Adult Hippocampal Stem Cells Research Articles

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

The transcription factor ZEB1 regulates stem cell self-renewal and cell fate in the adult hippocampus.

SummaryRadial glia-like (RGL) stem cells persist in the adult mammalian hippocampus, where they generate new neurons and astrocytes throughout life. The process of adult neurogenesis is well documented, but cell-autonomous factors regulating neuronal and astroglial differentiation are incompletely understood. Here, we evaluate the functions of the transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) in adult hippocampal RGL cells using a conditional-inducible mouse model. We find that ZEB1 is necessary for self-renewal of active RGL cells. Genetic deletion of Zeb1 causes a shift toward symmetric cell division that consumes the RGL cell and generates pro-neuronal progenies, resulting in an increase of newborn neurons and a decrease of newly generated astrocytes. We identify ZEB1 as positive regulator of the ets-domain transcription factor ETV5 that is critical for asymmetric division.

The Regulation of Adult Hippocampal Neurogenesis by Blood Circulating Factors in the Context of Anxiety and Depression

Recently, we found that adult hippocampal stem cells are in close contact with blood capillaries, suggesting that they may be regulated by circulating factors. The aim of this work is to test this possibility in the context of anxiety and depression.

Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells.

Quiescence is essential for the long-term maintenance of adult stem cells but how stem cells maintain quiescence is poorly understood. Here, we show that neural stem cells (NSCs) in the adult mouse hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activated or quiescent states. We found that the inhibitor of DNA binding protein Id4 is enriched in quiescent NSCs and that elimination of Id4 results in abnormal accumulation of Ascl1 protein and premature stem cell activation. Accordingly, Id4 and other Id proteins promote elimination of Ascl1 protein in NSC cultures. Id4 sequesters Ascl1 heterodimerization partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of NSC quiescence and reveal a role for Id4 as a quiescence-inducing factor, in contrast with its role of promoting the proliferation of embryonic neural progenitors.

Neurogenic differentiation by hippocampal neural stem and progenitor cells is biased by NFIX expression.

Our understanding of the transcriptional programme underpinning adult hippocampal neurogenesis is incomplete. In mice, under basal conditions, adult hippocampal neural stem cells (AH-NSCs) generate neurons and astrocytes, but not oligodendrocytes. The factors limiting oligodendrocyte production, however, remain unclear. Here, we reveal that the transcription factor NFIX plays a key role in this process. NFIX is expressed by AH-NSCs, and its expression is sharply upregulated in adult hippocampal neuroblasts. Conditional ablation of Nfix from AH-NSCs, coupled with lineage tracing, transcriptomic sequencing and behavioural studies collectively reveal that NFIX is cell-autonomously required for neuroblast maturation and survival. Moreover, a small number of AH-NSCs also develop into oligodendrocytes following Nfix deletion. Remarkably, when Nfix is deleted specifically from intermediate progenitor cells and neuroblasts using a Dcx-creERT2 driver, these cells also display elevated signatures of oligodendrocyte gene expression. Together, these results demonstrate the central role played by NFIX in neuroblasts within the adult hippocampal stem cell neurogenic niche in promoting the maturation and survival of these cells, while concomitantly repressing oligodendrocyte gene expression signatures.

Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome

Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice. Interestingly, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 TG mice, which were critical for determining fates of adult hippocampal NSCs between the quiescence and activation. In summary, we found that MeCP2 plays a critical role in regulating fate determination of adult NSCs. These evidences further suggest that abnormal development of NSCs may play a role in the pathogenesis of the MECP2 duplication syndrome.

GABAergic Regulation of Adult Hippocampal Neurogenesis.

Adult hippocampal neurogenesis has been implicated in several brain functions, including learning and memory processes. It also plays an important role in the aetiology of anxiety disorders, depression and age-related deficits. The endogenous stem cell pool is also known to hold great potential for ameliorating the diseased or aged brain. It has been shown that certain brain activities lead to an adjustment of adult neurogenesis, which can further be controlled by the interplay between inhibitory and excitatory processes. The roles of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the proliferation and differentiation of stem cells and progenitor cells, as well as in the control of network activity of hippocampal stem cells, have been extensively investigated in recent decades. This review highlights the general functions of GABAergic signalling and provides an exciting insight into the diverse functions of GABA in adult hippocampal stem cell biology.

The cyclin-dependent kinase inhibitor p27 kip1 regulates radial stem cell quiescence and neurogenesis in the adult hippocampus.

Members of the cyclin-dependent kinase (CDK)-inhibitory protein (CIP)/kinase-inhibitory protein (KIP) family of cyclin-dependent kinase inhibitors regulate proliferation and cell cycle exit of mammalian cells. In the adult brain, the CIP/KIP protein p27(kip1) has been related to the regulation of intermediate progenitor cells located in neurogenic niches. Here, we uncover a novel function of p27(kip1) in the adult hippocampus as a dual regulator of stem cell quiescence and of cell-cycle exit of immature neurons. In vivo, p27(kip1) is detected in radial stem cells expressing SOX2 and in newborn neurons of the dentate gyrus. In vitro, the Cdkn1b gene encoding p27(kip1) is transcriptionally upregulated by quiescence signals such as BMP4. The nuclear accumulation of p27(kip1) protein in adult hippocampal stem cells encompasses the BMP4-induced quiescent state and its overexpression is able to block proliferation. p27(kip1) is also expressed in immature neurons upon differentiation of adult hippocampal stem cell cultures. Loss of p27(kip1) leads to an increase in proliferation and neurogenesis in the adult dentate gyrus, which results from both a decrease in the percentage of radial stem cells that are quiescent and a delay in cell cycle exit of immature neurons. Analysis of animals carrying a disruption in the cyclin-CDK interaction domain of p27(kip1) indicates that the CDK inhibitory function of the protein is necessary to control the activity of radial stem cells. Thus, we report that p27(kip1) acts as a central player of the molecular program that keeps adult hippocampal stem cells out of the cell cycle.

Experimental epilepsy affects Notch1 signalling and the stem cell pool in the dentate gyrus

Temporal lobe epilepsy (TLE) is the most frequent form of epilepsy in adults. In addition to recurrent focal seizures, patients suffer from memory loss and depression. The factors contributing to these symptoms are unknown. In recent years, adult hippocampal neurogenesis has been implicated in certain aspects of learning and memory, as well as in depression and anhedonia. Here we investigated whether the adult hippocampal stem cell niche is affected by status epilepticus in a mouse model of TLE using unilateral intrahippocampal kainic acid injection. Eight days after status epilepticus, we found a strong diminution in Notch signalling, a key pathway involved in stem cell maintenance, as assayed by hes5 reporter gene activity. In particular, hes5-GFP expression in the subgranular zone of the dentate gyrus was diminished. Furthermore, Sox2-positive cells as well as stem cell proliferation were reduced, thus pointing to a disruption of the stem cell niche in epilepsy under the present experimental conditions.

Decreased Proliferation of Adult Hippocampal Stem Cells During Cocaine Withdrawal: Possible Role of the Cell Fate Regulator FADD

The current study uses an extended access rat model of cocaine self-administration (5-h session per day, 14 days), which elicits several features manifested during the transition to human addiction, to study the neural adaptations associated with cocaine withdrawal. Given that the hippocampus is thought to have an important role in maintaining addictive behavior and appears to be especially relevant to mechanisms associated with withdrawal, this study attempted to understand how extended access to cocaine impacts the hippocampus at the cellular and molecular levels, and how these alterations change over the course of withdrawal (1, 14, and 28 days). Therefore, at the cellular level, we examined the effects of cocaine withdrawal on cell proliferation (Ki-67+ and NeuroD+ cells) in the DG. At the molecular level, we employed a 'discovery' approach with gene expression profiling in the DG to uncover novel molecules possibly implicated in the neural adaptations that take place during cocaine withdrawal. Our results suggest that decreased hippocampal cell proliferation might participate in the adaptations associated with drug removal and identifies 14 days as a critical time-point of cocaine withdrawal. At the 14-day time-point, gene expression profiling of the DG revealed the dysregulation of several genes associated with cell fate regulation, highlighting two new neurobiological correlates (Ascl-1 and Dnmt3b) that accompany cessation of drug exposure. Moreover, the results point to Fas-Associated protein with Death Domain (FADD), a molecular marker previously associated with the propensity to substance abuse and cocaine sensitization, as a key cell fate regulator during cocaine withdrawal. Identifying molecules that may have a role in the restructuring of the hippocampus following substance abuse provides a better understanding of the adaptations associated with cocaine withdrawal and identifies novel targets for therapeutic intervention.

Division-Coupled Astrocytic Differentiation and Age-Related Depletion of Neural Stem Cells in the Adult Hippocampus

Production of new neurons in the adult hippocampus decreases with age; this decline may underlie age-related cognitive impairment. Here we show that continuous depletion of the neural stem cell pool, as a consequence of their division, may contribute to the age-related decrease in hippocampal neurogenesis. Our results indicate that adult hippocampal stem cells, upon exiting their quiescent state, rapidly undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons and subsequently convert into mature astrocytes. Thus, the decrease in the number of neural stem cells is a division-coupled process and is directly related to their production of new neurons. We presenta scheme of the neurogenesis cascade in the adult hippocampus that includes a proposed "disposable stem cell" model and accounts for the disappearance of hippocampal neural stem cells, the appearance of new astrocytes, and the age-related decline in the production of new neurons.

Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans

The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical en bloc hippocampus resections. After proliferation of the progenitor cell pool in vitro we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 ± 13% of in vitro cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 ± 2%). This was reflected by reduced numbers of proliferating cells in vivo as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity in vitro (r = 0.813; P < 0.001; linear regression: R²(adjusted) = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R²(adjusted) = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.

Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER(T2)/R26R-YFP/Notch1(loxP/loxP) [Notch1inducible knock-out (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER(T2)/R26R-YFP/Notch1(w/w)) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 d post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

Regulation of adult and aged mice hippocampal stem cell proliferation by acetylcholine

The role of cyclic ADP-ribose (cADPR) as the downstream signal of neuronal muscarinic acetylcholine receptors (mAChRs) and the enzyme responsible for its synthesis, ADP-ribosyl cyclase, were examined in the rat superior cervical ganglion (SCG). Application of acetylcholine or other mAChR agonists increased the ADP-ribosyl cyclase activity by about 250–300% in crude membrane fractions from the SCG of 14-day-old rats. This effect was inhibited by atropine or by the M1-mAChR antagonist, pirenzepine, and was mimicked by GTP. These results indicate that the M1 mAChRs couple to the membrane-bound form of ADP-ribosyl cyclase and suggest that cADPR is a second messenger of M1 mAChR signaling in nervous tissue.

Adult Neurogenesis, Mental Health, and Mental Illness: Hope or Hype?: Figure 1.

Psychiatric and neurologic disorders take an enormous toll on society. Alleviating the devastating symptoms and consequences of neuropsychiatric disorders such as addiction, depression, epilepsy, and schizophrenia is a main force driving clinical and basic researchers alike. By elucidating these disease neuromechanisms, researchers hope to better define treatments and preventive therapies. Research suggests that regulation of adult hippocampal neurogenesis represents a promising approach to treating and perhaps preventing mental illness. Here we appraise the role of adult hippocampal neurogenesis in major psychiatric and neurologic disorders within the essential framework of recent progress made in understanding "normal" adult neurogenesis. Topics addressed include the following: the life cycle of an adult hippocampal stem cell and the implications for aging; links between learning and hippocampal neurogenesis; the reciprocal relationship between cocaine self-administration and adult hippocampal neurogenesis; the role of adult neurogenesis in an animal model of depression and response to antidepressant exposure; the impact of neonatal seizures on dentate gyrus neurogenesis; and the contribution of a schizophrenia-susceptibility gene to adult hippocampal neurogenesis. These topics are discussed in light of the regulation of adult neurogenesis, the relationship to normal neurogenesis in adulthood and aging, and, importantly, the manipulation of neurogenesis to promote mental health and treat mental illness.

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Leptin, an adipose-derived hormone, has been implicated in several physiological processes involving the hippocampus. However, the role of leptin in adult hippocampal neurogenesis remains unknown. Here we show that leptin regulates neurogenesis in the dentate gyrus of adult mice as well as in cultured adult hippocampal progenitor cells. Chronic administration of leptin to adult mice increased cell proliferation without significant effects on the differentiation and the survival of newly proliferated cells in the dentate gyrus. The expression of the long form leptin receptor, LepRb, was detected in hippocampal progenitor cells by reverse transcription-PCR and immunohistochemistry. Leptin treatment also increased proliferation of cultured adult hippocampal progenitor cells. Analysis of signal transduction pathways revealed that leptin stimulated phosphorylation of Akt and STAT3 but not ERK1/2. Furthermore, pre-treating the cells with specific inhibitors of Akt or STAT3 attenuated leptin-induced cell proliferation in a dose-dependent manner. Taken together, our results support a role for leptin in adult hippocampal neurogenesis and suggest the involvement of the Akt and STAT3 signaling pathways in mediating the actions of leptin on neurogenesis.

Regulation of survival in adult hippocampal and glioblastoma stem cell lineages by the homeodomain-only protein HOP

BackgroundHomeodomain proteins play critical roles in shaping the development of the embryonic central nervous system in mammals. After birth, neurogenic activities are relegated to stem cell niches, which include the subgranular layer of the dentate gyrus of the hippocampus. Here, we have analyzed the function of HOP (Homeodomain only protein) in this stem cell niche and in human glioblastomas.ResultsWe find that HOP is strongly expressed by radial astrocytes of the dentate gyrus in mice, which are stem cells that give rise to hippocampal granular neurons throughout adulthood. Deletion or down-regulation of HOP results in a decrease of apoptosis of these stem cells without changes in proliferation, and in an increase in the number of newly formed granule neurons. We also find that human glioblastomas largely lack HOP expression and that reintroduction of HOP function in glioma cells cultured as gliomaspheres leads to enhanced apoptosis in a subset of cases. In these cells, HOP function decreases clonogenicity.ConclusionThese data suggest that HOP participates in the regulation of the adult mouse hippocampal stem cell niche by negatively affecting cell survival. In addition, HOP may work as a tumor suppressor in a subset of glioblastomas. HOP function thus appears to be critical in the adult brain in a region of continued plasticity, and its deregulation may contribute to disease.

Changes in adult neurogenesis in neurodegenerative diseases: cause or consequence?

This review addresses the role of adult hippocampal neurogenesis and stem cells in some of the most common neurodegenerative disorders and their related animal models. We discuss recent literature in relation to Alzheimer's disease and dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, alcoholism, ischemia, epilepsy and major depression.

Wnt Signals in the Mature Hippocampus

New dentate granule neurons derived from adult hippocampal stem (or progenitor) cells (AHPs) in the subgranular zone (SGZ) of the dentate gyrus (one of two regions in the adult mammalian brain where generation of new neurons from neural stem cells occurs) may play a role in hippocampal plasticity and learning. Although signals from neighboring astrocytes are known to regulate AHP proliferation and differentiation, the precise nature of these signals has been unclear. Lie et al. combined in situ hybridization with reverse transcription polymerase chain reaction analysis to show that Wnt3 was expressed in astrocytes near the SGZ of adult mice and that the Wnt receptor Frizzled 1 and components of the Wnt/β-catenin pathway (Dishevelled1 and Axin) were expressed in AHPs. Moreover, analysis of mice expressing a Wnt/β-catenin reporter indicated that this pathway was active in the SGZ and dentate granule cell layer. Coculture of AHPs with hippocampal astrocytes stimulated Wnt/β-catenin signaling in cells that developed neuronal markers, whereas differentiation into neurons of AHPs cocultured with hippocampal astrocytes was decreased in the presence of a Wnt inhibitor or when a dominant-negative inhibitor of Wnt/β-catenin signaling was expressed. Wnt3 overexpression in cultured AHPs enhanced neurogenesis by stimulating neuroblast proliferation and promoting neuronal fate commitment. Neurogenesis in the dentate gyrus of adult rats was reduced when Wnt signaling was inhibited by expression of a secreted Wnt1 mutant, whereas Wnt3 overexpression promoted adult hippocampal neurogenesis. Thus, Wnt signaling, which plays a critical role during brain development, also appears to regulate neurogenesis in the adult hippocampus. D.-C. Lie, S. A. Colamarino, H.-J. Song, L. Désiré, H. Mira, A. Consiglio, E. S. Lein, S. Jessberger, H. Lansford, A. R. Dearie, F. H. Gage, Wnt signalling regulates adult hippocampal neurogenesis. Nature 437 , 1370-1375 (2005). [PubMed]

Differentiating adult hippocampal stem cells into neural crest derivatives

To investigate the degree of plasticity of hippocampal neural stem cells from adult mice (mHNSC), we have analyzed their differentiation in co-culture with quail neural crest cells. In mixed culture, mHNSC give rise to several non-neuronal neural crest derivatives, including melanocytes, chondrocytes and smooth muscle cells. The data suggest that neural crest cell-derived short-range cues that are recognized across species can instruct adult mHNSC to differentiate into neural crest phenotypes.