Toll-like receptors modulate adult hippocampal neurogenesis

Neurogenesis - the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCalpha/beta-dependent activation of the NF-kappaB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.     

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.     

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.     

Spatial relational memory requires hippocampal adult neurogenesis

The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.     

感染炎性因子对成体动物海马区神经元再生的影响

摘要：在中枢神经系统,外部感染等引起的炎症反应中起重要作用的是由活化的胶质细胞产生的炎性因子,包括促炎因子（如白细胞介素1,6、肿瘤坏死因子-α、干扰素、趋化因子等）和抗炎因子（如白细胞介素4,10、转化生长因子β等）。海马作为学习和记忆相关的重要结构,其神经元再生受损可能与年老所致认知功能下降以及阿尔兹海默病、抑郁等疾病有关。而中枢神经系统炎症作为大脑损伤及许多神经退行性病变的并发症,对神经元再生的影响已引起了广泛的关注。炎性因子的种类、释放的时间及含量不同,可对神经元再生产生不同的影响。     

Systemically delivered Erythropoietin transiently enhances adult hippocampal neurogenesis

Erythropoietin is a primary regulator of erythropoiesis in the hematopoietic system. More recently erythropoietin has been shown to play a role in neurogenesis and provide neurotrophic support to injured CNS tissue. Here the effects of large systemic doses of erythropoietin on basal levels of adult hippocampal neurogenesis in mice were examined. A 7-day period of recombinant human erythropoietin (rhEPO) administration increased the number of bromodeoxyuridine [BrdU(+)] cells in the sub-granular zone (SGZ) by 30%. Analysis of cell phenotype revealed an increase in mitotically active doublecortin(+) neuronal progenitor cells and glial fibrillary acidic protein(+) SGZ radial astrocytes/stem cells but not mature S100beta(+) astrocytes. These effects appeared to be mediated, in part, by mitogen-activated protein kinase signaling and potentially regulated by suppressor of cytokine signaling-3. Hippocampal levels of phosphorylated extracellular signal-related kinase 42/44 and suppressor of cytokine signaling-3 were increased 2-6 h after a single systemic rhEPO injection. However, rhEPO had no observed effect on the long-term survival of new born cells in the SGZ, with similar numbers of BrdU(+) cells and BrdU(+)/NeuN(+) co-labeled cells after 4 weeks. Therefore, systemically delivered rhEPO transiently increased adult hippocampal neurogenesis without any apparent long-term effects.     

Functional implications of hippocampal adult neurogenesis in intellectual disabilities

The development of strategies capable to promote nervous system plasticity in adulthood is nowadays an important aim in neuroscience to improve not only cognitive abilities but also to ameliorate pathological dysfunctions. Several studies have demonstrated that adult neurogenesis is regulated by many physiological and pathological stimuli at almost every stage, from proliferation of neuronal precursors until integration and activation of newly formed neurons in the preexisting network. We review the process of generating functional neurons from precursors in the adult brain and its implications in intellectual disability disorders.     

Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

Donepezil hydrochloride is a potent and selective acetylcholinesterase inhibitor and has been treated for Alzheimer's disease, in which the cholinergic dysfunction is observed. Recently, the degeneration of medial septal cholinergic nuclei in adult rat suppressed the neurogenesis in hippocampal dentate gyrus (DG) was reported. Then, we determined whether donepezil which activated the brain cholinergic system could modulate hippocampal neurogenesis in normal rats. After the injection of 5'-bromo-2'-deoxyuridine (BrdU) to label dividing cells, we orally treated with donepezil (0.5 or 2mg/kg) once a day for 4 weeks. In the other group, we performed 4-week subcutaneous infusion of scopolamine (0.75 or 3mg/day), a muscarinic acetylcholine receptor blocker. The doses of donepezil and scopolamine we used in this study were reported to activate and inhibit cholinergic activity in rats, respectively. One day after the completion of drug treatment, the animals were sacrificed, and immunohistochemical analysis was performed. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the vehicle-treated control. Neither drug had any effects on the percentage of BrdU-positive cells that were also positive for a neuronal marker NeuN, nor the number of proliferating cell nuclear antigen-positive cells in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn neurons in the DG without affecting the proliferation of neural progenitor cell and the neuronal differentiation. We also found that chronic treatment of donepezil enhanced, and scopolamine suppressed phosphorylation of cAMP response element binding protein (CREB), which was involved in cell survival, in the DG. These results suggest that donepezil activates the central cholinergic transmission and enhances the survival of newborn neurons in the DG via CREB signaling.     

Copernican stem cells: regulatory constellations in adult hippocampal neurogenesis

In the adult, neurogenesis occurs where constellations of signaling molecules are correctly orchestrated and where competent cells are present to interpret these signals. As the instruments used to observe adult neurogenesis become more sophisticated, the concept of a discrete competent "stem cell" has become less concrete. Neural progenitor cells once thought committed to a single lineage can be influenced to become multipotent and somatic tissues appear to yield cells capable of tremendous peripheral and central lineage potential. The variety of cell types that appear competent to generate neurons suggests that the "Hilios" of adult neurogenesis may not necessarily be a single cellular entity but rather the sum of signals that dictate, "Make a new neuron here." These signals may not be limited to the recruitment of preexisting neural stem cells but may also, in some subtle way, reprogram local precursors to create "stem-like cells," where needed.     

Aging brain microenvironment decreases hippocampal neurogenesis through Wnt-mediated survivin signaling

Accumulating evidence suggests that adult hippocampal neurogenesis relies on the controlled and continued proliferation of neural progenitor cells (NPCs). With age, neurogenesis decreases through mechanisms that remain unclear but are believed to involve changes in the NPC microenvironment. Here, we provide evidence that NPC proliferation in the adult brain is in part regulated by astrocytes via Wnt signaling and that this cellular cross-talk is modified in the aging brain, leading to decreased proliferation of NPCs. Furthermore, we show that astrocytes regulate the NPC cell cycle by acting on the expression levels of survivin, a known mitotic regulator. Among cell cycle genes found down-regulated in aged NPCs, survivin was the only one that restored NPC proliferation in the aged brain. Our results provide a mechanism for the gradual loss of neurogenesis in the brain associated with aging and suggest that targeted modulation of survivin expression directly or through Wnt signaling could be used to stimulate adult neurogenesis.     

Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells

Neurogenesis in the adult human brain occurs within two principle neurogenic regions, the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Recent reports demonstrated the isolation of human neuroprogenitor cells (NPCs) from these regions, but due to limited tissue availability the knowledge of their phenotype and differentiation behavior is restricted. Here we characterize the phenotype and differentiation capacity of human adult hippocampal NPCs (hNPCs), derived from patients who underwent epilepsy surgery, on various feeder cells including fetal mixed cortical cultures, mouse embryonic fibroblasts (MEFs) and PA6 stromal cells. Isolated hNPCs were cultured in clonal density by transferring the cells to serum-free media supplemented with FGF-2 and EGF in 3% atmospheric oxygen. These hNPCs showed neurosphere formation, expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1 and Olig2, the NSC markers Nestin and Musashi1, the proliferation marker Ki67 and significant activity of telomerase. The phenotype was CD15low/-, CD34-, CD45- and CD133-. After removal of mitogens and plating them on poly D-lysine, they spontaneously differentiated into a neuronal (MAP2ab+), astroglial (GFAP+), and oligodendroglial (GalC+) phenotype. Differentiated hNPCs showed functional properties of neurons, such as sodium channels, action potentials and production of the neurotransmitters glutamate and GABA. Co-culture of hNPCs with fetal cortical cultures, MEFs and PA6 cells increased neurogenesis of hNPCs in vitro, while only MEFs and PA6 cells also led to a morphological and functional neurogenic maturation. Together we provide a first detailed characterization of the phenotype and differentiation potential of human adult hNPCs in vitro. Our findings reinforce the emerging view that the differentiation capacity of adult hNPCs is critically influenced by non-neuronal mesodermal feeder cells.     

Endocannabinoid signaling in adult hippocampal neurogenesis: A mechanistic and integrated perspective

Dentate gyrus of the hippocampus continuously gives rise to new neurons, namely, adult-born granule cells, which contribute to conferring plasticity to the mature brain throughout life. Within this neurogenic region, the fate and behavior of neural stem cells (NSCs) and their progeny result from a complex balance and integration of a variety of cell-autonomous and cell-to-cell-interaction signals and underlying pathways. Among these structurally and functionally diverse signals, there are endocannabinoids (eCBs), the main brain retrograde messengers. These pleiotropic bioactive lipids can directly and/or indirectly influence adult hippocampal neurogenesis (AHN) by modulating, both positively and negatively, multiple molecular and cellular processes in the hippocampal niche, depending on the cell type or stage of differentiation. Firstly, eCBs act directly as cell-intrinsic factors, cell-autonomously produced by NSCs following their stimulation. Secondly, in many, if not all, niche-associated cells, including some local neuronal and nonneuronal elements, the eCB system indirectly modulates the neurogenesis, linking neuronal and glial activity to regulating distinct stages of AHN. Herein, we discuss the crosstalk of the eCB system with other neurogenesis-relevant signal pathways and speculate how the hippocampus-dependent neurobehavioral effects elicited by (endo)cannabinergic medications are interpretable in light of the key regulatory role that eCBs play on AHN.     

RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression

In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential regulation, the underlying mechanism is unclear. Here, we show that the RNA-binding protein FXR2 specifically regulates DG neurogenesis by reducing the stability of Noggin mRNA. FXR2 deficiency leads to increased Noggin expression and subsequently reduced BMP signaling, which results in increased proliferation and altered fate specification of neural stem/progenitor cells in DG. In contrast, Noggin is not regulated by FXR2 in the SVZ, because Noggin expression is restricted to the ependymal cells of the lateral ventricles, where FXR2 is not expressed. Differential regulation of SVZ and DG stem cells by FXR2 may be a key component of the mechanism that governs the different neurogenic processes in these two adult germinal zones.     

Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones

Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.     

Cyclooxygenase (COX)-1 takes control of adult hippocampal neurogenesis

Comment on: Russo I, et al. Cell Cycle 2011; 10:2218-32.