Furthermore, we discuss the functional significance of adult neurogenesis in health and disease, and offer brief insight into the future directions of the adult neurogenesis field.

Adult neurogenesis and pattern separation in rodents： A critical evaluation of data, tasks and interpretation

The ability to discriminate and store similar inputs as distinct representations in memory is thought to rely on a process called pattern separation in the dentate gyrus of the hippocampus. Recent computational and empirical findings support a role for adult-born granule neurons in spatial pattern separation. We reviewed rodent studies that have manipulated both hippocampal adult neurogenesis and assessed pattern separation. The majority of studies report a supporting role of adult born neurons in pattern separation as measured at the behavioral level. However, closer evaluation of the published findings reveals variation in both pattern separation tasks and in the interpretation of behavioral performance that, taken together, suggests that the role of hippocampal adult neurogenesis in pattern separation may be less established than is currently assumed. Assessment of pattern separation at the network level through the use of immediate early gene expression, optogenetic, pharmacogenetic and/or in vivo electrophysiology studies could be instrumental in further confirming a role of adult born neurons in pattern separation further. Finally, hippocampal adult neurogenesis and pattern separation are not an exclusive pair, as evidence for hippocampal adult neurogenesis contributing to the temporal separation of events in memory, forgetting and cognitive flexibility has also been found. We conclude that whereas current empirical evidence for the involvement of hippocampal adult neurogenesis in pattern separation seems supportive, there is a need for careful interpretation of behavioral findings and an integration of the various proposed functions of adult born neurons.