Vascular niche for adult hippocampal neurogenesis

The thin lamina between the hippocampal hilus and granule cell layer, or subgranule zone (SGZ), is an area of active proliferation within the adult hippocampus known to generate new neurons throughout adult life. Although the neuronal fate of many dividing cells is well documented, little information is available about the phenotypes of cells in S-phase or how the dividing cells might interact with neighboring cells in the process of neurogenesis. Here, we make the unexpected observation that dividing cells are found in dense clusters associated with the vasculature and roughly 37% of all dividing cells are immunoreactive for endothelial markers. Most of the newborn endothelial cells disappear over several weeks, suggesting that neurogenesis is intimately associated with a process of active vascular recruitment and subsequent remodeling. The present data provide the first evidence that adult neurogenesis occurs within an angiogenic niche. This environment may provide a novel interface where mesenchyme-derived cells and circulating factors influence plasticity in the adult central nervous system.     

Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis

Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.     

VEGF is necessary for exercise-induced adult hippocampal neurogenesis

Declining learning and memory function is associated with the attenuation of adult hippocampal neurogenesis. As in humans, chronic stress or depression in animals is accompanied by hippocampal dysfunction, and neurogenesis is correspondingly down regulated, in part, by the activity of the hypothalamic-pituitary-adrenal axis as well as glutamatergic and serotonergic networks. Antidepressants can reverse this effect over time but one of the most clinically effective moderators of stress or depression and robust stimulators of neurogenesis is simple voluntary physical exercise such as running. Curiously, running also elevates circulating stress hormone levels yet neurogenesis is doubled in running animals. In evaluating the signalling that running provides to the central nervous system in mice, we have found that peripheral vascular endothelial growth factor (VEGF) is necessary for the effects of running on adult hippocampal neurogenesis. Peripheral blockade of VEGF abolished running-induced neurogenesis but had no detectable effect on baseline neurogenesis in non-running animals. These data suggest that VEGF is an important element of a 'somatic regulator' of adult neurogenesis and that these somatic signalling networks can function independently of the central regulatory networks that are typically considered in the context of hippocampal neurogenesis.     

Sex hormones and adult hippocampal neurogenesis: Regulation,implications, and potential mechanisms

Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis.     

Regulation of adult hippocampal neurogenesis: relevance to depression

Recent hypotheses suggest that depression may involve an inability to mount adaptive structural changes in key neuronal networks. In particular, the addition of new neurons within the hippocampus, a limbic region implicated in mood disorders, is compromised in animal models of depression. Adult hippocampal neurogenesis is also a target for chronic antidepressant treatments, and an increase in adult hippocampal neurogenesis is implicated in the behavioral effects of antidepressants in animal models. The 'neurogenic' hypothesis of depression raises the intriguing possibility that hippocampal neurogenesis may contribute to the pathogenesis and treatment of depressive disorders. While there remains substantial debate about the precise relevance of hippocampal neurogenesis to mood disorders, this provocative hypothesis has been the focus of many recent studies. In this review, we discuss the pathways that may mediate the effects of depression models and antidepressants on adult hippocampal neurogenesis, and the promise of these studies in the development of novel antidepressants.     

Memory consolidation during sleep and adult hippocampal neurogenesis

In anticipation of the massive burden of neurodegenerative disease within super-aged societies, great efforts have been made to utilize neural stem and progenitor cells for regenerative medicine. The capacity of intrinsic neural stem and progenitor cells to regenerate damaged brain tissue remains unclear, due in part to the lack of knowledge about how these newly born neurons integrate into functional circuitry. As sizable integration of adult-born neurons naturally occurs in the dentate gyrus region of the hippocampus, clarifying the mechanisms of this process could provide insights for applying neural stem and progenitor cells in clinical settings. There is convincing evidence of functional correlations between adult-born neurons and memory consolidation and sleep; therefore, we describe some new advances that were left untouched in our recent review.     

Neural plasticity and adult neurogenesis: the deep biology perspective

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology.     

Alpha-tocopherol,an exogenous factor of adult hippocampal neurogenesis regulation

In previous work, we found that adult hippocampal neurogenesis in rat is affected by vitamin E deficiency. Because vitamin E deficiency is a complex condition involving numerous biological systems, it is possible that its effect on postnatal new neuron production could be mediated by unknown changes in different factors that in turn play a role in this process. To clarify if vitamin E plays a direct role in regulating hippocampal neurogenesis, we studied the neurogenesis in adult control rats and in adult rats under supplementation with alpha-tocopherol, the most important compound of vitamin E. The alpha-tocopherol level in control and supplemented rats was monitored. Qualitative and quantitative analysis of cell proliferation and death was carried out and expression of immature neuron markers PSA-NCAM, TUC 4, and DCX was investigated in hippocampus dentate gyrus. alpha-Tocopherol levels increased significantly in both plasma and brain after supplementation. Cell proliferation was inhibited in alpha-tocopherol-supplemented rats, the number of dying cells was reduced, and the number of cells expressing the immature neuron markers was increased. The results obtained confirm and extend the idea that vitamin E is an exogenous factor playing a direct role in regulation of different steps of adult hippocampal neurogenesis. Some hypotheses about the possible mechanisms underlying the complex action of alpha-tocopherol, related to its antioxidant and molecule-specific non-antioxidant properties, are proposed and discussed.     

Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate.Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected.     

Ginsenoside Rd maintains adult neural stem cell proliferation during lead-impaired neurogenesis

Lead exposure attracts a great deal of public attention due to its harmful effects on human health. Even low-level lead (Pb) exposure reduces the capacity for neurogenesis. It is well known that microglia-mediated neurotoxicity can impair neurogenesis. Despite this, few in vivo studies have been conducted to understand the relationship between acute Pb exposure and microglial activation. We investigated whether the acute Pb exposure altered the expression of a marker of activated microglial cells (Iba-1), and markers of neurogenesis (BrdU and doublecortin) in aging rats. As compared to controls, Pb exposure significantly enhanced the expression of Iba-1 immunoreactivity; increased the expression levels of IL-1β, IL-6, and TNF-α and decreased the numbers of BrdU⁺ and doublecortin⁺ cells. Our prior work demonstrated that ginsenoside Rd (Rd), one of the major active ingredients in Panax ginseng, was neuroprotective in a variety of paradigms involving anti-inflammatory mechanisms. Thus, we further examined whether Rd could attenuate Pb-induced phenotypes. Compared with the Pb exposure group, Rd pretreatment indeed attenuated the effects of Pb exposure. These results suggest that Rd may be neuroprotective in old rats following acute Pb exposure, which involves limitation of microglial activation and maintenance of NSC proliferation.     

Dynamics of olfactory and hippocampal neurogenesis in adult sheep

Although adult neurogenesis has been conserved in higher vertebrates such as primates and humans, timing of generation, migration, and differentiation of new neurons appears to differ from that in rodents. Sheep could represent an alternative model to studying neurogenesis in primates because they possess a brain as large as a macaque monkey and have a similar life span. By using a marker of cell division, bromodeoxyuridine (BrdU), in combination with several markers, the maturation time of newborn cells in the dentate gyrus (DG) and the main olfactory bulb (MOB) was determined in sheep. In addition, to establish the origin of adult‐born neurons in the MOB, an adeno‐associated virus that infects neural cells in the ovine brain was injected into the subventricular zone (SVZ). A migratory stream was indicated from the SVZ up to the MOB, consisting of neuroblasts that formed chain‐like structures. Results also showed a long neuronal maturation time in both the DG and the MOB, similar to that in primates. The first new neurons were observed at 1 month in the DG and at 3 months in the MOB after BrdU injections. Thus, maturation of adult‐born cells in both the DG and the MOB is much longer than that in rodents and resembles that in nonhuman primates. This study points out the importance of studying the features of adult neurogenesis in models other than rodents, especially for translational research for human cellular therapy. J. Comp. Neurol. 521:169–188, 2013. © 2012 Wiley Periodicals, Inc.     

Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis

Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.     

Single alcohol exposure in early life damages hippocampal stem/progenitor cells and reduces adult neurogenesis

Alcohol exposure during pregnancy may cause fetal alcohol syndrome (FAS), characterized by impaired cognitive functions. Neurogenesis occurs in the adult hippocampus and is functionally associated with learning, memory, and mood disorders. However, whether early postnatal exposure to alcohol impairs neurogenesis and through which mechanisms it occurs is poorly understood. Here, we report that a single episode of alcohol exposure in postnatal day 7 (P7) decreases neurogenesis in the adult hippocampus. Furthermore, we demonstrate a co-localization of glial fibrillar acidic protein, nestin, and vimentin with activated caspase-3 12 h after ethanol treatment. Finally, we show that the number of primary neurospheres derived from the hippocampi of alcohol-exposed mice is reduced compared to controls. These findings suggest that alcohol exposure in postnatal mice reduces the pool of neural stem/progenitor cells in the DG, and subsequently results in a decrease of adult neurogenesis. This may explain certain aspects of impaired hippocampal functions in FAS.     

Schizophrenia and neurogenesis: A stem cell approach

Several recent research findings indicate that schizophrenia (SCZ) may begin with an abnormal neuro-genesis from embryonic Neural Stem Cells (NSCs) and that this process may be particularly vulnerable to a number of genetic and/or environmental disturbances of early brain development. Since it is now well known that neurogenesis is not confined to the womb, but is a protracted process continuing in postnatal life well into adolescence and beyond, and since in the majority of subjects diagnosed with SCZ the first psychotic break occurs in late adolescence or early adulthood, the aim of our paper is to summarize the main findings supporting a possible link between changes in developmental postnatal neurogenesis and SCZ, with a specific focus on the critical period of adolescence and associated environmental risk factors. Establishing a significant role of adult neurogenesis in the emergence of psychosis will help us not only to better understand the pathogenesis of this neuopsychiatric disorder, but also to provide the key to potential strategies toward possible treatments and/or early corrective interventions.     

Sex,drugs, and adult neurogenesis: Sex‐dependent effects of escalating adolescent cannabinoid exposure on adult hippocampal neurogenesis,stress reactivity,and amphetamine sensitization

Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB₁R) agonist, HU‐210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague‐Dawley rats. Escalating doses of HU‐210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5‐bromo‐2‐deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU‐ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic‐pituitary‐adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioral sensitization to d‐amphetamine sulfate (1‐2 mg/kg; PND 105‐134) were assessed in adulthood. Adolescent HU‐210 administration suppressed the density of BrdU‐ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU‐210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB₁R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB₁R activation during adolescence results in sex‐dependent, long‐term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex. © 2013 Wiley Periodicals, Inc.     

Neurofibromin modulates adult hippocampal neurogenesis and behavioral effects of antidepressants

Neurogenesis persists in the rodent dentate gyrus (DG) throughout adulthood but declines with age and stress. Neural progenitor cells (NPCs) residing in the subgranular zone of the DG are regulated by an array of growth factors and respond to the microenvironment, adjusting their proliferation level to determine the rate of neurogenesis. Here we report that genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors.     

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long‐term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long‐term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long‐term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, 2014 ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.     

A new chapter in the field of memory: adult hippocampal neurogenesis

Understanding the cellular mechanisms underlying learning and memory is a major challenge in neurobiology. Structural and functional changes occurring in the hippocampus such as synaptic remodeling and long-term potentiation are key signatures of long-term memory processes. The discovery of a de novo hippocampal production of neurons in the adult brain has been a breakthrough in the field of plasticity and memory, introducing a new actor that could sustain memory processes. Here we will review our current knowledge on the role of these adult new neurons in memory. In particular we will provide evidence showing that they are required for learning and memory and that an alteration in their production rate or maturation leads to memory impairments. Through a thorough survey of the literature, we will also acknowledge that there are many controversies regarding the specific role played by newborn neurons. The emerging picture is that they are involved in the establishment of spatiotemporal relationships among multiple environmental cues for the flexible use of the acquired information. Indeed, newborn neurons have been found to be required for separating events based on their spatial and temporal characteristics, a process that preserves the uniqueness of a memory representation. Thus, adult-born neurons are required for allocentric space representation, for long-term memory retention and for flexible inferential memory expression. Finally, we will conclude by highlighting directions for future research, emphasizing that the exact participation of newborn neurons in memory processes will not be approached without considering the hippocampal network in general.