Modification of hippocampal circuitry by adult neurogenesis

The adult hippocampus is one of the primary neural structures involved in memory formation. In addition to synapse-specific modifications thought to encode information at the subcellular level, changes in the intrahippocampal neuro-populational activity and dynamics at the circuit-level may contribute substantively to the functional capacity of this region. Within the hippocampus, the dentate gyrus has the potential to make a preferential contribution to neural circuit modification owing to the continuous addition of new granule cell population. The integration of newborn neurons into pre-existing circuitry is hypothesized to deliver a unique processing capacity, as opposed to merely replacing dying granule cells. Recent studies have begun to assess the impact of hippocampal neurogenesis by examining the extent to which adult-born neurons participate in hippocampal networks, including when newborn neurons become engaged in ongoing network activity and how they modulate circuit dynamics via their unique intrinsic physiological properties. Understanding the contributions of adult neurogenesis to hippocampal function will provide new insight into the fundamental aspects of brain plasticity, which can be used to guide therapeutic interventions to replace neural populations damaged by disease or injury.     

The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells

New neurons are continuously generated from resident pools of neural stem and precursor cells(NSPCs)in the adult brain.There are multiple pathways through which adult neurogenesis is regulated,and here we review the role of the N-methyl-D-aspartate receptor(NMDAR)in regulating the proliferation of NSPCs in the adult hippocampus.Hippocampal-dependent learning tasks,enriched environments,running,and activity-dependent synaptic plasticity,all potently up-regulate hippocampal NSPC proliferation.We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity,and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons.We address how specific NMDAR agonists and antagonists modulate proliferation,both in vivo and in vitro,and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs.We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis,given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons.In conditions such as age-related memory decline,neurodegeneration and psychiatric disease,mature neurons are lost or become defective;as such,stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions.     

Inhibition of cell proliferation in black‐capped chickadees suggests a role for neurogenesis in spatial learning

Following development, the avian brain continues to produce neurons throughout adulthood, which functionally integrate throughout the telencephalon, including the hippocampus. In food‐storing birds like the black‐capped chickadee (Poecile atricapillus), new neurons incorporated into the hippocampus are hypothesized to play a role in spatial learning. Previous results on the relation between hippocampal neurogenesis and spatial learning, however, are correlational. In this study, we experimentally suppressed hippocampal neuronal recruitment and tested for subsequent effects on spatial learning in adult chickadees. After chickadees exhibited significant learning, we treated birds with daily injections of either saline or methylazoxymethanol (MAM), a toxin that suppresses cell proliferation in the brain and monitored subsequent spatial learning. MAM treatment significantly reduced cell proliferation around the lateral ventricles and neuronal recruitment in the hippocampus, measured using the cell birth marker bromodeoxyuridine. MAM‐treated birds performed significantly worse than controls on the spatial learning task 12 days following the initiation of MAM treatment, a time when new neurons would begin functionally integrating into the hippocampus. This difference in learning, however, was limited to a single trial. MAM treatment did not affect any measure of body condition, suggesting learning impairments were not a product of non‐specific adverse effects of MAM. This is the first evidence of a potential causal link between hippocampal neurogenesis and spatial learning in birds. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1002–1010, 2014     

Defining structural homology between the mammalian and avian hippocampus through conserved gene expression patterns observed in the chick embryo

The mammalian hippocampus, a center of neurogenesis in the adult brain, is involved in critical functions such as learning and memory processing. Although there is an overall functional conservation between birds and mammals in the hippocampal region of the brain, there are several morphological differences. A few different models have been proposed for identifying regional and structural homology between the avian and mammalian hippocampus however a consensus is yet to be reached. In this study we have systematically and comprehensively characterized the developing chicken hippocampus at the molecular level. We have identified the time window of neurogenesis and apoptosis during hippocampal development as well as the likely origin and migration path of neurons of the ventral v-shaped region of chick hippocampus. In addition to this we have identified several genes with expression patterns that are conserved between the hippocampus of chicken and mice. Our study provides molecular data that partially supports one of the models reported in literature for structural homology between the avian and mammalian hippocampus. Functional characterization of the genes found in this study to be specifically expressed in the developing chicken hippocampus is likely to provide valuable information on the mechanisms regulating hippocampus development of birds and perhaps could be extrapolated to mammalian hippocampus development as well.     

神经元再生:抑郁症治疗的新策略

成年哺乳动物一生中,海马等脑区神经元是可以再生的,而海马脑区神经元再生的减少和增多分别是抑郁症发生和恢复的重要因素。如果神经元再生过程被抑制,在抑郁症的动物模型上抗抑郁剂将会失去其行为学效应。长期给予不同种类的抗抑郁剂可以显著地促进动物海马神经元再生。随着对神经元再生调节机制研究的不断深入,为进一步探讨抑郁症的发生机制,以及发展新型抗抑郁治疗药物提供了新的思路与视角。     

Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders.     

Age‐related decline in BubR1 impairs adult hippocampal neurogenesis

Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age‐related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging‐related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age‐related cognitive deficits.     

Sex and seasonal differences in hippocampal volume and neurogenesis in brood‐parasitic brown‐headed cowbirds (Molothrus ater)

Brown‐headed cowbirds (Molothrus ater) are one of few species in which females show more complex space use than males. Female cowbirds search for, revisit, and parasitize host nests and, in a previous study, outperformed males on an open field spatial search task. Previous research reported a female‐biased sex difference in the volume of the hippocampus, a region of the brain involved in spatial memory. Neurons produced by adult neurogenesis may be involved in the formation of new memories and replace older neurons that could cause interference in memory. We tested for sex and seasonal differences in hippocampal volume and neurogenesis of brood‐parasitic brown‐headed cowbirds and the closely related non‐brood‐parasitic red‐winged blackbird (Agelaius phoeniceus) to determine whether there were differences in the hippocampus that reflected space use in the wild. Females had a larger hippocampus than males in both species, but hippocampal neurogenesis, measured by doublecortin immunoreactivity (DCX+), was greater in female than in male cowbirds in the absence of any sex difference in blackbirds, supporting the hypothesis of hippocampal specialization in female cowbirds. Cowbirds of both sexes had a larger hippocampus with greater hippocampal DCX+ than blackbirds. Hippocampus volume remained stable between breeding conditions, but DCX+ was greater post‐breeding, indicating that old memories may be lost through hippocampal reorganization following breeding. Our results support, in part, the hypothesis that the hippocampus of cowbirds is specialized for brood parasitism. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1275–1290, 2016     

Neurogenesis in the adult hippocampus

New neurons continue to be generated in two privileged areas of the adult brain: the dentate gyrus of the hippocampal formation and the olfactory bulb. Adult neurogenesis has been found in all mammals studied to date, including humans. The process of adult neurogenesis encompasses the proliferation of resident neural stem and progenitor cells and their subsequent differentiation, migration, and functional integration into the pre-existing circuitry. This article summarizes recent findings regarding the developmental steps involved in adult hippocampal neurogenesis and the possible functional roles that new hippocampal neurons might play.     

The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis

The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT‐stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT‐destabilizing proteins. Stathmin is such a MT‐destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki‐67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA‐NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1226–1242, 2014     

Blockade of TrkB but not p75NTR activates a subpopulation of quiescent neural precursor cells and enhances neurogenesis in the adult mouse hippocampus

Brain‐derived neurotrophic factor (BDNF) signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75^NTR) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75^NTR receptors are expressed by hippocampal NPCs in the adult mouse brain. Using a clonal neurosphere assay, we demonstrate that pharmacological blockade of TrkB receptors directly activates a distinct subpopulation of NPCs. Moreover, we show that administration of ANA‐12, a TrkB‐selective antagonist, in vivo either by systemic intraperitoneal injection or by direct infusion within the hippocampus leads to an increase in the production of new neurons. In contrast, we found that NPC‐specific knockout of p75^NTR had no effect on the proliferation of NPCs and did not alter neurogenesis in the adult hippocampus. Collectively, these results demonstrate a novel role of TrkB receptors in directly regulating the activity of a subset of hippocampal NPCs and suggest that the transient blockade of these receptors could be used to enhance adult hippocampal neurogenesis.     

Nurr1 (NR4A2) regulates Alzheimer’s disease‐related pathogenesis and cognitive function in the 5XFAD mouse model

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.     

Activation of neural precursors in the adult neurogenic niches

The generation of new neurons within the dentate gyrus of the mature hippocampus is critical for spatial learning, object recognition and memory, whereas new neurons born in the subventricular zone (SVZ) contribute to olfactory function. Adult neurogenesis is a multistep process that begins with the activation and proliferation of a pool of stem/precursor cells. Although the presence of self-renewing and multipotent neural precursors is well established in the SVZ, it is only recently that the existence of such a precursor population has been demonstrated in the hippocampus, the region of the brain involved in learning and memory. Determining how this normally latent pool can be activated therefore offers considerable potential for the development of targeted neurogenic-based therapeutics to ameliorate the cognitive decline associated with hippocampal dysfunction in several neurodegenerative diseases. In this review, we summarize the effects of neural activity, various molecular factors and pharmaceutical agents, as well as voluntary exercise, in activating endogenous neural precursors in the two neurogenic niches of the adult brain, and highlight the role of activation-driven enhancement of neurogenesis for the treatment of psychiatric illness and aging dementia.     

Impact of diet on adult hippocampal neurogenesis

Research over the last 5 years has firmly established that learning and memory abilities, as well as mood, can be influenced by diet, although the mechanisms by which diet modulates mental health are not well understood. One of the brain structures associated with learning and memory, as well as mood, is the hippocampus. Interestingly, the hippocampus is one of the two structures in the adult brain where the formation of newborn neurons, or neurogenesis, persists. The level of neurogenesis in the adult hippocampus has been linked directly to cognition and mood. Therefore, modulation of adult hippocampal neurogenesis (AHN) by diet emerges as a possible mechanism by which nutrition impacts on mental health. In this study, we give an overview of the mechanisms and functional implications of AHN and summarize recent findings regarding the modulation of AHN by diet.     

Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression.     

Locating and labeling neural stem cells in the brain

The phenomenon of adult neurogenesis has been demonstrated in most mammals including humans. At least two regions of the adult brain maintain stem cells throughout life; the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the lateral ventricle wall. Both regions continuously produce neurons that mature and become integrated into functional networks that are involved in learning and memory and odor discrimination, respectively. Apart from these well‐studied regions neurogenesis has been reported in a number of other brain regions, such as amygdala and cortex. However, these studies have been contested and there is currently no well‐postulated function for non‐SVZ/SGZ neurogenesis. The studies of the regional localization of neurogenesis in the brain have been made possible due to several methods for detecting adult neurogenesis including; bromodeoxyuridine labeling (BrdU) together with markers of mature neurons, genetic labeling, by mouse transgenesis, or with the use of viral vectors. These techniques are already put to creative use and will be essential for the discovery of the nature of the adult neural stem cells. In this mini‐review, we will discuss the localization of neural stem/progenitor cells in the brain and their implications as well as discussing the pro's and con's of stem cell labeling techniques. J. Cell. Physiol. 226: 1–7, 2010. © 2010 Wiley‐Liss, Inc.