Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

PubMed Central

2014-01-01

Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function

USDA-ARS?s Scientific Manuscript database

Adult neurogenesis, a complex process by which stem cells in the hippocampal brain region differentiate and proliferate into new neurons and other resident brain cells, is known to be affected by many intrinsic and extrinsic factors, including diet. Neurogenesis plays a critical role in neural plas...

Blood-brain barrier-supported neurogenesis in healthy and diseased brain.

PubMed

Pozhilenkova, Elena A; Lopatina, Olga L; Komleva, Yulia K; Salmin, Vladimir V; Salmina, Alla B

2017-05-24

Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

Chemotherapy disrupts learning, neurogenesis and theta activity in the adult brain.

PubMed

Nokia, Miriam S; Anderson, Megan L; Shors, Tracey J

2012-12-01

Chemotherapy, especially if prolonged, disrupts attention, working memory and speed of processing in humans. Most cancer drugs that cross the blood-brain barrier also decrease adult neurogenesis. Because new neurons are generated in the hippocampus, this decrease may contribute to the deficits in working memory and related thought processes. The neurophysiological mechanisms that underlie these deficits are generally unknown. A possible mediator is hippocampal oscillatory activity within the theta range (3-12 Hz). Theta activity predicts and promotes efficient learning in healthy animals and humans. Here, we hypothesised that chemotherapy disrupts learning via decreases in hippocampal adult neurogenesis and theta activity. Temozolomide was administered to adult male Sprague-Dawley rats in a cyclic manner for several weeks. Treatment was followed by training with different types of eyeblink classical conditioning, a form of associative learning. Chemotherapy reduced both neurogenesis and endogenous theta activity, as well as disrupted learning and related theta-band responses to the conditioned stimulus. The detrimental effects of temozolomide only occurred after several weeks of treatment, and only on a task that requires the association of events across a temporal gap and not during training with temporally overlapping stimuli. Chemotherapy did not disrupt the memory for previously learned associations, a memory independent of (new neurons in) the hippocampus. In conclusion, prolonged systemic chemotherapy is associated with a decrease in hippocampal adult neurogenesis and theta activity that may explain the selective deficits in processes of learning that describe the 'chemobrain'. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

ERIC Educational Resources Information Center

Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

2009-01-01

The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

The adaptive significance of adult neurogenesis: an integrative approach

PubMed Central

Konefal, Sarah; Elliot, Mick; Crespi, Bernard

2013-01-01

Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and OB, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially relevant selective contexts. PMID:23882188

Localized CT-Guided Irradiation Inhibits Neurogenesis in Specific Regions of the Adult Mouse Brain

PubMed Central

Ford, E. C.; Achanta, P.; Purger, D.; Armour, M.; Reyes, J.; Fong, J.; Kleinberg, L.; Redmond, K.; Wong, J.; Jang, M. H.; Jun, H.; Song, H-J.; Quinones-Hinojosa, A.

2011-01-01

Radiation is used in the study of neurogenesis in the adult mouse both as a model for patients undergoing radiation therapy for CNS malignancies and as a tool to interrupt neurogenesis. We describe the use of a dedicated CT-guided precision device to irradiate specific sub-regions of the adult mouse brain. Improved CT visualization was accomplished with intrathecal injection of iodinated contrast agent, which enhances the lateral ventricles. T2-weighted MRI images were also used for target localization. Visualization of delivered beams (10 Gy) in tissue was accomplished with immunohistochemical staining for the protein γ-H2AX, a marker of DNA double-strand breaks. γ-H2AX stains showed that the lateral ventricle wall could be targeted with an accuracy of 0.19 mm (n = 10). In the hippocampus, γ-H2AX staining showed that the dentate gyrus can be irradiated unilaterally with a localized arc treatment. This resulted in a significant decrease of proliferative neural progenitor cells as measured by Ki-67 staining (P < 0.001) while leaving the contralateral side intact. Two months after localized irradiation, neurogenesis was significantly inhibited in the irradiated region as seen with EdU/NeuN double labeling (P < 0.001). Localized radiation in the rodent brain is a promising new tool for the study of neurogenesis. PMID:21449714

Neurogenesis in the aging brain.

PubMed

Apple, Deana M; Solano-Fonseca, Rene; Kokovay, Erzsebet

2017-10-01

Adult neurogenesis is the process of producing new neurons from neural stem cells (NSCs) for integration into the brain circuitry. Neurogenesis occurs throughout life in the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. However, during aging, NSCs and their progenitors exhibit reduced proliferation and neuron production, which is thought to contribute to age-related cognitive impairment and reduced plasticity that is necessary for some types of brain repair. In this review, we describe NSCs and their niches during tissue homeostasis and how they undergo age-associated remodeling and dysfunction. We also discuss some of the functional ramifications in the brain from NSC aging. Finally, we discuss some recent insights from interventions in NSC aging that could eventually translate into therapies for healthy brain aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise.

PubMed

Sun, Lina; Sun, Qingshan; Qi, Jinshun

2017-10-26

Depression is a prevalent devastating mental disorder that affects the normal life of patients and brings a heavy burden to whole society. Although many efforts have been made to attenuate depressive/anxiety symptoms, the current clinic antidepressants have limited effects. Scientists have long been making attempts to find some new strategies that can be applied as the alternative antidepressant therapy. Exercise, a widely recognized healthy lifestyle, has been suggested as a therapy that can relieve psychiatric stress. However, how exercise improves the brain functions and reaches the antidepressant target needs systematic summarization due to the complexity and heterogeneous feature of depression. Brain plasticity, especially adult neurogenesis in the hippocampus, is an important neurophysiology to facilitate animals for neurogenesis can occur in not only humans. Many studies indicated that an appropriate level of exercise can promote neurogenesis in the adult brains. In this article, we provide information about the antidepressant effects of exercise and its implications in adult neurogenesis. From the neurogenesis perspective, we summarize evidence about the effects of exercise in enhancing neurogenesis in the hippocampus through regulating growth factors, neurotrophins, neurotransmitters and metabolism as well as inflammations. Taken together, a large number of published works indicate the multiple benefits of exercise in the brain functions of animals, particularly brain plasticity like neurogenesis and synaptogenesis. Therefore, a new treatment method for depression therapy can be developed by regulating the exercise activity.

Np95/Uhrf1 regulates tumor suppressor gene expression of neural stem/precursor cells, contributing to neurogenesis in the adult mouse brain.

PubMed

Murao, Naoya; Matsubara, Shuzo; Matsuda, Taito; Noguchi, Hirofumi; Mutoh, Tetsuji; Mutoh, Masahiro; Koseki, Haruhiko; Namihira, Masakazu; Nakashima, Kinichi

2018-05-31

Adult neurogenesis is a process of generating new neurons from neural stem/precursor cells (NS/PCs) in restricted adult brain regions throughout life. It is now generally known that adult neurogenesis in the hippocampal dentate gyrus (DG) and subventricular zone participates in various higher brain functions, such as learning and memory formation, olfactory discrimination and repair after brain injury. However, the mechanisms underlying adult neurogenesis remain to be fully understood. Here, we show that Nuclear protein 95 KDa (Np95, also known as UHRF1 or ICBP90), which is an essential protein for maintaining DNA methylation during cell division, is involved in multiple processes of adult neurogenesis. Specific ablation of Np95 in adult NS/PCs (aNS/PCs) led to a decrease in their proliferation and an impairment of neuronal differentiation and to suppression of neuronal maturation associated with the impairment of dendritic formation in the hippocampal DG. We also found that deficiency of Np95 in NS/PCs increased the expression of tumor suppressor genes p16 and p53, and confirmed that expression of these genes in NS/PCs recapitulates the phenotype of Np95-deficient NS/PCs. Taken together, our findings suggest that Np95 plays an essential role in proliferation and differentiation of aNS/PCs through the regulation of tumor suppressor gene expression in adult neurogenesis. Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.

Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis

PubMed Central

Coleman, Leon G.; Oguz, Ipek; Lee, Joohwi; Styner, Martin; Crews, Fulton T.

2013-01-01

Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5g/kg, s.c., 2 hours apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV+IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology. PMID:22572057

Signaling mechanisms regulating adult neural stem cells and neurogenesis

PubMed Central

Faigle, Roland; Song, Hongjun

2012-01-01

Background Adult neurogenesis occurs throughout life in discrete regions of the mammalian brain and is tightly regulated via both extrinsic environmental influences and intrinsic genetic factors. In recent years, several crucial signaling pathways have been identified in regulating self-renewal, proliferation, and differentiation of neural stem cells, as well as migration and functional integration of developing neurons in the adult brain. Scope of review Here we review our current understanding of signaling mechanisms, including Wnt, notch, sonic hedgehog, growth and neurotrophic factors, bone morphogenetic proteins, neurotransmitters, transcription factors, and epigenetic modulators, and crosstalk between these signaling pathways in the regulation of adult neurogenesis. We also highlight emerging principles in the vastly growing field of adult neural stem cell biology and neural plasticity. Major conclusions Recent methodological advances have enabled the field to identify signaling mechanisms that fine-tune and coordinate neurogenesis in the adult brain, leading to a better characterization of both cell-intrinsic and environmental cues defining the neurogenic niche. Significant questions related to niche cell identity and underlying regulatory mechanisms remain to be fully addressed and will be the focus of future studies. General significance A full understanding of the role and function of individual signaling pathways in regulating neural stem cells and generation and integration of newborn neurons in the adult brain may lead to targeted new therapies for neurological diseases in humans. PMID:22982587

Neurogenesis in the Developing and Adult Brain—Similarities and Key Differences

PubMed Central

Götz, Magdalena; Nakafuku, Masato; Petrik, David

2017-01-01

Adult neurogenesis in the mammalian brain is often viewed as a continuation of neurogenesis at earlier, developmental stages. Here, we will critically review the extent to which this is the case highlighting similarities as well as key differences. Although many transcriptional regulators are shared in neurogenesis at embryonic and adult stages, recent findings on the molecular mechanisms by which these neuronal fate determinants control fate acquisition and maintenance have revealed profound differences between development and adulthood. Importantly, adult neurogenesis occurs in a gliogenic environment, hence requiring adult-specific additional and unique mechanisms of neuronal fate specification and maintenance. Thus, a better understanding of the molecular logic for continuous adult neurogenesis provides important clues to develop strategies to manipulate endogenous stem cells for the purpose of repair. PMID:27235475

Physical Exercise-Induced Adult Neurogenesis: A Good Strategy to Prevent Cognitive Decline in Neurodegenerative Diseases?

PubMed Central

Yau, Suk-yu; Christie, Brian R.; So, Kwok-fai

2014-01-01

Cumulative evidence has indicated that there is an important role for adult hippocampal neurogenesis in cognitive function. With the increasing prevalence of cognitive decline associated with neurodegenerative diseases among the ageing population, physical exercise, a potent enhancer of adult hippocampal neurogenesis, has emerged as a potential preventative strategy/treatment to reduce cognitive decline. Here we review the functional role of adult hippocampal neurogenesis in learning and memory, and how this form of structural plasticity is altered in neurodegenerative diseases known to involve cognitive impairment. We further discuss how physical exercise may contribute to cognitive improvement in the ageing brain by preserving adult neurogenesis, and review the recent approaches for measuring changes in neurogenesis in the live human brain. PMID:24818140

Detection and Phenotypic Characterization of Adult Neurogenesis

PubMed Central

Kuhn, H. Georg; Eisch, Amelia J.; Spalding, Kirsty; Peterson, Daniel A.

2016-01-01

Studies of adult neurogenesis have greatly expanded in the last decade, largely as a result of improved tools for detecting and quantifying neurogenesis. In this review, we summarize and critically evaluate detection methods for neurogenesis in mammalian and human brain tissue. Besides thymidine analog labeling, cell-cycle markers are discussed, as well as cell stage and lineage commitment markers. Use of these histological tools is critically evaluated in terms of their strengths and limitations, as well as possible artifacts. Finally, we discuss the method of radiocarbon dating for determining cell and tissue turnover in humans. PMID:26931327

TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

PubMed

Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

2013-12-15

TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

Stab wound injury of the zebrafish adult telencephalon: a method to investigate vertebrate brain neurogenesis and regeneration.

PubMed

Schmidt, Rebecca; Beil, Tanja; Strähle, Uwe; Rastegar, Sepand

2014-08-04

Adult zebrafish have an amazing capacity to regenerate their central nervous system after injury. To investigate the cellular response and the molecular mechanisms involved in zebrafish adult central nervous system (CNS) regeneration and repair, we developed a zebrafish model of adult telencephalic injury. In this approach, we manually generate an injury by pushing an insulin syringe needle into the zebrafish adult telencephalon. At different post injury days, fish are sacrificed, their brains are dissected out and stained by immunohistochemistry and/or in situ hybridization (ISH) with appropriate markers to observe cell proliferation, gliogenesis, and neurogenesis. The contralateral unlesioned hemisphere serves as an internal control. This method combined for example with RNA deep sequencing can help to screen for new genes with a role in zebrafish adult telencephalon neurogenesis, regeneration, and repair.

IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

PubMed Central

Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

2016-01-01

The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

Orchestrating brain-cell renewal: the role of immune cells in adult neurogenesis in health and disease.

PubMed

Ziv, Yaniv; Schwartz, Michal

2008-11-01

Immune cells and immune molecules have recently been shown to support neurogenesis from neural stem and progenitor cells in the adult brain. This non-classical immune activity takes place constantly under normal physiological conditions and is extended under acute pathological conditions to include the attraction of progenitor cells and induction of neurogenesis in regions of the adult central nervous system (CNS) in which formation of new neurons does not normally occur. We suggest that the immune system should be viewed as a novel player in the adult neural stem cell niche and a coordinator of cell renewal processes after injury. We discuss these notions in light of the well-known facts that both immune-cell activity and cell renewal are inherently limited in the adult CNS and that immune and stem cells provide the body's mechanisms of repair.

Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis.

PubMed

Valero, Jorge; Paris, Iñaki; Sierra, Amanda

2016-04-20

Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging.

Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders.

PubMed

Jun, Heechul; Mohammed Qasim Hussaini, Syed; Rigby, Michael J; Jang, Mi-Hyeon

2012-01-01

Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

Omega-3 fatty acids upregulate adult neurogenesis

PubMed Central

Beltz, Barbara S.; Tlusty, Michael F.; Benton, Jeannie L.; Sandeman, David C.

2007-01-01

Omega-3 fatty acids play crucial roles in the development and function of the central nervous system. These components, which must be obtained from dietary sources, have been implicated in a variety of neurodevelopmental and psychiatric disorders. Furthermore, the presence of omega-6 fatty acids may interfere with omega-3 fatty acid metabolism. The present study investigated whether changes in dietary ratios of omega-3:omega-6 fatty acids influence neurogenesis in the lobster (Homarus americanus) brain where, as in many vertebrate species, neurogenesis persists throughout life. The factors that regulate adult neurogenesis are highly conserved among species, and the crustacean brain has been successfully utilized as a model for investigating this process. In this study, lobsters were fed one of three diets that differed in fatty acid content. These animals were subsequently incubated in 5-bromo-2′-deoxyuridine (BrdU) to detect cells in S-phase of the cell cycle. A quantitative analysis of the resulting BrdU-labeled cells in the projection neuron cluster in the brain shows that short-term augmentation of dietary omega-3 relative to omega-6 fatty acids results in significant increases in the numbers of S-phase cells, and that the circadian pattern of neurogenesis is also altered. It is proposed that the ratio of omega-3:omega-6 fatty acids may alter neurogenesis via modulatory influences on membrane proteins, cytokines and/or neurotrophins. PMID:17240063

Does developmental hypothyroidism produce lasting effects on adult neurogenesis?

EPA Science Inventory

The subgranular zone of the dentate gyrus (DO) of the adult hippocampus generates new neurons throughout life. Thyroid hormones (TH) are essential for brain development, but impaired neurogenesis with adult hypothyroidism has also been reported. We investigated the role of milder...

Control of Cell Survival in Adult Mammalian Neurogenesis.

PubMed

Kuhn, H Georg

2015-10-28

The fact that continuous proliferation of stem cells and progenitors, as well as the production of new neurons, occurs in the adult mammalian central nervous system (CNS) raises several basic questions concerning the number of neurons required in a particular system. Can we observe continued growth of brain regions that sustain neurogenesis? Or does an elimination mechanism exist to maintain a constant number of cells? If so, are old neurons replaced, or are the new neurons competing for limited network access among each other? What signals support their survival and integration and what factors are responsible for their elimination? This review will address these and other questions regarding regulatory mechanisms that control cell-death and cell-survival mechanisms during neurogenesis in the intact adult mammalian brain. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

PubMed Central

Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

2016-01-01

New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors.

PubMed

Hill, Alexis S; Sahay, Amar; Hen, René

2015-09-01

Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.

Adult Hippocampal Neurogenesis is Impaired by Transient and Moderate Developmental Thyroid Hormone Disruption

EPA Science Inventory

Severe thyroid hormone (TH) deprivation during development impairs neurogenesis throughout the brain. The hippocampus also maintains a capacity for neurogenesis throughout life which is reduced in adult-onset hypothyroidism. This study examined hippocampal volume in the neonate a...

Inducible and Conditional Deletion of Extracellular Signal-regulated Kinase 5 Disrupts Adult Hippocampal Neurogenesis*

PubMed Central

Pan, Yung-Wei; Zou, Junhui; Wang, Wenbin; Sakagami, Hiroyuki; Garelick, Michael G.; Abel, Glen; Kuo, Chay T.; Storm, Daniel R.; Xia, Zhengui

2012-01-01

Recent studies have led to the exciting idea that adult-born neurons in the dentate gyrus of the hippocampus may play a role in hippocampus-dependent memory formation. However, signaling mechanisms that regulate adult hippocampal neurogenesis are not well defined. Here we report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, is selectively expressed in the neurogenic regions of the adult mouse brain. We present evidence that shRNA suppression of ERK5 in adult hippocampal neural stem/progenitor cells (aNPCs) reduces the number of neurons while increasing the number of cells expressing markers for stem/progenitor cells or proliferation. Furthermore, shERK5 attenuates both transcription and neuronal differentiation mediated by Neurogenin 2, a transcription factor expressed in adult hippocampal neural progenitor cells. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, promotes neurogenesis in cultured aNPCs and in the dentate gyrus of the mouse brain. Moreover, neurotrophins including NT3 activate ERK5 and stimulate neuronal differentiation in aNPCs in an ERK5-dependent manner. Finally, inducible and conditional deletion of ERK5 specifically in the neurogenic regions of the adult mouse brain delays the normal progression of neuronal differentiation and attenuates adult neurogenesis in vivo. These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis. PMID:22645146

Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice

PubMed Central

Barbieri, Raffaella; Contestabile, Andrea; Ciardo, Maria Grazia; Forte, Nicola; Marte, Antonella; Baldelli, Pietro; Benfenati, Fabio; Onofri, Franco

2018-01-01

Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain-derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn-deficient mice. PMID:29721159

Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice.

PubMed

Barbieri, Raffaella; Contestabile, Andrea; Ciardo, Maria Grazia; Forte, Nicola; Marte, Antonella; Baldelli, Pietro; Benfenati, Fabio; Onofri, Franco

2018-04-10

Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain-derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn-deficient mice.

Neurotransmitters couple brain activity to subventricular zone neurogenesis

PubMed Central

Young, Stephanie Z.; Taylor, M. Morgan; Bordey, Angélique

2011-01-01

Adult neurogenesis occurs in two privileged microenvironments, the hippocampal subgranular zone of the dentate gyrus and the subventricular zone (SVZ) along the lateral ventricle. This review focuses on accumulating evidence suggesting that the activity of specific brain regions or bodily states influences SVZ cell proliferation and neurogenesis. Neuromodulators such as dopamine and serotonin have been shown to have long-range effects through neuronal projections into the SVZ. Local GABA and glutamate signaling have demonstrated effects on SVZ proliferation and neurogenesis, but an extra-niche source of these neurotransmitters remains to be explored and options will be discussed. There is also accumulating evidence that diseases and bodily states such as Alzheimer's disease, seizures, sleep, and pregnancy influence SVZ cell proliferation. With such complex behavior and environmentally-driven factors that control subregion-specific activity, it will become necessary to account for overlapping roles of multiple neurotransmitter systems on neurogenesis when developing cell therapies or drug treatments. PMID:21395856

IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain.

PubMed

Bhattarai, Prabesh; Thomas, Alvin Kuriakose; Cosacak, Mehmet Ilyas; Papadimitriou, Christos; Mashkaryan, Violeta; Froc, Cynthia; Reinhardt, Susanne; Kurth, Thomas; Dahl, Andreas; Zhang, Yixin; Kizil, Caghan

2016-10-18

Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

BIRDS AS A MODEL TO STUDY ADULT NEUROGENESIS: BRIDGING EVOLUTIONARY, COMPARATIVE AND NEUROETHOLOGICAL APPROCHES

PubMed Central

BARNEA, ANAT; PRAVOSUDOV, VLADIMIR

2011-01-01

During the last few decades evidence has demonstrated that adult neurogenesis is a well-preserved feature throughout the animal kingdom. In birds, ongoing neuronal addition occurs rather broadly, to a number of brain regions. This review describes adult avian neurogenesis and neuronal recruitment, discusses factors that regulate these processes, and touches upon the question of their genetic control. Several attributes make birds an extremely advantageous model to study neurogenesis. First, song learning exhibits seasonal variation that is associated with seasonal variation in neuronal turnover in some song control brain nuclei, which seems to be regulated via adult neurogenesis. Second, food-caching birds naturally use memory-dependent behavior in learning locations of thousands of food caches scattered over their home ranges. In comparison with other birds, food-caching species have relatively enlarged hippocampi with more neurons and intense neurogenesis, which appears to be related to spatial learning. Finally, migratory behavior and naturally occurring social systems in birds also provide opportunities to investigate neurogenesis. Such diversity of naturally-occurring memory-based behaviors, combined with the fact that birds can be studied both in the wild and in the laboratory, make them ideal for investigation of neural processes underlying learning. This can be done by using various approaches, from evolutionary and comparative to neuroethological and molecular. Finally, we connect the avian arena to a broader view by providing a brief comparative and evolutionary overview of adult neurogenesis and by discussing the possible functional role of the new neurons. We conclude by indicating future directions and possible medical applications. PMID:21929623

Adult Neurogenesis and Mental Illness

PubMed Central

Schoenfeld, Timothy J; Cameron, Heather A

2015-01-01

Several lines of evidence suggest that adult neurogenesis, the production of new neurons in adulthood, may play a role in psychiatric disorders, including depression, anxiety, and schizophrenia. Medications and other treatments for mental disorders often promote the proliferation of new neurons; the time course for maturation and integration of new neurons in circuitry parallels the delayed efficacy of psychiatric therapies; adverse and beneficial experiences similarly affect development of mental illness and neurogenesis; and ablation of new neurons in adulthood alters the behavioral impact of drugs in animal models. At present, the links between adult neurogenesis and depression seem stronger than those suggesting a relationship between new neurons and anxiety or schizophrenia. Yet, even in the case of depression there is currently no direct evidence for a causative role. This article reviews the data relating adult neurogenesis to mental illness and discusses where research needs to head in the future. PMID:25178407

Decreased adult neurogenesis in hibernating Syrian hamster.

PubMed

León-Espinosa, Gonzalo; García, Esther; Gómez-Pinedo, Ulises; Hernández, Félix; DeFelipe, Javier; Ávila, Jesús

2016-10-01

Generation of new neurons from adult neural stem cells occurs in the dentate gyrus (DG) of the hippocampus and the lateral walls of the lateral ventricles. In this article, we study the neurogenesis that takes place during the hibernation of the Syrian hamster (Mesocricetus auratus). Using a variety of standard neurogenesis markers and 5-bromo-2-deoxyuridine (BrdU) incorporation, we describe a preferential decrease in the proliferation of newborn neurons in the subventricular zone (SVZ) of the hibernating hamsters (torpor) rather than in the hippocampus. Furthermore, we demonstrate that the proliferative capacity is recovered after 3-4days of torpor when arousal is triggered under natural conditions (i.e., not artificially provoked). In addition, we show that tau3R, a tau isoform with three microtubule-binding domains, is a suitable marker to study neurogenesis both in the SVZ and subgranular zone (SGZ) of the Syrian hamster brain. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Neurodevelopmental origin and adult neurogenesis of the neuroendocrine hypothalamus

PubMed Central

Maggi, Roberto; Zasso, Jacopo; Conti, Luciano

2015-01-01

The adult hypothalamus regulates many physiological functions and homeostatic loops, including growth, feeding and reproduction. In mammals, the hypothalamus derives from the ventral diencephalon where two distinct ventricular proliferative zones have been described. Although a set of transcription factors regulating the hypothalamic development has been identified, the exact molecular mechanisms that drive the differentiation of hypothalamic neural precursor cells (NPCs) toward specific neuroendocrine neuronal subtypes is yet not fully disclosed. Neurogenesis has been also reported in the adult hypothalamus at the level of specific niches located in the ventrolateral region of ventricle wall, where NPCs have been identified as radial glia-like tanycytes. Here we review the molecular and cellular systems proposed to support the neurogenic potential of developing and adult hypothalamic NPCs. We also report new insights on the mechanisms by which adult hypothalamic neurogenesis modulates key functions of this brain region. Finally, we discuss how environmental factors may modulate the adult hypothalamic neurogenic cascade. PMID:25610370

[Neurogenesis in the adult brain: the demise of a dogma and the advent of new treatments].

PubMed

Crespel, A; Baldy-Moulinier, M; Lerner Natoli, M

2004-12-01

Since the early sixties, many concepts concerning neurogenesis have been progressively ruled out. Proof of the persistence of a physiological neurogenesis in adult mammals, including humans, raised the concept of a unique precursor cell giving birth to neurons and glial cells. According to this concept, a real continuum between neuroepithelial cells, radial glia and astrocytes exists from the embryonic period to adult age and generates both neurons and glial cells. Different factors, either secreted in situ or transported by blood, can influence this physiological neurogenesis process. The targets and role of newborn neurons are not clearly understood. In pathological conditions (ischemia, epilepsy, lesions), the physiological neurogenesis process is enhanced; however the significance of this neurogenesis excess (beneficial or deleterious) is not completely known. Advances in understanding the regulation of neurogenesis in these different conditions represent hopes of new therapeutic procedures, not only by improving the control of differentiation and survival of transplanted stem cells, but also by the possibility of modifying the processes of "endogenous neurogenesis".

Adult Mammalian Neurogenesis and Motivated Behaviors.

PubMed

Jorgensen, Claudia

2018-05-31

Adult neurogenesis continues to captivate the curiosity of the scientific community; and researchers seem to have a particular interest in identifying the functional implications of such plasticity. While the majority of research focuses on the association between adult neurogenesis and learning and memory (including spatial learning associated with hippocampal neurogenesis and olfactory discrimination associated with neurogenesis in the olfactory system), the following review will explore the link to motivated behaviors. In particular, goal-directed behaviors such as sociosexual, parental, aggressive, as well as depression- and anxiety-like behaviors and their reciprocal association to adult neurogenesis will be evaluated. The review will detail research in humans and other mammalian species. Furthermore, the potential mechanisms underlying these neurogenic alterations will be highlighted. Lastly, the review will conclude with a discussion on the functional significance of these newly generated cells in mediating goal-directed behaviors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

HIPPOCAMPAL ADULT NEUROGENESIS: ITS REGULATION AND POTENTIAL ROLE IN SPATIAL LEARNING AND MEMORY

PubMed Central

Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin

2016-01-01

Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001

Voluntary running rescues adult hippocampal neurogenesis after irradiation of the young mouse brain

PubMed Central

Naylor, Andrew S.; Bull, Cecilia; Nilsson, Marie K. L.; Zhu, Changlian; Björk-Eriksson, Thomas; Eriksson, Peter S.; Blomgren, Klas; Kuhn, H. Georg

2008-01-01

Cranial radiation therapy is commonly used in the treatment of childhood cancers. It is associated with cognitive impairments tentatively linked to the hippocampus, a neurogenic region of the brain important in memory function and learning. Hippocampal neurogenesis is positively regulated by voluntary exercise, which is also known to improve hippocampal-dependent cognitive functions. In this work, we irradiated the brains of C57/BL6 mice on postnatal day 9 and evaluated both the acute effects of irradiation and the effects of voluntary running on hippocampal neurogenesis and behavior 3 months after irradiation. Voluntary running significantly restored precursor cell and neurogenesis levels after a clinically relevant, moderate dose of irradiation. We also found that irradiation perturbed the structural integration of immature neurons in the hippocampus and that this was reversed by voluntary exercise. Furthermore, irradiation-induced behavior alterations observed in the open-field test were ameliorated. Together, these results clearly demonstrate the usefulness of physical exercise for functional and structural recovery from radiation-induced injury to the juvenile brain, and they suggest that exercise should be evaluated in rehabilitation therapy of childhood cancer survivors. PMID:18765809

G-Protein-Coupled Receptors in Adult Neurogenesis

PubMed Central

Doze, Van A.

2012-01-01

The importance of adult neurogenesis has only recently been accepted, resulting in a completely new field of investigation within stem cell biology. The regulation and functional significance of adult neurogenesis is currently an area of highly active research. G-protein-coupled receptors (GPCRs) have emerged as potential modulators of adult neurogenesis. GPCRs represent a class of proteins with significant clinical importance, because approximately 30% of all modern therapeutic treatments target these receptors. GPCRs bind to a large class of neurotransmitters and neuromodulators such as norepinephrine, dopamine, and serotonin. Besides their typical role in cellular communication, GPCRs are expressed on adult neural stem cells and their progenitors that relay specific signals to regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting adult neurogenesis as a model for self-repair in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed. PMID:22611178

Neurogenesis enhancer RO 25-6981 facilitates repeated spatial learning in adult rats.

PubMed

Soloviova, O A; Proshin, A T; Storozheva, Z I; Sherstnev, V V

2012-09-01

The effects of Ro 25-6981 (selective NMDA receptor blocker) in a dose stimulating neurogenesis on repeated learning, reversal learning, and memory reconsolidation were studied in adult rats in Morris water maze. Ro 25-6981 facilitated repeated learning 13 days after injection, but did not influence reversal learning. The blocker injected directly before reminder did not disturb repeated learning and reversal learning in Morris water maze. These effects of Ro 25-6981 on the dynamics of repeated learning seemed to be due to its effects on neurogenesis processes in adult brain.

Regulation by commensal bacteria of neurogenesis in the subventricular zone of adult mouse brain.

PubMed

Sawada, Naoki; Kotani, Takenori; Konno, Tasuku; Setiawan, Jajar; Nishigaito, Yuka; Saito, Yasuyuki; Murata, Yoji; Nibu, Ken-Ichi; Matozaki, Takashi

2018-04-15

In the mouse olfactory bulb (OB), interneurons such as granule cells and periglomerular cells are continuously replaced by adult-born neurons, which are generated in the subventricular zone (SVZ) of the brain. We have now investigated the role of commensal bacteria in regulation of such neuronal cell turnover in the adult mouse brain. Administration of mixture of antibiotics to specific pathogen-free (SPF) mice markedly attenuated the incorporation of bromodeoxyuridine (BrdU) into the SVZ cells. The treatment with antibiotics also reduced newly generated BrdU-positive neurons in the mouse OB. In addition, the incorporation of BrdU into the SVZ cells of germ-free (GF) mice was markedly reduced compared to that apparent for SPF mice. In contrast, the reduced incorporation of BrdU into the SVZ cells of GF mice was recovered by their co-housing with SPF mice, suggesting that commensal bacteria promote the incorporation of BrdU into the SVZ cells. Finally, we found that administration of ampicillin markedly attenuated the incorporation of BrdU into the SVZ cells of SPF mice. Our results thus suggest that ampicillin-sensitive commensal bacteria regulate the neurogenesis in the SVZ of adult mouse brain. Copyright © 2018 Elsevier Inc. All rights reserved.

Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

PubMed Central

Lucassen, Paul J.; Oomen, Charlotte A.; Naninck, Eva F.G.; Fitzsimons, Carlos P.; van Dam, Anne-Marie; Czeh, Boldizsár; Korosi, Aniko

2015-01-01

Exposure to stress is one of the best-known negative regulators of adult neurogenesis (AN). We discuss changes in neurogenesis in relation to exposure to stress, glucocorticoid hormones, and inflammation, with a particular focus on early development and on lasting effects of stress. Although the effects of acute and mild stress on AN are generally brief and can be quickly overcome, chronic exposure or more severe forms of stress can induce longer lasting reductions in neurogenesis that can, however, in part, be overcome by subsequent exposure to exercise, drugs targeting the stress system, and some antidepressants. Exposure to stress, particularly during the sensitive period of early life, may (re)program brain plasticity, in particular, in the hippocampus. This may increase the risk to develop cognitive or anxiety symptoms, common to brain diseases like dementia and depression in which plasticity changes occur, and a normalization of neurogenesis may be required for a successful treatment response and recovery. PMID:26330520

Adult neurogenesis: optimizing hippocampal function to suit the environment.

PubMed

Glasper, Erica R; Schoenfeld, Timothy J; Gould, Elizabeth

2012-02-14

Numerous studies have attempted to determine the function of adult neurogenesis in the hippocampus using methods to deplete new neurons and examine changes in behaviors associated with this brain region. This approach has produced a set of findings that, although not entirely consistent, suggest new neurons are associated with improved learning and reduced anxiety. This paper attempts to synthesize some of these findings into a model that proposes adaptive significance to experience-dependent alterations in new neuron formation. We suggest that the modulation of adult neurogenesis, as well as of the microcircuitry associated with new neurons, by experience prepares the hippocampus to meet the specific demands of an environment that is predictably similar to one that existed previously. Reduced neurogenesis that occurs with persistent exposure to a high threat environment produces a hippocampus that is more likely to respond with behavior that maximizes the chance of survival. Conversely, enhanced neurogenesis that occurs with continual exposure to a rewarding environment leads to behavior that optimizes the chances of successful reproduction. The persistence of this form of plasticity throughout adulthood may provide the neural substrate for adaptive responding to both stable and dynamic environmental conditions. Copyright © 2011. Published by Elsevier B.V.

Sexual interactions with unfamiliar females reduce hippocampal neurogenesis among adult male rats.

PubMed

Spritzer, M D; Curtis, M G; DeLoach, J P; Maher, J; Shulman, L M

2016-03-24

Recent experiments have shown that sexual interactions prior to cell proliferation cause an increase in neurogenesis in adult male rats. Because adult neurogenesis is critical for some forms of memory, we hypothesized that sexually induced changes in neurogenesis may be involved in mate recognition. Sexually naive adult male rats were either exposed repeatedly to the same sexual partner (familiar group) or to a series of novel sexual partners (unfamiliar group), while control males never engaged in sexual interactions. Ovariectomized female rats were induced into estrus every four days. Males were given two injections of 5-bromo-2'-deoxyuridine (BrdU) (200mg/kg) to label proliferating cells, and the first sexual interactions occurred three days later. Males in the familiar and unfamiliar groups engaged in four, 30-min sexual interactions at four-day intervals, and brain tissue was collected the day after the last sexual interaction. Immunohistochemistry followed by microscopy was used to quantify BrdU-labeled cells. Sexual interactions with unfamiliar females caused a significant reduction in neurogenesis in the dentate gyrus compared to males that interacted with familiar females and compared to the control group. The familiar group showed no difference in neurogenesis compared to the control group. Males in the familiar group engaged in significantly more sexual behavior (ejaculations and intromissions) than did males in the unfamiliar group, suggesting that level of sexual activity may influence neurogenesis levels. In a second experiment, we tested whether this effect was unique to sexual interactions by replicating the entire procedure using anestrus females. We found that interactions with unfamiliar anestrus females reduced neurogenesis relative to the other groups, but this effect was not statistically significant. In combination, these results indicate that interactions with unfamiliar females reduce adult neurogenesis and the effect is stronger for sexual

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

PubMed Central

Numakawa, Tadahiro; Odaka, Haruki; Adachi, Naoki

2017-01-01

Altered neurogenesis is suggested to be involved in the onset of brain diseases, including mental disorders and neurodegenerative diseases. Neurotrophic factors are well known for their positive effects on the proliferation/differentiation of both embryonic and adult neural stem/progenitor cells (NSCs/NPCs). Especially, brain-derived neurotrophic factor (BDNF) has been extensively investigated because of its roles in the differentiation/maturation of NSCs/NPCs. On the other hand, recent evidence indicates a negative impact of the stress hormone glucocorticoids (GCs) on the cell fate of NSCs/NPCs, which is also related to the pathophysiology of brain diseases, such as depression and autism spectrum disorder. Furthermore, studies including ours have demonstrated functional interactions between neurotrophic factors and GCs in neural events, including neurogenesis. In this review, we show and discuss relationships among the behaviors of NSCs/NPCs, BDNF, and GCs. PMID:29099059

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

PubMed Central

Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

2015-01-01

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. PMID:25875952

Postnatal loss of hap1 reduces hippocampal neurogenesis and causes adult depressive-like behavior in mice.

PubMed

Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

2015-04-01

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.

SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory.

PubMed

Chen, Qian; Kogan, Jeffrey H; Gross, Adam K; Zhou, Yuan; Walton, Noah M; Shin, Rick; Heusner, Carrie L; Miyake, Shinichi; Tajinda, Katsunori; Tamura, Kouichi; Matsumoto, Mitsuyuki

2012-09-01

SREB2/GPR85, a member of the super-conserved receptor expressed in brain (SREB) family, is the most conserved G-protein-coupled receptor in vertebrate evolution. Previous human and mouse genetic studies have indicated a possible link between SREB2 and schizophrenia. SREB2 is robustly expressed in the hippocampal formation, especially in the dentate gyrus, a structure with an established involvement in psychiatric disorders and cognition. However, the function of SREB2 in the hippocampus remains elusive. Here we show that SREB2 regulates hippocampal adult neurogenesis, which impacts on cognitive function. Bromodeoxyuridine incorporation and immunohistochemistry were conducted in SREB2 transgenic (Tg, over-expression) and knockout (KO, null-mutant) mice to quantitatively assay adult neurogenesis and newborn neuron dendritic morphology. Cognitive responses associated with adult neurogenesis alteration were evaluated in SREB2 mutant mice. In SREB2 Tg mice, both new cell proliferation and new neuron survival were decreased in the dentate gyrus, whereas an enhancement of new neuron survival occurred in SREB2 KO mouse dentate gyrus. Doublecortin staining revealed dendritic morphology deficits of newly generated neurons in SREB2 Tg mice. In a spatial pattern separation task, SREB2 Tg mice displayed a decreased ability to discriminate spatial relationships, whereas SREB2 KO mice had enhanced abilities in this task. Additionally, SREB2 Tg and KO mice had reciprocal phenotypes in a Y-maze working memory task. Our results indicate that SREB2 is a negative regulator of adult neurogenesis and consequential cognitive functions. Inhibition of SREB2 function may be a novel approach to enhance hippocampal adult neurogenesis and cognitive abilities to ameliorate core symptoms of psychiatric patients. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Adult Neurogenesis in Sheep: Characterization and Contribution to Reproduction and Behavior

PubMed Central

Lévy, Frederic; Batailler, Martine; Meurisse, Maryse; Migaud, Martine

2017-01-01

Sheep have many advantages to study neurogenesis in comparison to the well-known rodent models. Their development and life expectancy are relatively long and they possess a gyrencephalic brain. Sheep are also seasonal breeders, a characteristic that allows studying the involvement of hypothalamic neurogenesis in the control of seasonal reproduction. Sheep are also able to individually recognize their conspecifics and develop selective and lasting bonds. Adult olfactory neurogenesis could be adapted to social behavior by supporting recognition of conspecifics. The present review reveals the distinctive features of the hippocampal, olfactory, and hypothalamic neurogenesis in sheep. In particular, the organization of the subventricular zone and the dynamic of neuronal maturation differs from that of rodents. In addition, we show that various physiological conditions, such as seasonal reproduction, gestation, and lactation differently modulate these three neurogenic niches. Last, we discuss recent evidence indicating that hypothalamic neurogenesis acts as an important regulator of the seasonal control of reproduction and that olfactory neurogenesis could be involved in odor processing in the context of maternal behavior. PMID:29109674

All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

PubMed

Vivar, Carmen; Potter, Michelle C; van Praag, Henriette

2013-01-01

Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

Hyperbaric Oxygen Therapy Alleviates Carbon Monoxide Poisoning-Induced Delayed Memory Impairment by Preserving Brain-Derived Neurotrophic Factor-Dependent Hippocampal Neurogenesis.

PubMed

Liu, Wen-Chung; Yang, San-Nan; Wu, Chih-Wei J; Chen, Lee-Wei; Chan, Julie Y H

2016-01-01

To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute carbon monoxide poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor in the hippocampus. Laboratory animal experiments. University/Medical center research laboratory. Adult, male Sprague-Dawley rats. Rats were divided into five groups: (1) non-carbon monoxide-treated control, (2) acute carbon monoxide poisoning, (3) acute carbon monoxide poisoning followed by 7-day hyperbaric oxygen treatment, (4) carbon monoxide + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute carbon monoxide poisoning followed by intracerebroventricular infusion of brain-derived neurotrophic factor. Acute carbon monoxide poisoning was achieved by exposing the rats to carbon monoxide at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after carbon monoxide poisoning. Recombinant human TrkB-Fc chimera or brain-derived neurotrophic factor was infused into the lateral ventricle via the implanted osmotic minipump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of brain-derived neurotrophic factor was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze. Acute carbon monoxide poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67⁺, and doublecortin⁺ cells in the subgranular zone of the dentate gyrus. This

Intracerebral estrogen provision increases cytogenesis and neurogenesis in the injured zebra finch brain

PubMed Central

Walters, Bradley J.; Alexiades, Nikita G.; Saldanha, Colin J.

2010-01-01

To determine whether or not local, injury-induced aromatization and/orestrogen provision can affect cyto-or neuro-genesis following mechanical brain damage, two groups of adult male zebra finches sustained bilateral penetrating brain injuries. The first received contralateral injections of vehicle or the aromatase inhibitor fadrozole. The second group received contalateral injections of fadrozole, or fadrozole with 17β-estradiol. Subsequent to injury, birds were injected with the thymidine analog 5-Bromo-2′-deoxyuridine (BrdU). Two weeks following injury, the birds were perfused, and coronal sections were labeled using antibodies against BrdU and the neuronal proteins HuC/HuD. In a double blind fashion, BrdU positive cells and BrdU/Hu double-labeled cells in the subventricular zone (SVZ) and at the injury site (INJ) were imaged and sampled. The average numbers of cells per image were compared across brain regions and treatments using repeated measures ANOVAs and, where applicable, post-hoc, pairwise comparisons. Fadrozole administration had no detectable effect on cytogenesis or neurogenesis, however, fadrozole coupled with estradiol significantly increased both measures. The dorsal SVZ had the greatest proportion of new cells that differentiated into neurons, though the highest numbers of BrdU labeled and BrdU, Hu double-labeled cells were detected at the injury site. In the adult zebra finch brain, local estradiol provision can increase cytogenesis and neurogenesis, however, whether or not endogenous glial aromatization is sufficient to similarly affect these processes remains to be seen. PMID:20878945

Role of Neuroinflammation in Adult Neurogenesis and Alzheimer Disease: Therapeutic Approaches

PubMed Central

Llorens-Martín, María; Hernández, Félix; Avila, Jesús

2013-01-01

Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field. PMID:23690659

In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis.

PubMed

Lim, Daniel A; Suárez-Fariñas, Mayte; Naef, Felix; Hacker, Coleen R; Menn, Benedicte; Takebayashi, Hirohide; Magnasco, Marcelo; Patil, Nila; Alvarez-Buylla, Arturo

2006-01-01

Neural stem cells and neurogenesis persist in the adult mammalian brain subventricular zone (SVZ). Cells born in the rodent SVZ migrate to the olfactory bulb (Ob) where they differentiate into interneurons. To determine the gene expression and functional profile of SVZ neurogenesis, we performed three complementary sets of transcriptional analysis experiments using Affymetrix GeneChips: (1) comparison of adult mouse SVZ and Ob gene expression profiles with those of the striatum, cerebral cortex, and hippocampus; (2) profiling of SVZ stem cells and ependyma isolated by fluorescent-activated cell sorting (FACS); and (3) analysis of gene expression changes during in vivo SVZ regeneration after anti-mitotic treatment. Gene Ontology (GO) analysis of data from these three separate approaches showed that in adult SVZ neurogenesis, RNA splicing and chromatin remodeling are biological processes as statistically significant as cell proliferation, transcription, and neurogenesis. In non-neurogenic brain regions, RNA splicing and chromatin remodeling were not prominent processes. Fourteen mRNA splicing factors including Sf3b1, Sfrs2, Lsm4, and Khdrbs1/Sam68 were detected along with 9 chromatin remodeling genes including Mll, Bmi1, Smarcad1, Baf53a, and Hat1. We validated the transcriptional profile data with Northern blot analysis and in situ hybridization. The data greatly expand the catalogue of cell cycle components, transcription factors, and migration genes for adult SVZ neurogenesis and reveal RNA splicing and chromatin remodeling as prominent biological processes for these germinal cells.

Adult neurogenesis is necessary to refine and maintain circuit specificity.

PubMed

Cummings, Diana M; Snyder, Jason S; Brewer, Michelle; Cameron, Heather A; Belluscio, Leonardo

2014-10-08

The circuitry of the olfactory bulb contains a precise anatomical map that links isofunctional regions within each olfactory bulb. This intrabulbar map forms perinatally and undergoes activity-dependent refinement during the first postnatal weeks. Although this map retains its plasticity throughout adulthood, its organization is remarkably stable despite the addition of millions of new neurons to this circuit. Here we show that the continuous supply of new neuroblasts from the subventricular zone is necessary for both the restoration and maintenance of this precise central circuit. Using pharmacogenetic methods to conditionally ablate adult neurogenesis in transgenic mice, we find that the influx of neuroblasts is required for recovery of intrabulbar map precision after disruption due to sensory block. We further demonstrate that eliminating adult-born interneurons in naive animals leads to an expansion of tufted cell axons that is identical to the changes caused by sensory block, thus revealing an essential role for new neurons in circuit maintenance under baseline conditions. These findings show, for the first time, that inhibiting adult neurogenesis alters the circuitry of projection neurons in brain regions that receive new interneurons and points to a critical role for adult-born neurons in stabilizing a brain circuit that exhibits high levels of plasticity. Copyright © 2014 the authors 0270-6474/14/3413801-10$15.00/0.

Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

PubMed

Taupin, Philippe

2009-05-01

The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone.

PubMed

Coburn, Jacki L; Cole, Toby B; Dao, Khoi T; Costa, Lucio G

2018-05-01

Adult neurogenesis is the process by which neural stem cells give rise to new functional neurons in specific regions of the adult brain, a process that occurs throughout life. Significantly, neurodegenerative and psychiatric disorders present suppressed neurogenesis, activated microglia, and neuroinflammation. Traffic-related air pollution has been shown to adversely affect the central nervous system. As the cardinal effects of air pollution exposure are microglial activation, and ensuing oxidative stress and neuroinflammation, we investigated whether acute exposures to diesel exhaust (DE) would inhibit adult neurogenesis in mice. Mice were exposed for 6 h to DE at a PM 2.5 concentration of 250-300 μg/m 3 , followed by assessment of adult neurogenesis in the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and olfactory bulb (OB). DE impaired cellular proliferation in the SGZ and SVZ in males, but not females. DE reduced adult neurogenesis, with male mice showing fewer new neurons in the SGZ, SVZ, and OB, and females showing fewer new neurons only in the OB. To assess whether blocking microglial activation protected against DE-induced suppression of adult hippocampal neurogenesis, male mice were pre-treated with pioglitazone (PGZ) prior to DE exposure. The effects of DE exposure on microglia, as well as neuroinflammation and oxidative stress, were reduced by PGZ. PGZ also antagonized DE-induced suppression of neurogenesis in the SGZ. These results suggest that DE exposure impairs adult neurogenesis in a sex-dependent manner, by a mechanism likely to involve microglia activation and neuroinflammation.

Chronic peripheral inflammation, hippocampal neurogenesis, and behavior.

PubMed

Chesnokova, Vera; Pechnick, Robert N; Wawrowsky, Kolja

2016-11-01

Adult hippocampal neurogenesis is involved in memory and learning, and disrupted neurogenesis is implicated in cognitive impairment and mood disorders, including anxiety and depression. Some long-term peripheral illnesses and metabolic disorders, as well as normal aging, create a state of chronic peripheral inflammation. These conditions are associated with behavioral disturbances linked to disrupted adult hippocampal neurogenesis, such as cognitive impairment, deficits in learning and memory, and depression and anxiety. Pro-inflammatory cytokines released in the periphery are involved in peripheral immune system-to-brain communication by activating resident microglia in the brain. Activated microglia reduce neurogenesis by suppressing neuronal stem cell proliferation, increasing apoptosis of neuronal progenitor cells, and decreasing survival of newly developing neurons and their integration into existing neuronal circuits. In this review, we summarize evolving evidence that the state of chronic peripheral inflammation reduces adult hippocampal neurogenesis, which, in turn, produces the behavioral disturbances observed in chronic inflammatory disorders. As there are no data available on neurogenesis in humans with chronic peripheral inflammatory disease, we focus on animal models and, in parallel, consider the evidence of cognitive disturbance and mood disorders in human patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Adult Hippocampal Neurogenesis in Natural Populations of Mammals

PubMed Central

Amrein, Irmgard

2015-01-01

This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. PMID:25934014

The nuclear receptor tailless is required for neurogenesis in the adult subventricular zone

PubMed Central

Liu, Hai-Kun; Belz, Thorsten; Bock, Dagmar; Takacs, Andrea; Wu, Hui; Lichter, Peter; Chai, Minqiang; Schütz, Günther

2008-01-01

The tailless (Tlx) gene encodes an orphan nuclear receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). The function of Tlx in neural stem cells of the adult SVZ remains largely unknown. We show here that in the SVZ of the adult brain Tlx is exclusively expressed in astrocyte-like B cells. An inducible mutation of the Tlx gene in the adult brain leads to complete loss of SVZ neurogenesis. Furthermore, analysis indicates that Tlx is required for the transition from radial glial cells to astrocyte-like neural stem cells. These findings demonstrate the crucial role of Tlx in the generation and maintenance of NSCs in the adult SVZ in vivo. PMID:18794344

Prenatal ethanol exposure differentially affects hippocampal neurogenesis in the adolescent and aged brain.

PubMed

Gil-Mohapel, J; Titterness, A K; Patten, A R; Taylor, S; Ratzlaff, A; Ratzlaff, T; Helfer, J; Christie, B R

2014-07-25

Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. The hippocampus is composed of two interlocking gyri, the cornu ammonis (CA) and the dentate gyrus (DG), and they are differentially affected by prenatal ethanol exposure. The CA shows a more consistent loss in neuronal numbers, with different ethanol exposure paradigms, than the DG, which in contrast shows more pronounced and consistent deficits in synaptic plasticity. In this study we show that significant deficits in adult hippocampal neurogenesis are apparent in aged animals following prenatal ethanol exposure. Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life. Copyright © 2014. Published by Elsevier Ltd.

Involvement of Adult Hippocampal Neurogenesis in Learning and Forgetting

PubMed Central

Yau, Suk-yu; Li, Ang; So, Kwok-Fai

2015-01-01

Adult hippocampal neurogenesis is a process involving the continuous generation of newborn neurons in the hippocampus of adult animals. Mounting evidence has suggested that hippocampal neurogenesis contributes to some forms of hippocampus-dependent learning and memory; however, the detailed mechanism concerning how this small number of newborn neurons could affect learning and memory remains unclear. In this review, we discuss the relationship between adult-born neurons and learning and memory, with a highlight on recently discovered potential roles of neurogenesis in pattern separation and forgetting. PMID:26380120

Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms

PubMed Central

Seo, Dong-oh; Carillo, Mary Ann; Chih-Hsiung Lim, Sean; Tanaka, Kenji F.

2015-01-01

Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning. SIGNIFICANCE STATEMENT The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult

Adult hippocampal neurogenesis in natural populations of mammals.

PubMed

Amrein, Irmgard

2015-05-01

This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

GABA regulates synaptic integration of newly generated neurons in the adult brain

NASA Astrophysics Data System (ADS)

Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

2006-02-01

Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

Reparative neurogenesis after cerebral ischemia: Clinical application prospects

NASA Astrophysics Data System (ADS)

Khodanovich, M. Yu.

2015-11-01

At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer’s Disease

PubMed Central

Sun, Binggui; Halabisky, Brian; Zhou, Yungui; Palop, Jorge J.; Yu, Guiqiu; Mucke, Lennart; Gan, Li

2009-01-01

SUMMARY Adult neurogenesis regulates plasticity and function in the hippocampus, which is critical for memory and vulnerable to Alzheimer’s disease (AD). Promoting neurogenesis may improve hippocampal function in AD brains. However, how amyloid β (Aβ), the key AD pathogen, affects the development and function of adult-born neurons remains unknown. Adult-born granule cells (GCs) in human amyloid precursor protein (hAPP) transgenic mice, an AD model, showed greater dendritic length, spine density, and functional responses than controls early in development, but were impaired morphologically and functionally during later maturation. Early inhibition of GABAA receptors to suppress GABAergic signaling or late inhibition of calcineurin to enhance glutamatergic signaling normalized the development of adult-born GCs in hAPP mice with high Aβ levels. Aβ-induced increases in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission may contribute to impaired neurogenesis in AD. PMID:19951690

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro.

PubMed

Morales-García, Jose A; de la Fuente Revenga, Mario; Alonso-Gil, Sandra; Rodríguez-Franco, María Isabel; Feilding, Amanda; Perez-Castillo, Ana; Riba, Jordi

2017-07-13

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Hericium erinaceus Extract Reduces Anxiety and Depressive Behaviors by Promoting Hippocampal Neurogenesis in the Adult Mouse Brain.

PubMed

Ryu, Sun; Kim, Hyoun Geun; Kim, Joo Youn; Kim, Seong Yun; Cho, Kyung-Ok

2018-02-01

Versatile biological activities of Hericium erinaceus (HE) have been reported in many brain diseases. However, roles of HE in major psychiatric disorders such as depression and anxiety remain to be investigated. Therefore, we evaluated whether HE could reduce anxiety and depressive behaviors in the adult mouse and its underlying mechanisms. Male C57BL/6 mice were administered HE (20 or 60 mg/kg, p.o.) or saline once a day for 4 weeks. Open field and tail suspension tests were performed 30 min after the last administration of HE, followed by forced swim test 2 days later. We found that chronic administration of HE showed anxiolytic and antidepressant-like effects. To elucidate possible mechanisms, proliferative activity of the hippocampal progenitor cells was assessed by immunohistochemistry of proliferating cell nuclear antigen (PCNA) and Ki67. Moreover, to evaluate neuronal survival in the dentate gyrus, 5-bromo-2'-deoxyuridine (BrdU) (120 mg/kg, i.p.) was given at the first day of HE administration, followed by isolation of the brains 4 weeks later. HE (60 mg/kg) increased the number of PCNA- and Ki67-positive cells in the subgranular zone of the hippocampus, indicating increased proliferation of hippocampal progenitors. In addition, BrdU- and BrdU/NeuN-positive cells in the dentate gyrus were significantly increased when treated with HE (60 mg/kg) compared with the saline-treated group, demonstrating enhanced neurogenesis by HE treatment. Taken together, the results indicate that chronic HE administration can exert anxiolytic and antidepressant-like effects, possibly by enhancing adult hippocampal neurogenesis.

Is there a relationship between adult neurogenesis and neuron generation following injury across evolution?

PubMed

Ferretti, Patrizia

2011-09-01

All vertebrates can produce new neurons postnatally in discrete regions of their nervous system, but only some lower vertebrates (fish and amphibians) can significantly repair several neural structures, including brain, spinal cord, retina, olfactory and auditory-vestibular system, to compensate for neural tissue loss and recover significant functionality. Some regenerative ability, however, is found also in reptiles and birds, and even in mammals. The recognition that neurogenesis indeed occurs in the CNS of all adult vertebrates challenges the view that there is a simple relationship between maintenance of neurogenic regions in the adult CNS and regenerative capability. The aim of this review is to revisit this relationship in the light of recent literature focusing on selected examples of neurogenesis and regeneration, and discuss possible frameworks that may help to elucidate the relationship between adult neurogenesis and regeneration. This could provide useful paradigms for harnessing regeneration in the human CNS. © 2011 The Author. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Excitation-neurogenesis coupling in adult neural stem/progenitor cells.

PubMed

Deisseroth, Karl; Singla, Sheela; Toda, Hiroki; Monje, Michelle; Palmer, Theo D; Malenka, Robert C

2004-05-27

A wide variety of in vivo manipulations influence neurogenesis in the adult hippocampus. It is not known, however, if adult neural stem/progenitor cells (NPCs) can intrinsically sense excitatory neural activity and thereby implement a direct coupling between excitation and neurogenesis. Moreover, the theoretical significance of activity-dependent neurogenesis in hippocampal-type memory processing networks has not been explored. Here we demonstrate that excitatory stimuli act directly on adult hippocampal NPCs to favor neuron production. The excitation is sensed via Ca(v)1.2/1.3 (L-type) Ca(2+) channels and NMDA receptors on the proliferating precursors. Excitation through this pathway acts to inhibit expression of the glial fate genes Hes1 and Id2 and increase expression of NeuroD, a positive regulator of neuronal differentiation. These activity-sensing properties of the adult NPCs, when applied as an "excitation-neurogenesis coupling rule" within a Hebbian neural network, predict significant advantages for both the temporary storage and the clearance of memories.

Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors1,2

PubMed Central

Zou, Junhui; Wang, Wenbin; Pan, Yung-Wei; Abel, Glen M.

2015-01-01

Abstract Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal’s susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression. PMID:26464972

Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability.

PubMed

Mooney, Skyler J; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

2016-01-01

Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier.

Intense Exercise Promotes Adult Hippocampal Neurogenesis But Not Spatial Discrimination

PubMed Central

So, Ji H.; Huang, Chao; Ge, Minyan; Cai, Guangyao; Zhang, Lanqiu; Lu, Yisheng; Mu, Yangling

2017-01-01

Hippocampal neurogenesis persists throughout adult life and plays an important role in learning and memory. Although the influence of physical exercise on neurogenesis has been intensively studied, there is controversy in regard to how the impact of exercise may vary with its regime. Less is known about how distinct exercise paradigms may differentially affect the learning behavior. Here we found that, chronic moderate treadmill running led to an increase of cell proliferation, survival, neuronal differentiation, and migration. In contrast, intense running only promoted neuronal differentiation and migration, which was accompanied with lower expressions of vascular endothelial growth factor, brain-derived neurotrophic factor, insulin-like growth factor 1, and erythropoietin. In addition, the intensely but not mildly exercised animals exhibited a lower mitochondrial activity in the dentate gyrus. Correspondingly, neurogenesis induced by moderate but not intense exercise was sufficient to improve the animal’s ability in spatial pattern separation. Our data indicate that the effect of exercise on spatial learning is intensity-dependent and may involve mechanisms other than a simple increase in the number of new neurons. PMID:28197080

NT-3 Facilitates Hippocampal Plasticity and Learning and Memory by Regulating Neurogenesis

ERIC Educational Resources Information Center

Sakata, Kazuko; Akbarian, Schahram; Bates, Brian; Jaenisch, Rudolf; Lu, Bai; Shimazu, Kazuhiro; Zhao, Mingrui

2006-01-01

In the adult brain, the expression of NT-3 is largely confined to the hippocampal dentate gyrus (DG), an area exhibiting significant neurogenesis. Using a conditional mutant line in which the "NT-3" gene is deleted in the brain, we investigated the role of NT-3 in adult neurogenesis, hippocampal plasticity, and memory. Bromodeoxyuridine…

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

PubMed

Mahmoud, Rand; Wainwright, Steven R; Galea, Liisa A M

2016-04-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Reparative neurogenesis after cerebral ischemia: Clinical application prospects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khodanovich, M. Yu., E-mail: khodanovich@mail.tsu.ru

At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die beforemore » reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.« less

Nitric Oxide in the Crustacean Brain: Regulation of Neurogenesis and Morphogenesis in the Developing Olfactory Pathway

PubMed Central

Benton, J.L.; Sandeman, D.C.; Beltz, B.S.

2009-01-01

Nitric oxide (NO) plays major roles during development and in adult organisms. We examined the temporal and spatial patterns of nitric oxide synthase (NOS) appearance in the embryonic lobster brain to localize sources of NO activity; potential NO targets were identified by defining the distribution of NO-induced cGMP. Staining patterns are compared with NOS and cyclic 3,5 guanosine monophosphate (cGMP) distribution in adult lobster brains. Manipulation of NO levels influences olfactory glomerular formation and stabilization, as well as levels of neurogenesis among the olfactory projection neurons. In the first 2 days following ablation of the lateral antennular flagella in juvenile lobsters, a wave of increased NOS immunoreactivity and a reduction in neurogenesis occur. These studies implicate nitric oxide as a developmental architect and also support a role for this molecule in the neural response to injury in the olfactory pathway. PMID:17948307

Adult hippocampal neurogenesis in the pathogenesis of addiction and dual diagnosis disorders.

PubMed

Chambers, R Andrew

2013-06-01

As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Adult Hippocampal Neurogenesis in the Pathogenesis of Addiction and Dual Diagnosis Disorders

PubMed Central

Chambers, R. Andrew

2013-01-01

Background As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Methods Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. Results While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Conclusions Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders. PMID:23279925

Regulation and Function of Adult Neurogenesis: From Genes to Cognition

PubMed Central

Aimone, James B.; Li, Yan; Lee, Star W.; Clemenson, Gregory D.; Deng, Wei; Gage, Fred H.

2014-01-01

Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders. PMID:25287858

Regulation and Function of Adult Neurogenesis. From Genes to Cognition

DOE PAGES

Aimone, J. B.; Li, Y.; Lee, S. W.; ...

2014-10-01

Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages ofmore » maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.« less

Regulation and Function of Adult Neurogenesis. From Genes to Cognition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aimone, J. B.; Li, Y.; Lee, S. W.

Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages ofmore » maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.« less

Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis.

PubMed

Crews, Leslie; Adame, Anthony; Patrick, Christina; Delaney, Alexandra; Pham, Emiley; Rockenstein, Edward; Hansen, Lawrence; Masliah, Eliezer

2010-09-15

During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-β(1-42) protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits.

Neurofibromin Modulates Adult Hippocampal Neurogenesis and Behavioral Effects of Antidepressants

PubMed Central

Li, Yun; Li, Yanjiao; McKay, Renée M.; Riethmacher, Dieter; Parada, Luis F.

2012-01-01

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. PMID:22399775

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior.

PubMed

Sun, Dong; Sun, Xiang-Dong; Zhao, Lu; Lee, Dae-Hoon; Hu, Jin-Xia; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Zhu, Xiao-Juan; Xiong, Wen-Cheng

2018-01-08

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats

PubMed Central

Glenn, Melissa J.; Gibson, Erin M.; Kirby, Elizabeth D.; Mellott, Tiffany J.; Blusztajn, Jan K.; Williams, Christina L.

2008-01-01

Increased dietary intake of choline early in life improves performance of adult rats on memory tasks and prevents their age-related memory decline. Because neurogenesis in the adult hippocampus also declines with age, we investigated whether prenatal choline availability affects hippocampal neurogenesis in adult Sprague–Dawley rats and modifies their neurogenic response to environmental stimulation. On embryonic days (ED) 12−17, pregnant rats ate a choline-supplemented (SUP-5 g/kg), choline sufficient (SFF-1.1 g/kg), or choline-free (DEF) semisynthetic diet. Adult offspring either remained in standard housing or were given 21 daily visits to explore a maze. On the last ten exploration days, all rats received daily injections of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg). The number of BrdU+ cells was significantly greater in the dentate gyrus in SUP rats compared to SFF or DEF rats. While maze experience increased the number of BrdU+ cells in SFF rats to the level seen in the SUP rats, this enriching experience did not alter cell proliferation in DEF rats. Similar patterns of cell proliferation were obtained with immunohistochemical staining for neuronal marker doublecortin, confirming that diet and exploration affected hippocampal neurogenesis. Moreover, hippocampal levels of the brain-derived neurotrophic factor (BDNF) were increased in SUP rats as compared to SFF and DEF animals. We conclude that prenatal choline intake has enduring effects on adult hippocampal neurogenesis, possibly via up-regulation of BDNF levels, and suggest that these alterations of neurogenesis may contribute to the mechanism of life-long changes in cognitive function governed by the availability of choline during gestation. PMID:17445242

Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome

PubMed Central

Velazquez, Ramon; Ash, Jessica A.; Powers, Brian E.; Kelley, Christy M.; Strawderman, Myla; Luscher, Zoe I.; Ginsberg, Stephen D.; Mufson, Elliott J.; Strupp, Barbara J.

2014-01-01

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer’s disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS. PMID:23643842

Sex steroids and neurogenesis.

PubMed

Heberden, Christine

2017-10-01

The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives. Copyright © 2017 Elsevier Inc. All rights reserved.

Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression After Whole-Brain Irradiation

PubMed Central

Wong-Goodrich, Sarah J.E.; Pfau, Madeline L.; Flores, Catherine T.; Fraser, Jennifer A.; Williams, Christina L.; Jones, Lee W.

2010-01-01

Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention, and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to four months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting one month after sham- or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdU) immunolabeling and ELISA indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdU+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor, and occurred despite irradiation-induced elevations in hippocampal pro-inflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. PMID:20884629

p53 Mutation suppresses adult neurogenesis in medaka fish (Oryzias latipes)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Isoe, Yasuko; Okuyama, Teruhiro; Taniguchi, Yoshihito

2012-07-13

Highlights: Black-Right-Pointing-Pointer Progenitor migration is accompanied by an increase in their numbers in the adult brain. Black-Right-Pointing-Pointer p53 Mutation suppressed an increase in the number of the migrated progenitors. Black-Right-Pointing-Pointer The decreased progenitor number is not due to enhanced cell death. Black-Right-Pointing-Pointer p53 Mutation did not affect proliferation of stem cells. -- Abstract: Tumor suppressor p53 negatively regulates self-renewal of neural stem cells in the adult murine brain. Here, we report that the p53 null mutation in medaka fish (Oryzias latipes) suppressed neurogenesis in the telencephalon, independent of cell death. By using 5-bromo-29-deoxyuridine (BrdU) immunohistochemistry, we identified 18 proliferation zonesmore » in the brains of young medaka fish; in situ hybridization showed that p53 was expressed selectively in at least 12 proliferation zones. We also compared the number of BrdU-positive cells present in the whole telencephalon of wild-type (WT) and p53 mutant fish. Immediately after BrdU exposure, the number of BrdU-positive cells did not differ significantly between them. One week after BrdU-exposure, the BrdU-positive cells migrated from the proliferation zone, which was accompanied by an increased number in the WT brain. In contrast, no significant increase was observed in the p53 mutant brain. Terminal deoxynucleotidyl transferase (dUTP) nick end-labeling revealed that there was no significant difference in the number of apoptotic cells in the telencephalon of p53 mutant and WT medaka, suggesting that the decreased number of BrdU-positive cells in the mutant may be due to the suppression of proliferation rather than the enhancement of neural cell death. These results suggest that p53 positively regulates neurogenesis via cell proliferation.« less

RNA-seq of the aging brain in the short-lived fish N. furzeri - conserved pathways and novel genes associated with neurogenesis.

PubMed

Baumgart, Mario; Groth, Marco; Priebe, Steffen; Savino, Aurora; Testa, Giovanna; Dix, Andreas; Ripa, Roberto; Spallotta, Francesco; Gaetano, Carlo; Ori, Michela; Terzibasi Tozzini, Eva; Guthke, Reinhard; Platzer, Matthias; Cellerino, Alessandro

2014-12-01

The brains of teleost fish show extensive adult neurogenesis and neuronal regeneration. The patterns of gene regulation during fish brain aging are unknown. The short-lived teleost fish Nothobranchius furzeri shows markers of brain aging including reduced learning performances, gliosis, and reduced adult neurogenesis. We used RNA-seq to quantify genome-wide transcript regulation and sampled five different time points to characterize whole-genome transcript regulation during brain aging of N. furzeri. Comparison with human datasets revealed conserved up-regulation of ribosome, lysosome, and complement activation and conserved down-regulation of synapse, mitochondrion, proteasome, and spliceosome. Down-regulated genes differ in their temporal profiles: neurogenesis and extracellular matrix genes showed rapid decay, synaptic and axonal genes a progressive decay. A substantial proportion of differentially expressed genes (~40%) showed inversion of their temporal profiles in the last time point: spliceosome and proteasome showed initial down-regulation and stress-response genes initial up-regulation. Extensive regulation was detected for chromatin remodelers of the DNMT and CBX families as well as members of the polycomb complex and was mirrored by an up-regulation of the H3K27me3 epigenetic mark. Network analysis showed extensive coregulation of cell cycle/DNA synthesis genes with the uncharacterized zinc-finger protein ZNF367 as central hub. In situ hybridization showed that ZNF367 is expressed in neuronal stem cell niches of both embryonic zebrafish and adult N. furzeri. Other genes down-regulated with age, not previously associated with adult neurogenesis and with similar patterns of expression are AGR2, DNMT3A, KRCP, MEX3A, SCML4, and CBX1. CBX7, on the other hand, was up-regulated with age. © 2014 The Authors. Aging cell published by the Anatomical Society and John Wiley & Sons Ltd.

Tamoxifen Activation of Cre-Recombinase Has No Persisting Effects on Adult Neurogenesis or Learning and Anxiety

PubMed Central

Rotheneichner, Peter; Romanelli, Pasquale; Bieler, Lara; Pagitsch, Sebastian; Zaunmair, Pia; Kreutzer, Christina; König, Richard; Marschallinger, Julia; Aigner, Ludwig; Couillard-Després, Sébastien

2017-01-01

Adult neurogenesis is a tightly regulated process continuously taking place in the central nervous system of most mammalian species. In neuroscience research, transgenic animals bearing the tamoxifen-inducible CreERT2-Lox system are widely used. In this study, we made use of a Nestin-CreERT2/R26R-YFP transgenic mouse model in which the CreERT2 activates the expression of YFP in multipotent neural stem cells upon tamoxifen application. Humoral factors, such as the levels of estrogens, have been reported to affect the hippocampal neurogenesis. The application of tamoxifen, a mixed agonist/antagonist of the estrogen receptor that permeates the blood-brain-barrier, could thus influence adult neurogenesis. Although the functions of adult neurogenesis are yet to be fully deciphered, a reciprocal interaction between rates of neurogenesis on the one hand and learning and mood regulation on the other hand, has been suggested. The impact of tamoxifen on neurogenesis and behavior was therefore addressed following five daily applications according to the open field test, the elevated plus maze, and Morris water maze. In addition, the impact of short-term tamoxifen application on progenitor cell proliferation, morphology, and fate in the neurogenic niche of the dentate gyrus were investigated. Finally, the influence of the route of administration (oral vs. intra-peritoneal) and gender-specific response were scrutinized. The sub-acute analysis did neither reveal significant differences in behavior, such as voluntary motor activity, anxiety behavior, and spatial learning, nor in cell proliferation, cell survival, dendritic arborization or maturation rate within the dentate gyrus between saline solution-, corn oil-, and tamoxifen-treated groups. Finally, neither the route of application, nor the gender of treated mice influenced the response to tamoxifen. We conclude that short tamoxifen treatments used to activate the CreERT2 system in transgenic mouse models does not have a

VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

PubMed Central

Licht, Tamar; Rothe, Gadiel; Kreisel, Tirzah; Wolf, Brachi; Benny, Ofra; Rooney, Alasdair G.; ffrench-Constant, Charles; Enikolopov, Grigori; Keshet, Eli

2016-01-01

Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal “juvenile” NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an “aged” systemic milieu. PMID:27849577

Effects of Maternal Behavior Induction and Pup Exposure on Neurogenesis in Adult, Virgin Female Rats

PubMed Central

Furuta, Miyako; Bridges, Robert S.

2009-01-01

The states of pregnancy and lactation bring about a range of physiological and behavioral changes in the adult mammal that prepare the mother to care for her young. Cell proliferation increases in the subventricular zone (SVZ) of the female rodent brain during both pregnancy and lactation when compared to that in cycling, diestrous females. In the present study, the effects of maternal behavior induction and pup exposure on neurogenesis in nulliparous rats were examined in order to determine whether maternal behavior itself, independent of pregnancy and lactation, might affect neurogenesis. Adult, nulliparous, Sprague-Dawley, female rats were exposed daily to foster young in order to induce maternal behavior. Following the induction of maternal behavior each maternal subject plus females that were exposed to pups for a comparable number of test days, but did not display maternal behavior, and subjects that had received no pup exposure were injected with bromodeoxyuridine (BrdU, 90 mg/kg, i.v.). Brain sections were double-labeled for BrdU and the neural marker, NeuN, to examine the proliferating cell population. Increases in the number of double-labeled cells were found in the maternal virgin brain when compared with the number of double-labeled cells present in non-maternal, pup-exposed nulliparous rats and in females not exposed to young. No changes were evident in the dentate gyrus of the hippocampus as a function of maternal behavior. These data indicate that in nulliparous female rats maternal behavior itself is associated with the stimulation of neurogenesis in the SVZ. PMID:19712726

Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome.

PubMed

Velazquez, Ramon; Ash, Jessica A; Powers, Brian E; Kelley, Christy M; Strawderman, Myla; Luscher, Zoe I; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J

2013-10-01

In addition to intellectual disability, individuals with Down syndrome (DS) exhibit dementia by the third or fourth decade of life, due to the early onset of neuropathological changes typical of Alzheimer's disease (AD). Deficient ontogenetic neurogenesis contributes to the brain hypoplasia and hypocellularity evident in fetuses and children with DS. A murine model of DS and AD (the Ts65Dn mouse) exhibits key features of these disorders, notably deficient ontogenetic neurogenesis, degeneration of basal forebrain cholinergic neurons (BFCNs), and cognitive deficits. Adult hippocampal (HP) neurogenesis is also deficient in Ts65Dn mice and may contribute to the observed cognitive dysfunction. Herein, we demonstrate that supplementing the maternal diet with additional choline (approximately 4.5 times the amount in normal rodent chow) dramatically improved the performance of the adult trisomic offspring in a radial arm water maze task. Ts65Dn offspring of choline-supplemented dams performed significantly better than unsupplemented Ts65Dn mice. Furthermore, adult hippocampal neurogenesis was partially normalized in the maternal choline supplemented (MCS) trisomic offspring relative to their unsupplemented counterparts. A significant correlation was observed between adult hippocampal neurogenesis and performance in the water maze, suggesting that the increased neurogenesis seen in the supplemented trisomic mice contributed functionally to their improved spatial cognition. These findings suggest that supplementing the maternal diet with additional choline has significant translational potential for DS. Copyright © 2013 Elsevier Inc. All rights reserved.

Untangling the Influences of Voluntary Running, Environmental Complexity, Social Housing and Stress on Adult Hippocampal Neurogenesis

PubMed Central

Grégoire, Catherine-Alexandra; Bonenfant, David; Le Nguyen, Adalie; Aumont, Anne; Fernandes, Karl J. L.

2014-01-01

Environmental enrichment (EE) exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel “Alternating EE” paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1) voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2) a complex environment (comprised of both social interactions and rotated inanimate objects) had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions) and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects); and (3) neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this “Alternating EE” paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity. PMID:24465980

Life-long stability of neurons: a century of research on neurogenesis, neuronal death and neuron quantification in adult CNS.

PubMed

Turlejski, Kris; Djavadian, Ruzanna

2002-01-01

In this chapter we provide an extensive review of 100 years of research on the stability of neurons in the mammalian brain, with special emphasis on humans. Although Cajal formulated the Neuronal Doctrine, he was wrong in his beliefs that adult neurogenesis did not occur and adult neurons are dying throughout life. These two beliefs became accepted "common knowledge" and have shaped much of neuroscience research and provided much of the basis for clinical treatment of age-related brain diseases. In this review, we consider adult neurogenesis from a historical and evolutionary perspective. It is concluded, that while adult neurogenesis is a factor in the dynamics of the dentate gyrus and olfactory bulb, it is probably not a major factor during the life-span in most brain areas. Likewise, the acceptance of neuronal death as an explanation for normal age-related senility is challenged with evidence collected over the last fifty years. Much of the problem in changing this common belief of dying neurons was the inadequacies of neuronal counting methods. In this review we discuss in detail implications of recent improvements in neuronal quantification. We conclude: First, age-related neuronal atrophy is the major factor in functional deterioration of existing neurons and could be slowed down, or even reversed by various pharmacological interventions. Second, in most cases neuronal degeneration during aging is a pathology that in principle may be avoided. Third, loss of myelin and of the white matter is more frequent and important than the limited neuronal death in normal aging.

Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

PubMed

Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

2013-11-01

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress. © 2013 British Society for Neuroendocrinology.

Cell-autonomous inactivation of the Reelin pathway impairs adult neurogenesis in the hippocampus

PubMed Central

Teixeira, Catia M.; Kron, Michelle M.; Masachs, Nuria; Zhang, Helen; Lagace, Diane C.; Martinez, Albert; Reillo, Isabel; Duan, Xin; Bosch, Carles; Pujadas, Lluis; Brunso, Lucas; Song, Hongjun; Eisch, Amelia J.; Borrell, Victor; Howell, Brian W.; Parent, Jack M.; Soriano, Eduardo

2012-01-01

Adult hippocampal neurogenesis is thought to be essential for learning and memory and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of disabled-1 (Dab1), an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain- and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. PMID:22933789

Cellular responses to recurrent pentylenetetrazole-induced seizures in the adult zebrafish brain

PubMed Central

Duy, Phan Q; Berberoglu, Michael A; Beattie, Christine E; Hall, Charles W

2017-01-01

A seizure is a sustained increase in brain electrical activity that can result in loss of consciousness and injury. Understanding how the brain responds to seizures is important for development of new treatment strategies for epilepsy, a neurological condition characterized by recurrent and unprovoked seizures. Pharmacological induction of seizures in rodent models results in a myriad of cellular alterations, including inflammation, angiogenesis, and adult neurogenesis. The purpose of this study is to investigate the cellular responses to recurrent pentylenetetrazole seizures in the adult zebrafish brain. We subjected zebrafish to five once daily pentylenetetrazole induced seizures and characterized the cellular consequences of these seizures. In response to recurrent seizures, we found histologic evidence of vasodilatation, perivascular leukocyte egress and leukocyte proliferation suggesting seizure-induced acute CNS inflammation. We also found evidence of increased proliferation, neurogenesis, and reactive gliosis. Collectively, our results suggest that the cellular responses to seizures in the adult zebrafish brain are similar to those observed in mammalian brains. PMID:28238851

Forebrain neurogenesis: From embryo to adult.

PubMed

Dennis, Daniel; Picketts, David; Slack, Ruth S; Schuurmans, Carol

2016-01-01

A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16-17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis : From embryo to adult . The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with 'state of the art' techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

NFκB signaling regulates embryonic and adult neurogenesis

PubMed Central

ZHANG, Yonggang; HU, Wenhui

2013-01-01

Both embryonic and adult neurogenesis involves the self-renewal/proliferation, survival, migration and lineage differentiation of neural stem/progenitor cells. Such dynamic process is tightly regulated by intrinsic and extrinsic factors and complex signaling pathways. Misregulated neurogenesis contributes much to a large range of neurodevelopmental defects and neurodegenerative diseases. The signaling of NFκB regulates many genes important in inflammation, immunity, cell survival and neural plasticity. During neurogenesis, NFκB signaling mediates the effect of numerous niche factors such as cytokines, chemokines, growth factors, extracellular matrix molecules, but also crosstalks with other signaling pathways such as Notch, Shh, Wnt/β-catenin. This review summarizes current progress on the NFκB signaling in all aspects of neurogenesis, focusing on the novel role of NFκB signaling in initiating early neural differentiation of neural stem cells and embryonic stem cells. PMID:24324484

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

PubMed Central

Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J.; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario

2016-01-01

Background: Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. Methodology: We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. Results: We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. Conclusions: This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation.

PubMed

Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario; Castro, Carmen

2015-07-29

Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal. © The

Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus.

PubMed

Aberg, Elin; Perlmann, Thomas; Olson, Lars; Brené, Stefan

2008-01-01

Both vitamin A deficiency and high doses of retinoids can result in learning and memory impairments, depression as well as decreases in cell proliferation, neurogenesis and cell survival. Physical activity enhances hippocampal neurogenesis and can also exert an antidepressant effect. Here we elucidate a putative link between running, retinoid signaling, and neurogenesis in hippocampus. Adult transgenic reporter mice designed to detect ligand-activated retinoic acid receptors (RAR) or retinoid X receptors (RXR) were used to localize the distribution of activated RAR or RXR at the single-cell level in the brain. Two months of voluntary wheel-running induced an increase in hippocampal neurogenesis as indicated by an almost two-fold increase in doublecortin-immunoreactive cells. Running activity was correlated with neurogenesis. Under basal conditions a distinct pattern of RAR-activated cells was detected in the granule cell layer of the dentate gyrus (DG), thalamus, and cerebral cortex layers 3-4 and to a lesser extent in hippocampal pyramidal cell layers CA1-CA3. Running did not change the number of RAR-activated cells in the DG. There was no correlation between running and RAR activation or between RAR activation and neurogenesis in the DG of hippocampus. Only a few scattered activated retinoid X receptors were found in the DG under basal conditions and after wheel-running, but RXR was detected in other areas such as in the hilus region of hippocampus and in layer VI of cortex cerebri. RAR agonists affect mood in humans and reduce neurogenesis, learning and memory in animal models. In our study, long-term running increased neurogenesis but did not alter RAR ligand activation in the DG in individually housed mice. Thus, our data suggest that the effects of exercise on neurogenesis and other plasticity changes in the hippocampal formation are mediated by mechanisms that do not involve retinoid receptor activation. (c) 2008 Wiley-Liss, Inc.

The helix-loop-helix protein id1 controls stem cell proliferation during regenerative neurogenesis in the adult zebrafish telencephalon.

PubMed

Rodriguez Viales, Rebecca; Diotel, Nicolas; Ferg, Marco; Armant, Olivier; Eich, Julia; Alunni, Alessandro; März, Martin; Bally-Cuif, Laure; Rastegar, Sepand; Strähle, Uwe

2015-03-01

The teleost brain has the remarkable ability to generate new neurons and to repair injuries during adult life stages. Maintaining life-long neurogenesis requires careful management of neural stem cell pools. In a genome-wide expression screen for transcription regulators, the id1 gene, encoding a negative regulator of E-proteins, was found to be upregulated in response to injury. id1 expression was mapped to quiescent type I neural stem cells in the adult telencephalic stem cell niche. Gain and loss of id1 function in vivo demonstrated that Id1 promotes stem cell quiescence. The increased id1 expression observed in neural stem cells in response to injury appeared independent of inflammatory signals, suggesting multiple antagonistic pathways in the regulation of reactive neurogenesis. Together, we propose that Id1 acts to maintain the neural stem cell pool by counteracting neurogenesis-promoting signals. © 2014 AlphaMed Press.

Developmental basis for telencephalon expansion in waterfowl: enlargement prior to neurogenesis

PubMed Central

Charvet, Christine J.; Striedter, Georg F.

2009-01-01

Some altricial and some precocial species of birds have evolved enlarged telencephalons compared with other birds. Previous work has shown that finches and parakeets, two species that hatch in an immature (i.e. altricial) state, enlarged their telencephalon by delaying telencephalic neurogenesis. To determine whether species that hatch in a relatively mature (i.e. precocial) state also enlarged their telencephalon by delaying telencephalic neurogenesis, we examined brain development in geese, ducks, turkeys and chickens, which are all precocial. Whereas the telencephalon occupies less than 55 per cent of the brain in chickens and turkeys, it occupies more than 65 per cent in ducks and geese. To determine how these species differences in adult brain region proportions arise during development, we examined brain maturation (i.e. neurogenesis timing) and estimated telencephalon, tectum and medulla volumes from serial Nissl-stained sections in the four species. We found that incubation time predicts the timing of neurogenesis in all major brain regions and that the telencephalon is proportionally larger in ducks and geese before telencephalic neurogenesis begins. These findings demonstrate that the expansion of the telencephalon in ducks and geese is achieved by altering development prior to neurogenesis onset. Thus, precocial and altricial species evolved different developmental strategies to expand their telencephalon. PMID:19605398

Developmental basis for telencephalon expansion in waterfowl: enlargement prior to neurogenesis.

PubMed

Charvet, Christine J; Striedter, Georg F

2009-10-07

Some altricial and some precocial species of birds have evolved enlarged telencephalons compared with other birds. Previous work has shown that finches and parakeets, two species that hatch in an immature (i.e. altricial) state, enlarged their telencephalon by delaying telencephalic neurogenesis. To determine whether species that hatch in a relatively mature (i.e. precocial) state also enlarged their telencephalon by delaying telencephalic neurogenesis, we examined brain development in geese, ducks, turkeys and chickens, which are all precocial. Whereas the telencephalon occupies less than 55 per cent of the brain in chickens and turkeys, it occupies more than 65 per cent in ducks and geese. To determine how these species differences in adult brain region proportions arise during development, we examined brain maturation (i.e. neurogenesis timing) and estimated telencephalon, tectum and medulla volumes from serial Nissl-stained sections in the four species. We found that incubation time predicts the timing of neurogenesis in all major brain regions and that the telencephalon is proportionally larger in ducks and geese before telencephalic neurogenesis begins. These findings demonstrate that the expansion of the telencephalon in ducks and geese is achieved by altering development prior to neurogenesis onset. Thus, precocial and altricial species evolved different developmental strategies to expand their telencephalon.

Cerebroventricular Microinjection (CVMI) into Adult Zebrafish Brain Is an Efficient Misexpression Method for Forebrain Ventricular Cells

PubMed Central

Kizil, Caghan; Brand, Michael

2011-01-01

The teleost fish Danio rerio (zebrafish) has a remarkable ability to generate newborn neurons in its brain at adult stages of its lifespan-a process called adult neurogenesis. This ability relies on proliferating ventricular progenitors and is in striking contrast to mammalian brains that have rather restricted capacity for adult neurogenesis. Therefore, investigating the zebrafish brain can help not only to elucidate the molecular mechanisms of widespread adult neurogenesis in a vertebrate species, but also to design therapies in humans with what we learn from this teleost. Yet, understanding the cellular behavior and molecular programs underlying different biological processes in the adult zebrafish brain requires techniques that allow manipulation of gene function. As a complementary method to the currently used misexpression techniques in zebrafish, such as transgenic approaches or electroporation-based delivery of DNA, we devised a cerebroventricular microinjection (CVMI)-assisted knockdown protocol that relies on vivo morpholino oligonucleotides, which do not require electroporation for cellular uptake. This rapid method allows uniform and efficient knockdown of genes in the ventricular cells of the zebrafish brain, which contain the neurogenic progenitors. We also provide data on the use of CVMI for growth factor administration to the brain – in our case FGF8, which modulates the proliferation rate of the ventricular cells. In this paper, we describe the CVMI method and discuss its potential uses in zebrafish. PMID:22076157

Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

PubMed

Duarte-Guterman, Paula; Yagi, Shunya; Chow, Carmen; Galea, Liisa A M

2015-08-01

This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

In vivo contribution of nestin- and GLAST-lineage cells to adult hippocampal neurogenesis

PubMed Central

DeCarolis, Nathan A.; Mechanic, Maxwell; Petrik, David; Carlton, Adam; Ables, Jessica L.; Malhotra, Shveta; Bachoo, Robert; Götz, Magdalena; Lagace, Diane C.; Eisch, Amelia J.

2013-01-01

Radial glia-like cells (RGCs) are the hypothesized source of adult hippocampal neurogenesis. However, the current model of hippocampal neurogenesis does not fully incorporate the in vivo heterogeneity of RGCs. In order to better understand the contribution of different RGC subtypes to adult hippocampal neurogenesis, we employed widely-used transgenic lines (Nestin-CreERT2 and GLAST∷CreERT2 mice) to explore how RGCs contribute to neurogenesis under basal conditions and after stimulation and depletion of neural progenitor cells. We first used these inducible fate-tracking transgenic lines to define the similarities and differences in the contribution of nestin- and GLAST-lineage cells to basal long-term hippocampal neurogenesis. We then explored the ability of nestin- and GLAST-lineage RGCs to contribute to neurogenesis, after experimental manipulations that either ablate neurogenesis (i.c.v. application of the anti-mitotic AraC, cytosine-β-D-arabinofuranoside) or stimulate neurogenesis (wheel running). Interestingly, in both ablation and stimulation experiments, labeled RGCs in GLAST∷CreERT2 mice appear to contribute to neurogenesis, whereas RGCs in Nestin-CreERT2 mice do not. Finally, using NestinGFP reporter mice, we expanded on previous research by showing that not all RGCs in the adult dentate gyrus subgranular zone express nestin, and therefore RGCs are antigenically heterogeneous. These findings are important for the field, as they allow appropriately conservative interpretation of existing and future data that emerge from these inducible transgenic lines. These findings also raise important questions about the differences between transgenic driver lines, the heterogeneity of RGCs, and the potential differences in progenitor cell behavior between transgenic lines. As these findings highlight the possible differences in the contribution of nestin and GLAST lineage cells to long-term neurogenesis in vivo, they indicate that the current models of hippocampal

Factors That Modulate Neurogenesis: A Top-Down Approach.

PubMed

LaDage, Lara D

2016-08-24

Although hippocampal neurogenesis in the adult brain has been conserved across the vertebrate lineage, laboratory studies have primarily examined this phenomenon in rodent models. This approach has been successful in elucidating important factors and mechanisms that can modulate rates of hippocampal neurogenesis, including hormones, environmental complexity, learning and memory, motor stimulation, and stress. However, recent studies have found that neurobiological research on neurogenesis in rodents may not easily translate to, or explain, neurogenesis patterns in nonrodent systems, particularly in species examined in the field. This review examines some of the evolutionary and ecological variables that may also modulate neurogenesis patterns. This 'top-down' and more naturalistic approach, which incorporates ecology and natural history, particularly of nonmodel species, may allow for a more comprehensive understanding of the functional significance of neurogenesis. © 2016 S. Karger AG, Basel.

Endocrine and social regulation of adult neurogenesis in songbirds.

PubMed

Balthazart, Jacques; Ball, Gregory F

2016-04-01

The identification of pronounced seasonal changes in the volume of avian song control nuclei stimulated the discovery of adult neurogenesis in songbirds as well as renewed studies in mammals including humans. Neurogenesis in songbirds is modulated by testosterone and other factors such as photoperiod, singing activity and social environment. Adult neurogenesis has been widely studied by labeling, with tritiated thymidine or its analog BrdU, cells duplicating their DNA in anticipation of their last mitotic division and following their fate as new neurons. New methods based on endogenous markers of cell cycling or of various stages of neuronal life have allowed for additional progress. In particular immunocytochemical visualization of the microtubule-associated protein doublecortin has provided an integrated view of neuronal replacement in the song control nucleus HVC. Multiple questions remain however concerning the specific steps in the neuronal life cycle that are modulated by various factors and the underlying cellular mechanisms. Copyright © 2016. Published by Elsevier Inc.

Homeostatic regulation of adult hippocampal neurogenesis in aging rats: long-term effects of early exercise

PubMed Central

Merkley, Christina M.; Jian, Charles; Mosa, Adam; Tan, Yao-Fang; Wojtowicz, J. Martin

2014-01-01

Adult neurogenesis is highly responsive to environmental and physiological factors. The majority of studies to date have examined short-term consequences of enhancing or blocking neurogenesis but long-term changes remain less well understood. Current evidence for age-related declines in neurogenesis warrant further investigation into these long-term changes. In this report we address the hypothesis that early life experience, such as a period of voluntary running in juvenile rats, can alter properties of adult neurogenesis for the remainder of the animal's life. The results indicate that the number of proliferating and differentiating neuronal precursors is not altered in runners beyond the initial weeks post-running, suggesting homeostatic regulation of these processes. However, the rate of neuronal maturation and survival during a 4 week period after cell division was enhanced up to 11 months of age (the end of the study period). This study is the first to show that a transient period of physical activity at a young age promotes changes in neurogenesis that persist over the long-term, which is important for our understanding of the modulation of neurogenesis by exercise with age. Functional integration of adult-born neurons within the hippocampus that resist homeostatic regulation with aging, rather than the absolute number of adult-born neurons, may be an essential feature of adult neurogenesis that promotes the maintenance of neural plasticity in old age. PMID:25071426

Interaction between Neurogenesis and Hippocampal Memory System: New Vistas

PubMed Central

Abrous, Djoher Nora; Wojtowicz, Jan Martin

2015-01-01

During the last decade, the questions on the functionality of adult neurogenesis have changed their emphasis from if to how the adult-born neurons participate in a variety of memory processes. The emerging answers are complex because we are overwhelmed by a variety of behavioral tasks that apparently require new neurons to be performed optimally. With few exceptions, the hippocampal memory system seems to use the newly generated neurons for multiple roles. Adult neurogenesis has given the dentate gyrus new capabilities not previously thought possible within the scope of traditional synaptic plasticity. Looking at these new developments from the perspective of past discoveries, the science of adult neurogenesis has emerged from its initial phase of being, first, a surprising oddity and, later, exciting possibility, to the present state of being an integral part of mainstream neuroscience. The answers to many remaining questions regarding adult neurogenesis will come along only with our growing understanding of the functionality of the brain as a whole. This, in turn, will require integration of multiple levels of organization from molecules and cells to circuits and systems, ultimately resulting in comprehension of behavioral outcomes. PMID:26032718

Adult neurogenesis in the central olfactory pathway of dendrobranchiate and caridean shrimps: New insights into the evolution of the deutocerebral proliferative system in reptant decapods.

PubMed

Wittfoth, Christin; Harzsch, Steffen

2018-04-16

Persistent neurogenesis in the central olfactory pathway characterizes many reptant decapods such as lobsters, crayfish and crabs. In these animals, the deutocerebral proliferative system generates new neurons which integrate into the neuronal network of the first order processing neuropil of the olfactory system, the deutocerebral chemosensory lobes (also called olfactory lobes). However, differences concerning the phenotype and the mechanisms that drive adult neurogenesis were reported in crayfish versus spiny lobsters. While numerous studies have focussed on these mechanisms and regulation of adult neurogenesis, investigations about the phylogenetic distribution are missing. To contribute an evolutionary perspective on adult neurogenesis in decapods, we investigated two representatives of basally diverging lineages, the dendrobranchiate Penaeus vannamei and the caridean Crangon crangon using the thymidine analogue Bromodeoxyuridine (BrdU) as marker for the S phase of cycling cells. Compared to reptant decapods, our results suggest a simpler mechanism of neurogenesis in the adult brain of dendrobranchiate and caridean shrimps. Observed differences in the rate of proliferation and spatial dimensions are suggested to correlate with the complexity of the olfactory system. We assume that a more complex and mitotically more active proliferative system in reptant decapods evolved with the emergence of another processing neuropil, the accessory lobes. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

SoxC Transcription Factors Are Required for Neuronal Differentiation in Adult Hippocampal Neurogenesis

PubMed Central

Mu, Lifang; Berti, Lucia; Masserdotti, Giacomo; Covic, Marcela; Michaelidis, Theologos M.; Doberauer, Kathrin; Merz, Katharina; Rehfeld, Frederick; Haslinger, Anja; Wegner, Michael; Sock, Elisabeth; Lefebvre, Veronique; Couillard-Despres, Sebastien; Aigner, Ludwig; Berninger, Benedikt; Lie, D. Chichung

2012-01-01

Neural stem cells (NSCs) generate new hippocampal dentate granule neurons throughout adulthood. The genetic programs controlling neuronal differentiation of adult NSCs are only poorly understood. Here we show that, in the adult mouse hippocampus, expression of the SoxC transcription factors Sox4 and Sox11 is initiated around the time of neuronal commitment of adult NSCs and is maintained in immature neurons. Overexpression of Sox4 and Sox11 strongly promotes in vitro neurogenesis from adult NSCs, whereas ablation of Sox4/Sox11 prevents in vitro and in vivo neurogenesis from adult NSCs. Moreover, we demonstrate that SoxC transcription factors target the promoters of genes that are induced on neuronal differentiation of adult NSCs. Finally, we show that reprogramming of astroglia into neurons is dependent on the presence of SoxC factors. These data identify SoxC proteins as essential contributors to the genetic network controlling neuronal differentiation in adult neurogenesis and neuronal reprogramming of somatic cells. PMID:22378879

Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment.

PubMed

Vivar, Carmen

2015-01-01

The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols.

Exposure to swainsonine impairs adult neurogenesis and spatial learning and memory.

PubMed

Wang, Jiutao; Song, Lingzhen; Zhang, Qi; Zhang, Wei; An, Lei; Zhang, Yamei; Tong, Dewen; Zhao, Baoyu; Chen, Shulin; Zhao, Shanting

2015-01-05

Swainsonine (SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase (AMA) and accumulation of intracellular oligosaccharide. However, the effects of SW on adult neurogenesis and cognition have remained unclear. Therefore, the present study was conducted to examine the effects of SW on adult neurogenesis and learning as well as memory performance in adult mice. SW (10μg/mL in drinking water) was administered orally to mice for 4 weeks. Our results showed that SW reduced proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin (DCX) and synaptophysin (SYP) in the hippocampus. However, caspase 3 and glial fibrillary acidic protein (GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Targeting the Brain with a Neuroprotective Omega-3 Fatty Acid to Enhance Neurogenesis in Hypoxic Condition in Culture.

PubMed

Lo Van, Amanda; Sakayori, Nobuyuki; Hachem, Mayssa; Belkouch, Mounir; Picq, Madeleine; Fourmaux, Baptiste; Lagarde, Michel; Osumi, Noriko; Bernoud-Hubac, Nathalie

2018-06-01

Docosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA) that is required for proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases, a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with aging or neurodegenerative diseases. In this context, targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases. We previously synthesized a stabilized form of DHA-containing lysophosphatidylcholine a major vector of DHA transportation to the brain, which is 1-acetyl,2-docoshexaenoyl-glycerophosphocholine, named AceDoPC®. Injection of AceDoPC® or DHA after experimental ischemic stroke showed that both molecules had neuroprotective effects but AceDoPC® was the most potent. This study aims to investigate the beneficial effects of DHA either unesterified or esterified within AceDoPC® on a model of neurogenesis in vitro, under physiological or pathological conditions. The effect of protectin DX (PDX, a double lipoxygenase product of DHA) was also tested. We cultured neural stem progenitor cells (NSPCs) derived from the adult mouse brain under normal or hypoxigenic (ischemic) conditions in vitro. Neurogenesis study of cell cultures with AceDoPC® showed enhanced neurogenesis compared to addition of unesterified DHA, PDX, or vehicle control, especially under pathological conditions. Our studies of the potential mechanisms involved in neuroprotection hinted that AceDoPC® neuroprotective and regenerative effects might be due in part to its anti-oxidative effects. These results indicate the potential for novel therapeutics against stroke that target the brain.

Ablation of Mouse Adult Neurogenesis Alters Olfactory Bulb Structure and Olfactory Fear Conditioning

PubMed Central

Valley, Matthew T.; Mullen, Tanner R.; Schultz, Lucy C.; Sagdullaev, Botir T.; Firestein, Stuart

2009-01-01

Adult neurogenesis replenishes olfactory bulb (OB) interneurons throughout the life of most mammals, yet during this constant flux it remains unclear how the OB maintains a constant structure and function. In the mouse OB, we investigated the dynamics of turnover and its impact on olfactory function by ablating adult neurogenesis with an x-ray lesion to the sub-ventricular zone (SVZ). Regardless of the magnitude of the lesion to the SVZ, we found no change in the survival of young adult born granule cells (GCs) born after the lesion, and a gradual decrease in the population of GCs born before the lesion. After a lesion producing a 96% reduction of incoming adult born GCs to the OB, we found a diminished behavioral fear response to conditioned odor cues but not to audio cues. Interestingly, despite this behavioral deficit and gradual anatomical changes, we found no electrophysiological changes in the GC population assayed in vivo through dendro-dendritic synaptic plasticity and odor-evoked local field potential oscillations. These data indicate that turnover in the granule cell layer is generally decoupled from the rate of adult neurogenesis, and that OB adult neurogenesis plays a role in a wide behavioral system extending beyond the OB. PMID:20582278

Hypertension impairs hippocampus-related adult neurogenesis, CA1 neuron dendritic arborization and long-term memory.

PubMed

Shih, Y-H; Tsai, S-F; Huang, S-H; Chiang, Y-T; Hughes, M W; Wu, S-Y; Lee, C-W; Yang, T-T; Kuo, Y-M

2016-05-13

Hypertension is associated with neurodegenerative diseases and cognitive impairment. Several studies using spontaneous hypertensive rats to study the effect of hypertension on memory performance and adult hippocampal neurogenesis have reached inconsistent conclusions. The contradictory findings may be related to the genetic variability of spontaneous hypertensive rats due to the conventional breeding practices. The objective of this study is to examine the effect of hypertension on hippocampal structure and function in isogenic mice. Hypertension was induced by the '2 kidneys, 1 clip' method (2K1C) which constricted one of the two renal arteries. The blood pressures of 2K1C mice were higher than the sham group on post-operation day 7 and remained high up to day 28. Mice with 2K1C-induced hypertension had impaired long-term, but not short-term, memory. Dendritic complexity of CA1 neurons and hippocampal neurogenesis were reduced by 2K1C-induced hypertension on post-operation day 28. Furthermore, 2K1C decreased the levels of hippocampal brain-derived neurotrophic factor, while blood vessel density and activation status of astrocytes and microglia were not affected. In conclusion, hypertension impairs hippocampus-associated long-term memory, dendritic arborization and neurogenesis, which may be caused by down-regulation of brain-derived neurotrophic factor signaling pathways. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Moderate ethanol consumption increases hippocampal cell proliferation and neurogenesis in the adult mouse.

PubMed

Aberg, Elin; Hofstetter, Christoph P; Olson, Lars; Brené, Stefan

2005-12-01

Alcoholism is a lifelong disease often associated with emotional disturbances and a high risk of relapse even years after detoxification. To explore if cell proliferation in the dentate gyrus of the hippocampus might be important for alcohol-induced brain adaptation, we analysed hippocampal neurogenesis and gliogenesis in adult C57BL/6 mice that consumed moderate levels of ethanol (~6 g/kg.d) in a two-bottle free-choice model during ~10 wk. The mice developed a 53% preference for ethanol vs. water and displayed a blood ethanol concentration of 0.24 per thousand at the time of sacrifice. Bromo-deoxy-uridine (BrdU) was administered in different regimes to analyse proliferation, survival, cell distribution and differentiation of new cells in the dentate gyrus. Moderate ethanol consumption increased the proliferation of cells, which survived and developed a neural phenotype. Ethanol consumption did not induce apoptosis, neither did it change differentiation or the distribution patterns of the newly formed cells. The cell proliferation rate in the dentate gyrus returned to basal levels 3 d after ethanol withdrawal. We conclude that voluntary ethanol intake by mice can change the rate of cell proliferation in the dentate gyrus. These observations add to the emerging picture of dentate gyrus neurogenesis as a highly regulated process. Since there was no increase in apoptosis concomitant with the ethanol-induced increase in neurogenesis, it is possible that the new cells in the dentate gyrus may contribute to the long-lasting changes of brain function after ethanol consumption.

The endogenous regenerative capacity of the damaged newborn brain: boosting neurogenesis with mesenchymal stem cell treatment.

PubMed

Donega, Vanessa; van Velthoven, Cindy T J; Nijboer, Cora H; Kavelaars, Annemieke; Heijnen, Cobi J

2013-05-01

Neurogenesis continues throughout adulthood. The neurogenic capacity of the brain increases after injury by, e.g., hypoxia-ischemia. However, it is well known that in many cases brain damage does not resolve spontaneously, indicating that the endogenous regenerative capacity of the brain is insufficient. Neonatal encephalopathy leads to high mortality rates and long-term neurologic deficits in babies worldwide. Therefore, there is an urgent need to develop more efficient therapeutic strategies. The latest findings indicate that stem cells represent a novel therapeutic possibility to improve outcome in models of neonatal encephalopathy. Transplanted stem cells secrete factors that stimulate and maintain neurogenesis, thereby increasing cell proliferation, neuronal differentiation, and functional integration. Understanding the molecular and cellular mechanisms underlying neurogenesis after an insult is crucial for developing tools to enhance the neurogenic capacity of the brain. The aim of this review is to discuss the endogenous capacity of the neonatal brain to regenerate after a cerebral ischemic insult. We present an overview of the molecular and cellular mechanisms underlying endogenous regenerative processes during development as well as after a cerebral ischemic insult. Furthermore, we will consider the potential to use stem cell transplantation as a means to boost endogenous neurogenesis and restore brain function.

Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats.

PubMed

Soares, Rita; Ribeiro, Filipa F; Xapelli, Sara; Genebra, Tânia; Ribeiro, Maria F; Sebastião, Ana M; Rodrigues, Cecília M P; Solá, Susana

2018-05-01

Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.

Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory.

PubMed

Parihar, V K; Hattiangady, B; Kuruba, R; Shuai, B; Shetty, A K

2011-02-01

Maintenance of neurogenesis in adult hippocampus is important for functions such as mood and memory. As exposure to unpredictable chronic stress (UCS) results in decreased hippocampal neurogenesis, enhanced depressive- and anxiety-like behaviors, and memory dysfunction, it is believed that declined hippocampal neurogenesis mainly underlies the behavioral and cognitive abnormalities after UCS. However, the effects of predictable chronic mild stress (PCMS) such as the routine stress experienced in day-to-day life on functions such as mood, memory and hippocampal neurogenesis are unknown. Using FST and EPM tests on a prototype of adult rats, we demonstrate that PCMS (comprising 5 min of daily restraint stress for 28 days) decreases depressive- and anxiety-like behaviors for prolonged periods. Moreover, we illustrate that decreased depression and anxiety scores after PCMS are associated with ~1.8-fold increase in the production and growth of new neurons in the hippocampus. Additionally, we found that PCMS leads to enhanced memory function in WMT as well as NORT. Collectively, these findings reveal that PCMS is beneficial to adult brain function, which is exemplified by increased hippocampal neurogenesis and improved mood and cognitive function.

Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain.

PubMed

Potts, Matthew B; Rola, Radoslaw; Claus, Catherine P; Ferriero, Donna M; Fike, John R; Noble-Haeusslein, Linda J

2009-06-01

Traumatic brain injury (TBI) is a leading cause of disability among young children and is associated with long-term cognitive deficits. These clinical findings have prompted an investigation of the hippocampus in an experimental model of trauma to the developing brain at postnatal day (p21). Previous studies using this model have revealed a progressive loss of neurons in the hippocampus as brain-injured animals mature to young adulthood. Here we determined whether this hippocampal vulnerability is likewise reflected in altered neurogenesis and whether the antioxidant glutathione peroxidase (GPx) modulates neurogenesis during maturation of the injured immature brain. Male transgenic mice that overexpress GPx and wild-type littermates were subjected to controlled cortical impact or sham surgery on p21. At 2 weeks postinjury, the numbers of proliferating cells and immature neurons within the subgranular zone were measured by using Ki-67 and doublecortin, respectively. Bromodeoxyuridine (BrdU) was used to label dividing cells beginning 2 weeks postinjury. Survival (BrdU(+)) and neuronal differentiation (BrdU(+)/NeuN(+)) were then measured 4 weeks later via confocal microscopy. Two-way ANOVA revealed no significant interaction between genotype and injury. Subsequent analysis of the individual effects of injury and genotype, however, showed a significant reduction in subgranular zone proliferation (Ki-67) at 2 weeks postinjury (P = 0.0003) and precursor cell survival (BrdU(+)) at 6 weeks postinjury (P = 0.016) and a trend toward reduced neuronal differentiation (BrdU(+)/NeuN(+)) at 6 weeks postinjury (P = 0.087). Overall, these data demonstrate that traumatic injury to the injured immature brain impairs neurogenesis during maturation and suggest that GPx cannot rescue this reduced neurogenesis. (c) 2009 Wiley-Liss, Inc.

Human Adult Neurogenesis: Evidence and Remaining Questions.

PubMed

Kempermann, Gerd; Gage, Fred H; Aigner, Ludwig; Song, Hongjun; Curtis, Maurice A; Thuret, Sandrine; Kuhn, H Georg; Jessberger, Sebastian; Frankland, Paul W; Cameron, Heather A; Gould, Elizabeth; Hen, Rene; Abrous, D Nora; Toni, Nicolas; Schinder, Alejandro F; Zhao, Xinyu; Lucassen, Paul J; Frisén, Jonas

2018-04-18

Renewed discussion about whether or not adult neurogenesis exists in the human hippocampus, and the nature and strength of the supporting evidence, has been reignited by two prominently published reports with opposite conclusions. Here, we summarize the state of the field and argue that there is currently no reason to abandon the idea that adult-generated neurons make important functional contributions to neural plasticity and cognition across the human lifespan. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of Chronic Fluoxetine Treatment on Neurogenesis and Tryptophan Hydroxylase Expression in Adolescent and Adult Rats

PubMed Central

Meerhoff, Gideon F.

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population. PMID:24827731

Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

PubMed

Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

Neurogenesis and pattern separation: time for a divorce.

PubMed

Becker, Suzanna

2017-05-01

The generation of new neurons in the adult mammalian brain has led to numerous theories as to their functional significance. One of the most widely held views is that adult neurogenesis promotes pattern separation, a process by which overlapping patterns of neural activation are mapped to less overlapping representations. While a large body of evidence supports a role for neurogenesis in high interference memory tasks, it does not support the proposed function of neurogenesis in mediating pattern separation. Instead, the adult-generated neurons seem to generate highly overlapping and yet distinct distributed representations for similar events. One way in which these immature, highly plastic, hyperactive neurons may contribute to novel memory formation while avoiding interference is by virtue of their extremely sparse connectivity with incoming perforant path fibers. Another intriguing proposal, awaiting empirical confirmation, is that the young neurons' recruitment into memory formation is gated by a novelty/mismatch mechanism mediated by CA3 or hilar back-projections. Ongoing research into the intriguing link between neurogenesis, stress-related mood disorders, and age-related neurodegeneration may lead to promising neurogenesis-based treatments for this wide range of clinical disorders. WIREs Cogn Sci 2017, 8:e1427. doi: 10.1002/wcs.1427 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Harnessing neurogenesis for the possible treatment of Parkinson's disease.

PubMed

Lamm, Omri; Ganz, Javier; Melamed, Eldad; Offen, Daniel

2014-08-15

The discovery of neurogenesis in the adult brain has created new possibilities for therapeutics in neurodegenerative diseases. Neural precursor cells, which have been found in various parts of the brain, e.g., the subventricular zone (SVZ) and substantia nigra (SN), have promising potential to replace the extensive loss of neurons occurring in neurodegenerative disorders. In Parkinson's disease (PD) the degeneration of nigral dopaminergic neurons and consequently the nigrostriatal pathway, which has been found to innervate proximally to the SVZ, causes motor and cognitive impairments. There is strong evidence that neurogenesis is impaired in PD, which has been related to the nonmotor symptoms of the disease. Recent evidence supports that this impairment in neurogenesis is partially caused by the lack of dopamine in one of the adult neurogenic niches, the SVZ. Thus, restoring the dopaminergic pathway in PD patients may have implications not only for motor function improvement, but for other cognitive and autonomic symptoms. Currently, there are no effective treatments that can stop or reverse the neurodegeneration process in the brain. Here we review the neurogenic process and observed alterations found in PD animal models and postmortem brains of PD patients. Finally, we review several attempts to stimulate the neurogenic process for nigral and/or striatal dopaminergic restoration by transgenic expression, exercise, or cell therapy. © 2014 Wiley Periodicals, Inc.

Electroacupuncture Improves Cognitive Function and Hippocampal Neurogenesis after Brain Irradiation.

PubMed

Fan, Xing-Wen; Liu, Huan-Huan; Wang, Hong-Bing; Chen, Fu; Yang, Yu; Chen, Yan; Guan, Shi-Kuo; Wu, Kai-Liang

2017-06-01

Cognitive impairments after brain irradiation seriously affect quality of life for patients, and there is currently no effective treatment. In this study using an irradiated rat model, the role of electroacupuncture was investigated for treatment of radiation-induced brain injury. Animals received 10 Gy exposure to the entire brain, and electroacupuncture was administered 3 days before irradiation as well as up to 2 weeks postirradiation. Behavioral tests were performed one month postirradiation, and rats were then sacrificed for histology or molecular studies. Electroacupuncture markedly improved animal performance in the novel place recognition test. In the emotion test, electroacupuncture reduced defecation during the open-field test, and latency to consumption of food in the novelty suppressed feeding test. Brain irradiation inhibited the generation of immature neurons, but did not cause neural stem cell loss. Electroacupuncture partially restored hippocampal neurogenesis. Electroacupuncture decreased the amount of activated microglia and increased resting microglia in the hippocampus after irradiation. In addition, electroacupuncture promoted mRNA and protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In conclusion, electroacupuncture could improve cognitive function and hippocampal neurogenesis after irradiation, and the protective effect of electroacupuncture was associated with the modulation of microglia and upregulation of BDNF in the hippocampus.

Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain.

PubMed

Tang, Jason J; Podratz, Jewel L; Lange, Miranda; Scrable, Heidi J; Jang, Mi-Hyeon; Windebank, Anthony J

2017-07-07

Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.

Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

PubMed

Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

2016-09-15

It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

PubMed Central

Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.

2011-01-01

Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261

Early Life Stress Differentially Modulates Distinct Forms of Brain Plasticity in Young and Adult Mice

PubMed Central

Reichardt, Wilfried; Clark, Kristin; Geiger, Julia; Gross, Claus M.; Heyer, Andrea; Neagu, Valentin; Bhatia, Harsharan; Atas, Hasan C.; Fiebich, Bernd L.; Bischofberger, Josef; Haas, Carola A.; Normann, Claus

2012-01-01

Background Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity. Methodology/Principal Findings Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation. Conclusion Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood. PMID:23071534

Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

PubMed Central

Sierra, Amanda; Beccari, Sol; Diaz-Aparicio, Irune; Encinas, Juan M.; Comeau, Samuel; Tremblay, Marie-Ève

2014-01-01

Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory. PMID:24772353

A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis.

PubMed

Castilla-Ortega, Estela; Serrano, Antonia; Blanco, Eduardo; Araos, Pedro; Suárez, Juan; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Santín, Luis J

2016-07-01

Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug-induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

Youssef, Mary; Krish, Varsha S; Kirshenbaum, Greer S; Atsak, Piray; Lass, Tamara J; Lieberman, Sophie R; Leonardo, E David; Dranovsky, Alex

2018-05-09

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 et al., 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. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis.

PubMed

Meyer, Urs; Knuesel, Irene; Nyffeler, Myriel; Feldon, Joram

2010-03-01

Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age. In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis. This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that maternal PolyI:C (5 mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3 weeks) administration of clozapine (5 mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis. Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropathology.

Deficient plasticity in the hippocampus and the spiral of addiction: focus on adult neurogenesis.

PubMed

Canales, Juan J

2013-01-01

Addiction is a complex neuropsychiatric disorder which causes disruption at multiple levels, including cognitive, emotional, and behavioral domains. Traditional biological theories of addiction have focused on the mesolimbic dopamine pathway and the nucleus accumbens as anatomical substrates mediating addictive-like behaviors. More recently, we have begun to recognize the engagement and dynamic influence of a much broader circuitry which encompasses the frontal cortex, the amygdala, and the hippocampus. In particular, neurogenesis in the adult hippocampus has become a major focus of attention due to its ability to influence memory, motivation, and affect, all of which are disrupted in addiction. First, I summarize toxicological data that reveal strongly suppressive effects of drug exposure on adult hippocampal neurogenesis. Then, I discuss the impact of deficient neurogenesis on learning and memory function, stress responsiveness and affective behavior, as they relate to addiction. Finally, I examine recent behavioral observations that implicate neurogenesis in the adult hippocampus in the emergence and maintenance of addictive behavior. The evidence reviewed here suggests that deficient neurogenesis is associated with several components of the downward spiraling loop that characterizes addiction, including elevated sensitivity to drug-induced reward and reinforcement, enhanced neurohormonal responsiveness, emergence of a negative affective state, memory impairment, and inflexible behavior.

Using High Performance Computing to Examine the Processes of Neurogenesis Underlying Pattern Separation and Completion of Episodic Information.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aimone, James Bradley; Bernard, Michael Lewis; Vineyard, Craig Michael

2014-10-01

Adult neurogenesis in the hippocampus region of the brain is a neurobiological process that is believed to contribute to the brain's advanced abilities in complex pattern recognition and cognition. Here, we describe how realistic scale simulations of the neurogenesis process can offer both a unique perspective on the biological relevance of this process and confer computational insights that are suggestive of novel machine learning techniques. First, supercomputer based scaling studies of the neurogenesis process demonstrate how a small fraction of adult-born neurons have a uniquely larger impact in biologically realistic scaled networks. Second, we describe a novel technical approach bymore » which the information content of ensembles of neurons can be estimated. Finally, we illustrate several examples of broader algorithmic impact of neurogenesis, including both extending existing machine learning approaches and novel approaches for intelligent sensing.« less

Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain.

PubMed

Khacho, Mireille; Slack, Ruth S

2018-01-01

Mitochondria are classically known to be the cellular energy producers, but a renewed appreciation for these organelles has developed with the accumulating discoveries of additional functions. The importance of mitochondria within the brain has been long known, particularly given the high-energy demanding nature of neurons. The energy demands imposed by neurons require the well-orchestrated morphological adaptation and distribution of mitochondria. Recent studies now reveal the importance of mitochondrial dynamics not only in mature neurons but also during neural development, particularly during the process of neurogenesis and neural stem cell fate decisions. In this review, we will highlight the recent findings that illustrate the importance of mitochondrial dynamics in neurodevelopment and neural stem cell function. Developmental Dynamics 247:47-53, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The Long Run: Neuroprotective Effects of Physical Exercise on Adult Neurogenesis from Youth to Old Age

PubMed Central

Saraulli, Daniele; Costanzi, Marco; Mastrorilli, Valentina; Farioli-Vecchioli, Stefano

2017-01-01

Background The rapid lengthening of life expectancy has raised the problem of providing social programs to counteract the age-related cognitive decline in a growing number of older people. Physical activity stands among the most promising interventions aimed at brain wellbeing, because of its effective neuroprotective action and low social cost. The purpose of this review is to describe the neuroprotective role exerted by physical activity in different life stages. In particular, we focus on adult neurogenesis, a process which has proved being highly responsive to physical exercise and may represent a major factor of brain health over the lifespan. Methods The most recent literature related to the subject has been reviewed. The text has been divided into three main sections, addressing the effects of physical exercise during childhood/adolescence, adulthood and aging, respectively. For each one, the most relevant studies, carried out on both human participants and rodent models, have been described. Results The data reviewed converge in indicating that physical activity exerts a positive effect on brain functioning throughout the lifespan. However, uncertainty remains about the magnitude of the effect and its biological underpinnings. Cellular and synaptic plasticity provided by adult neurogenesis are highly probable mediators, but the mechanism for their action has yet to be conclusively established. Conclusion Despite alternative mechanisms of action are currently debated, age-appropriate physical activity programs may constitute a large-scale, relatively inexpensive and powerful approach to dampen the individual and social impact of age-related cognitive decline. PMID:27000776

Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis.

PubMed

Kuwabara, Tomoko; Hsieh, Jenny; Muotri, Alysson; Yeo, Gene; Warashina, Masaki; Lie, Dieter Chichung; Moore, Lynne; Nakashima, Kinichi; Asashima, Makoto; Gage, Fred H

2009-09-01

In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats

PubMed Central

Rojas, Manuel J.; Cardenas P., Fernando

2017-01-01

Background Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis), causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. Methods An experimental design with two groups was developed: the experimental group (n = 12) was subject to a forced exercise program for five days, whereas the control group (n = 9) stayed in the home cage. Six to eight weeks after training, the rats’ working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. Results No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding), or in the levels of BrdU positive cells. Discussion Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level. PMID:28503368

Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice.

PubMed

Ben Abdallah, Nada M-B; Filipkowski, Robert K; Pruschy, Martin; Jaholkowski, Piotr; Winkler, Juergen; Kaczmarek, Leszek; Lipp, Hans-Peter

2013-09-01

In adult rodents, decreasing hippocampal neurogenesis experimentally using different approaches often impairs performance in hippocampus-dependent processes. Nonetheless, functional relevance of adult neurogenesis is far from being unraveled, and deficits so far described in animal models often lack reproducibility. One hypothesis is that such differences might be the consequence of the extent of the methodological specificity used to alter neurogenesis rather than the extent to which adult neurogenesis is altered. To address this, we focused on cranial irradiation, the most widely used technique to impair hippocampal neurogenesis and consequentially induce hippocampus-dependent behavioral deficits. To investigate the specificity of the technique, we thus exposed 4-5 months old female cyclin D2 knockout mice, a model lacking physiological levels of olfactory and hippocampal neurogenesis, to an X-ray dose of 10 Gy, reported to specifically affect transiently amplifying precursors. After a recovery period of 1.5 months, behavioral tests were performed and probed for locomotor activity, habituation, anxiety, and spatial learning and memory. Spatial learning in the Morris water maze was intact in all experimental groups. Although spatial memory retention assessed 24h following acquisition was also intact in all mice, irradiated wild type and cyclin D2 knockout mice displayed memory deficits one week after acquisition. In addition, we observed significant differences in tests addressing anxiety and locomotor activity dependent on the technique used to alter neurogenesis. Whereas irradiated mice were hyperactive regardless of their genotype, cyclin D2 knockout mice were hypoactive in most of the tests and displayed altered habituation. The present study emphasizes that different approaches aimed at decreasing adult hippocampal neurogenesis may result in distinct behavioral impairments related to locomotion and anxiety. In contrast, spatial long-term memory retention is

The orexigenic hormone acyl-ghrelin increases adult hippocampal neurogenesis and enhances pattern separation

PubMed Central

Kent, Brianne A.; Beynon, Amy L.; Hornsby, Amanda K.E.; Bekinschtein, Pedro; Bussey, Timothy J.; Davies, Jeffrey S.; Saksida, Lisa M.

2015-01-01

Summary An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8–10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain. PMID:25462915

Bi-Parental Care Contributes to Sexually Dimorphic Neural Cell Genesis in the Adult Mammalian Brain

PubMed Central

Mak, Gloria K.; Antle, Michael C.; Dyck, Richard H.; Weiss, Samuel

2013-01-01

Early life events can modulate brain development to produce persistent physiological and behavioural phenotypes that are transmissible across generations. However, whether neural precursor cells are altered by early life events, to produce persistent and transmissible behavioural changes, is unknown. Here, we show that bi-parental care, in early life, increases neural cell genesis in the adult rodent brain in a sexually dimorphic manner. Bi-parentally raised male mice display enhanced adult dentate gyrus neurogenesis, which improves hippocampal neurogenesis-dependent learning and memory. Female mice display enhanced adult white matter oligodendrocyte production, which increases proficiency in bilateral motor coordination and preference for social investigation. Surprisingly, single parent-raised male and female offspring, whose fathers and mothers received bi-parental care, respectively, display a similar enhancement in adult neural cell genesis and phenotypic behaviour. Therefore, neural plasticity and behavioural effects due to bi-parental care persist throughout life and are transmitted to the next generation. PMID:23650527

Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus

PubMed Central

Matas-Rico, Elisa; García-Diaz, Beatriz; Llebrez-Zayas, Pedro; López-Barroso, Diana; Santín, Luis; Pedraza, Carmen; Smith-Fernández, Anibal; Fernández-Llebrez, Pedro; Tellez, Teresa; Redondo; Chun, Jerold; De Fonseca, Fernando Rodríguez; Estivill-Torrús, Guillermo

2013-01-01

Neurogenesis persists in certain regions of the adult brain including the subgranular zone of the hippocampal dentate gyrus wherein its regulation is essential, particularly in relation to learning, stress and modulation of mood. Lysophosphatidic acid (LPA) is an extracellular signaling phospholipid with important neural regulatory properties mediated by specific G protein-coupled receptors, LPA1-5. LPA1 is highly expressed in the developing neurogenic ventricular zone wherein it is required for normal embryonic neurogenesis, and, by extension may play a role in adult neurogenesis as well. By means of the analyses of a variant of the original LPA1-null mutant mouse, termed the Malaga variant or “maLPA1-null,” which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA1 in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA1 under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA1-null mice demonstrated alterations in brain-derived neurotrophic factor and insulin growth factor 1 levels after enrichment and exercise. Morphological analyses of doublecortin positive cells revealed the anomalous prevalence of bipolar cells in the subgranular zone, supporting the operation of LPA1 signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors. PMID:18708146

Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms

PubMed Central

Pereira Dias, Gisele; Hollywood, Ronan; Bevilaqua, Mário Cesar do Nascimento; da Silveira da Luz, Anna Claudia Domingos; Hindges, Robert; Nardi, Antonio Egidio; Thuret, Sandrine

2014-01-01

The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients. PMID:24470543

Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms.

PubMed

Pereira Dias, Gisele; Hollywood, Ronan; Bevilaqua, Mário Cesar do Nascimento; da Luz, Anna Claudia Domingos da Silveira; Hindges, Robert; Nardi, Antonio Egidio; Thuret, Sandrine

2014-04-01

The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients.

CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS.

EPA Science Inventory

CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS. ME Gilbert1, ME Kelly2, S. Salant3, T Shafer1, J Goodman3 1Neurotoxicology Div, US EPA, RTP, NC, 27711, 2Children's Hospital, Philadelphia, PA, 19104, 3Helen Hayes Hospital, Haverstraw, NY, 10993.
...

Adult neurogenesis and neuronal regeneration in the central nervous system of teleost fish.

PubMed

Zupanc, Günther K H; Sîrbulescu, Ruxandra F

2011-09-01

Teleost fish are distinguished by their ability to constitutively generate new neurons in the adult central nervous system ('adult neurogenesis'), and to regenerate whole neurons after injury ('neuronal regeneration'). In the brain, new neurons are produced in large numbers in several dozens of proliferation zones. In the spinal cord, proliferating cells are present in the ependymal layer and throughout the parenchyma. In the retina, new cells arise from the ciliary marginal zone and from Müller glia. Experimental evidence has suggested that both radial glia and non-glial cells can function as adult stem cells. The proliferative activity of these cells can be regulated by molecular factors, such as fibroblast growth factor and Notch, as well as by social and behavioral experience. The young cells may either reside near the respective proliferation zone, or migrate to specific target areas. Approximately half of the newly generated cells persist for the rest of the fish's life, and many of them differentiate into neurons. After injury, a massive surge of apoptotic cell death occurs at the lesion site within a few hours. Apoptosis is followed by a marked increase in cell proliferation and neurogenesis, leading to repair of the tissue. The structural regeneration is paralleled by partial or complete recovery of function. Recent investigations have led to the identification of several dozens of molecular factors that are potentially involved in the process of regeneration. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Putative adult neurogenesis in two domestic pigeon breeds (Columba livia domestica): racing homer versus utility carneau pigeons

PubMed Central

Mazengenya, Pedzisai; Bhagwandin, Adhil; Nkomozepi, Pilani; Manger, Paul R.; Ihunwo, Amadi O.

2017-01-01

Generation of neurons in the brains of adult birds has been studied extensively in the telencephalon of song birds and few studies are reported on the distribution of PCNA and DCX in the telencephalon of adult non-song learning birds. We report here on adult neurogenesis throughout the brains of two breeds of adult domestic pigeons (Columba livia domestica), the racing homer and utility carneau using endogenous immunohistochemical markers proliferating cell nuclear antigen (PCNA) for proliferating cells and doublecortin (DCX) for immature and migrating neurons. The distribution of PCNA and DCX immunoreactivity was very similar in both pigeon breeds with only a few minor differences. In both pigeons, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, walls of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and cerebellum. Generally, the olfactory bulbs and telencephalon had more PCNA and DCX cells than other regions. Two proliferative hotspots were evident in the dorsal and ventral poles of the lateral ventricles. PCNA- and DCX-immunoreactive cells migrated radially from the walls of the lateral ventricle into the parenchyma. In most telencephalic regions, the density of PCNA- and DCX-immunoreactive cells increased from rostral to caudal, except in the mesopallium where the density decreased from rostral to middle levels and then increased caudally. DCX immunoreactivity was more intense in fibres than in cell bodies and DCX-immunoreactive cells included small granular cells, fusiform bipolar cells, large round and or polygonal multipolar cells. The similarity in the distribution of proliferating cells and new neurons in the telencephalon of the two breeds of pigeons may suggest that adult neurogenesis is a conserved trait as an ecological adaptation irrespective of body size. PMID:28852390

Putative adult neurogenesis in two domestic pigeon breeds (Columba livia domestica): racing homer versus utility carneau pigeons.

PubMed

Mazengenya, Pedzisai; Bhagwandin, Adhil; Nkomozepi, Pilani; Manger, Paul R; Ihunwo, Amadi O

2017-07-01

Generation of neurons in the brains of adult birds has been studied extensively in the telencephalon of song birds and few studies are reported on the distribution of PCNA and DCX in the telencephalon of adult non-song learning birds. We report here on adult neurogenesis throughout the brains of two breeds of adult domestic pigeons (Columba livia domestica), the racing homer and utility carneau using endogenous immunohistochemical markers proliferating cell nuclear antigen (PCNA) for proliferating cells and doublecortin (DCX) for immature and migrating neurons. The distribution of PCNA and DCX immunoreactivity was very similar in both pigeon breeds with only a few minor differences. In both pigeons, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, walls of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and cerebellum. Generally, the olfactory bulbs and telencephalon had more PCNA and DCX cells than other regions. Two proliferative hotspots were evident in the dorsal and ventral poles of the lateral ventricles. PCNA- and DCX-immunoreactive cells migrated radially from the walls of the lateral ventricle into the parenchyma. In most telencephalic regions, the density of PCNA- and DCX-immunoreactive cells increased from rostral to caudal, except in the mesopallium where the density decreased from rostral to middle levels and then increased caudally. DCX immunoreactivity was more intense in fibres than in cell bodies and DCX-immunoreactive cells included small granular cells, fusiform bipolar cells, large round and or polygonal multipolar cells. The similarity in the distribution of proliferating cells and new neurons in the telencephalon of the two breeds of pigeons may suggest that adult neurogenesis is a conserved trait as an ecological adaptation irrespective of body size.

Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

PubMed Central

Lensu, Sanna; Ahtiainen, Juha P.; Johansson, Petra P.; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki

2016-01-01

Key points Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents.Little is known about the effects of high‐intensity interval training (HIT) or of purely anaerobic resistance training on AHN.Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats.We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity.Our results confirm that sustained aerobic exercise is key in improving AHN. Abstract Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high‐intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low‐response trainer (LRT) and high‐response trainer (HRT) adult male rats to various forms of physical exercise for 6–8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin‐positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non‐significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength

Decoding the ubiquitous role of microRNAs in neurogenesis.

PubMed

Nampoothiri, Sreekala S; Rajanikant, G K

2017-04-01

Neurogenesis generates fledgling neurons that mature to form an intricate neuronal circuitry. The delusion on adult neurogenesis was far resolved in the past decade and became one of the largely explored domains to identify multifaceted mechanisms bridging neurodevelopment and neuropathology. Neurogenesis encompasses multiple processes including neural stem cell proliferation, neuronal differentiation, and cell fate determination. Each neurogenic process is specifically governed by manifold signaling pathways, several growth factors, coding, and non-coding RNAs. A class of small non-coding RNAs, microRNAs (miRNAs), is ubiquitously expressed in the brain and has emerged to be potent regulators of neurogenesis. It functions by fine-tuning the expression of specific neurogenic gene targets at the post-transcriptional level and modulates the development of mature neurons from neural progenitor cells. Besides the commonly discussed intrinsic factors, the neuronal morphogenesis is also under the control of several extrinsic temporal cues, which in turn are regulated by miRNAs. This review enlightens on dicer controlled switch from neurogenesis to gliogenesis, miRNA regulation of neuronal maturation and the differential expression of miRNAs in response to various extrinsic cues affecting neurogenesis.

56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

NASA Astrophysics Data System (ADS)

DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal R.; Chen, Benjamin P. C.; Eisch, Amelia J.

2014-07-01

The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24 h), intermediate (7 d), and/or long time points (2-3 mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

Enrichment increases hippocampal neurogenesis independent of blood monocyte-derived microglia presence following high-dose total body irradiation.

PubMed

Ruitenberg, Marc J; Wells, Julia; Bartlett, Perry F; Harvey, Alan R; Vukovic, Jana

2017-06-01

Birth of new neurons in the hippocampus persists in the brain of adult mammals and critically underpins optimal learning and memory. The process of adult neurogenesis is significantly reduced following brain irradiation and this correlates with impaired cognitive function. In this study, we aimed to compare the long-term effects of two environmental paradigms (i.e. enriched environment and exercise) on adult neurogenesis following high-dose (10Gy) total body irradiation. When housed in standard (sedentary) conditions, irradiated mice revealed a long-lasting (up to 4 months) deficit in neurogenesis in the granule cell layer of the dentate gyrus, the region that harbors the neurogenic niche. This depressive effect of total body irradiation on adult neurogenesis was partially alleviated by exposure to enriched environment but not voluntary exercise, where mice were single-housed with unlimited access to a running wheel. Exposure to voluntary exercise, but not enriched environment, did lead to significant increases in microglia density in the granule cell layer of the hippocampus; our study shows that these changes result from local microglia proliferation rather than recruitment and infiltration of circulating Cx 3 cr1 +/gfp blood monocytes that subsequently differentiate into microglia-like cells. In summary, latent neural precursor cells remain present in the neurogenic niche of the adult hippocampus up to 8 weeks following high-dose total body irradiation. Environmental enrichment can partially restore the adult neurogenic process in this part of the brain following high-dose irradiation, and this was found to be independent of blood monocyte-derived microglia presence. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

BDNF Expression in Larval and Adult Zebrafish Brain: Distribution and Cell Identification

PubMed Central

Cacialli, Pietro; Gueguen, Marie-Madeleine; Coumailleau, Pascal; D’Angelo, Livia; Kah, Olivier; Lucini, Carla; Pellegrini, Elisabeth

2016-01-01

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has emerged as an active mediator in many essential functions in the central nervous system of mammals. BDNF plays significant roles in neurogenesis, neuronal maturation and/or synaptic plasticity and is involved in cognitive functions such as learning and memory. Despite the vast literature present in mammals, studies devoted to BDNF in the brain of other animal models are scarse. Zebrafish is a teleost fish widely known for developmental genetic studies and is emerging as model for translational neuroscience research. In addition, its brain shows many sites of adult neurogenesis allowing higher regenerative properties after traumatic injuries. To add further knowledge on neurotrophic factors in vertebrate brain models, we decided to determine the distribution of bdnf mRNAs in the larval and adult zebrafish brain and to characterize the phenotype of cells expressing bdnf mRNAs by means of double staining studies. Our results showed that bdnf mRNAs were widely expressed in the brain of 7 days old larvae and throughout the whole brain of mature female and male zebrafish. In adults, bdnf mRNAs were mainly observed in the dorsal telencephalon, preoptic area, dorsal thalamus, posterior tuberculum, hypothalamus, synencephalon, optic tectum and medulla oblongata. By combining immunohistochemistry with in situ hybridization, we showed that bdnf mRNAs were never expressed by radial glial cells or proliferating cells. By contrast, bdnf transcripts were expressed in cells with neuronal phenotype in all brain regions investigated. Our results provide the first demonstration that the brain of zebrafish expresses bdnf mRNAs in neurons and open new fields of research on the role of the BDNF factor in brain mechanisms in normal and brain repairs situations. PMID:27336917

The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis.

PubMed

Meneghini, Vasco; Cuccurazzu, Bruna; Bortolotto, Valeria; Ramazzotti, Vera; Ubezio, Federica; Tzschentke, Thomas M; Canonico, Pier Luigi; Grilli, Mariagrazia

2014-05-01

Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining μ-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of β2 and α2 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates.

Alternative Splicing in Neurogenesis and Brain Development.

PubMed

Su, Chun-Hao; D, Dhananjaya; Tarn, Woan-Yuh

2018-01-01

Alternative splicing of precursor mRNA is an important mechanism that increases transcriptomic and proteomic diversity and also post-transcriptionally regulates mRNA levels. Alternative splicing occurs at high frequency in brain tissues and contributes to every step of nervous system development, including cell-fate decisions, neuronal migration, axon guidance, and synaptogenesis. Genetic manipulation and RNA sequencing have provided insights into the molecular mechanisms underlying the effects of alternative splicing in stem cell self-renewal and neuronal fate specification. Timely expression and perhaps post-translational modification of neuron-specific splicing regulators play important roles in neuronal development. Alternative splicing of many key transcription regulators or epigenetic factors reprograms the transcriptome and hence contributes to stem cell fate determination. During neuronal differentiation, alternative splicing also modulates signaling activity, centriolar dynamics, and metabolic pathways. Moreover, alternative splicing impacts cortical lamination and neuronal development and function. In this review, we focus on recent progress toward understanding the contributions of alternative splicing to neurogenesis and brain development, which has shed light on how splicing defects may cause brain disorders and diseases.

Putative Adult Neurogenesis in Old World Parrots: The Congo African Grey Parrot (Psittacus erithacus) and Timneh Grey Parrot (Psittacus timneh).

PubMed

Mazengenya, Pedzisai; Bhagwandin, Adhil; Manger, Paul R; Ihunwo, Amadi O

2018-01-01

In the current study, we examined for the first time, the potential for adult neurogenesis throughout the brain of the Congo African grey parrot ( Psittacus erithacus ) and Timneh grey parrot ( Psittacus timneh ) using immunohistochemistry for the endogenous markers proliferating cell nuclear antigen (PCNA), which labels proliferating cells, and doublecortin (DCX), which stains immature and migrating neurons. A similar distribution of PCNA and DCX immunoreactivity was found throughout the brain of the Congo African grey and Timneh grey parrots, but minor differences were also observed. In both species of parrots, PCNA and DCX immunoreactivity was observed in the olfactory bulbs, subventricular zone of the lateral wall of the lateral ventricle, telencephalic subdivisions of the pallium and subpallium, diencephalon, mesencephalon and the rhombencephalon. The olfactory bulb and telencephalic subdivisions exhibited a higher density of both PCNA and DCX immunoreactive cells than any other brain region. DCX immunoreactive staining was stronger in the telencephalon than in the subtelencephalic structures. There was evidence of proliferative hot spots in the dorsal and ventral poles of the lateral ventricle in the Congo African grey parrots at rostral levels, whereas only the dorsal accumulation of proliferating cells was observed in the Timneh grey parrot. In most pallial regions the density of PCNA and DCX stained cells increased from rostral to caudal levels with the densest staining in the nidopallium caudolaterale (NCL). The widespread distribution of PCNA and DCX in the brains of both parrot species suggest the importance of adult neurogenesis and neuronal plasticity during learning and adaptation to external environmental variations.

Disruption of neurogenesis by hypothalamic inflammation in obesity or aging.

PubMed

Purkayastha, Sudarshana; Cai, Dongsheng

2013-12-01

Adult neural stem cells contribute to neurogenesis and plasticity of the brain which is essential for central regulation of systemic homeostasis. Damage to these homeostatic components, depending on locations in the brain, poses threat to impaired neurogenesis, neurodegeneration, cognitive loss and energy imbalance. Recent research has identified brain metabolic inflammation via proinflammatory IκB kinase-β (IKKβ) and its downstream nuclear transcription factor NF-κB pathway as a non-classical linker of metabolic and neurodegenerative disorders. Chronic activation of the pathway results in impairment of energy balance and nutrient metabolism, impediment of neurogenesis, neural stem cell proliferation and differentiation, collectively converging on metabolic and cognitive decline. Hypothalamic IKKβ/NF-κB via inflammatory crosstalk between microglia and neurons has been discovered to direct systemic aging by inhibiting the production of gonadotropin-releasing hormone (GnRH) and inhibition of inflammation or GnRH therapy could revert aging related degenerative symptoms at least in part. This article reviews the crucial role of hypothalamic inflammation in affecting neural stem cells which mediates the neurodegenerative mechanisms of causing metabolic derangements as well as aging-associated disorders or diseases.

Effects of neuroinflammation on the regenerative capacity of brain stem cells.

PubMed

Russo, Isabella; Barlati, Sergio; Bosetti, Francesca

2011-03-01

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis. In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the lipopolysaccharide-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Embryonic Cerebrospinal Fluid Increases Neurogenic Activity in the Brain Ventricular-Subventricular Zone of Adult Mice.

PubMed

Alonso, Maria I; Lamus, Francisco; Carnicero, Estela; Moro, Jose A; de la Mano, Anibal; Fernández, Jose M F; Desmond, Mary E; Gato, Angel

2017-01-01

Neurogenesis is a very intensive process during early embryonic brain development, becoming dramatically restricted in the adult brain in terms of extension and intensity. We have previously demonstrated the key role of embryonic cerebrospinal fluid (CSF) in developing brain neurogenic activity. We also showed that cultured adult brain neural stem cells (NSCs) remain competent when responding to the neurogenic influence of embryonic CSF. However, adult CSF loses its neurogenic inductive properties. Here, by means of an organotypic culture of adult mouse brain sections, we show that local administration of embryonic CSF in the subventricular zone (SVZ) niche is able to trigger a neurogenic program in NSCs. This leads to a significant increase in the number of non-differentiated NSCs, and also in the number of new neurons which show normal migration, differentiation and maturation. These new data reveal that embryonic CSF activates adult brain NSCs, supporting the previous idea that it contains key instructive components which could be useful in adult brain neuroregenerative strategies.

Embryonic Cerebrospinal Fluid Increases Neurogenic Activity in the Brain Ventricular-Subventricular Zone of Adult Mice

PubMed Central

Alonso, Maria I.; Lamus, Francisco; Carnicero, Estela; Moro, Jose A.; de la Mano, Anibal; Fernández, Jose M. F.; Desmond, Mary E.; Gato, Angel

2017-01-01

Neurogenesis is a very intensive process during early embryonic brain development, becoming dramatically restricted in the adult brain in terms of extension and intensity. We have previously demonstrated the key role of embryonic cerebrospinal fluid (CSF) in developing brain neurogenic activity. We also showed that cultured adult brain neural stem cells (NSCs) remain competent when responding to the neurogenic influence of embryonic CSF. However, adult CSF loses its neurogenic inductive properties. Here, by means of an organotypic culture of adult mouse brain sections, we show that local administration of embryonic CSF in the subventricular zone (SVZ) niche is able to trigger a neurogenic program in NSCs. This leads to a significant increase in the number of non-differentiated NSCs, and also in the number of new neurons which show normal migration, differentiation and maturation. These new data reveal that embryonic CSF activates adult brain NSCs, supporting the previous idea that it contains key instructive components which could be useful in adult brain neuroregenerative strategies. PMID:29311854

Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP{sub swe}/PS1{sub {Delta}E9} transgenic mouse model of Alzheimer's disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, Jun; Department of Physiology, Third Military Medical University, Chongqing 400038; Song, Min

2009-07-31

In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP{sub swe}/PS1{submore » {Delta}E9} mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP{sub swe}/PS1{sub {Delta}E9} transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.« less

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

PubMed Central

López-Hidalgo, Rosa; Ballestín, Raul; Vega, Jessica; Blasco-Ibáñez, José M.; Crespo, Carlos; Gilabert-Juan, Javier; Nácher, Juan; Varea, Emilio

2016-01-01

Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5′BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5′BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice

Decrease in Adult Neurogenesis and Neuroinflammation Are Involved in Spatial Memory Impairment in the Streptozotocin-Induced Model of Sporadic Alzheimer's Disease in Rats.

PubMed

Bassani, Taysa Bervian; Bonato, Jéssica M; Machado, Meira M F; Cóppola-Segovia, Valentín; Moura, Eric L R; Zanata, Silvio M; Oliveira, Rúbia M M W; Vital, Maria A B F

2018-05-01

Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer's disease (sAD). Intracerebroventricular (ICV) injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD.

Hippocampal Adult Neurogenesis is Enhanced by Chronic Eszopiclone Treatment in Rats

PubMed Central

Methippara, Melvi; Bashir, Tariq; Suntsova, Natalia; Szymusiak, Ron; McGinty, Dennis

2010-01-01

Summary The adult hippocampal dentate gyrus (DG) exhibits cell proliferation and neurogenesis throughout life. We examined the effects of daily administration of eszopiclone (Esz), a commonly used hypnotic drug and GABA agonist, compared to vehicle, on DG cell proliferation and neurogenesis, and on sleep-wake patterns. Esz was administered during the usual sleep period of rats, to mimic typical use in humans. Esz treatment for 7 days did not affect the rate of cell proliferation, as measured by 5-bromo-2’-deoxyuridine (BrdU) immunostaining. However, twice daily Esz administration for two weeks increased survival of newborn cells, by 46%. Most surviving cells exhibited a neuronal phenotype, identified BrdU-NeuN double-labeling. NeuN (Neuronal nuclei) is a marker of neurons. NREM sleep was increased on day one, but not on days 7 or 14 of Esz administration. Delta EEG activity was increased on days 1 and 7 of treatment, but not on day 14. There is evidence that enhancement of DG neurogenesis is a critical component of the effects of antidepressant treatments of major depressive disorder (MDD). Adult born DG cells are responsive to GABAergic stimulation which promotes cell maturation. The present study suggests that Esz, presumably acting as a GABA agonist, has pro-neurogenic effects in the adult DG. This result is consistent with evidence that Esz enhances antidepressant treatment response of MDD patients with insomnia. PMID:20408925

NeuroD modulates opioid agonist-selective regulation of adult neurogenesis and contextual memory extinction.

PubMed

Zheng, Hui; Zhang, Yue; Li, Wen; Loh, Horace H; Law, Ping-Yee

2013-04-01

Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.

n-3 fatty acids: role in neurogenesis and neuroplasticity.

PubMed

Crupi, R; Marino, A; Cuzzocrea, S

2013-01-01

Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n-3 fatty acids, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and antiapoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer's disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out.

Implantation of Neuronal Stem Cells Enhances Object Recognition without Increasing Neurogenesis after Lateral Fluid Percussion Injury in Mice

PubMed Central

Ngwenya, Laura B.; Mazumder, Sarmistha; Porter, Zachary R.; Oswald, Duane J.

2018-01-01

Cognitive deficits after traumatic brain injury (TBI) are debilitating and contribute to the morbidity and loss of productivity of over 10 million people worldwide. Cell transplantation has been linked to enhanced cognitive function after experimental traumatic brain injury, yet the mechanism of recovery is poorly understood. Since the hippocampus is a critical structure for learning and memory, supports adult neurogenesis, and is particularly vulnerable after TBI, we hypothesized that stem cell transplantation after TBI enhances cognitive recovery by modulation of endogenous hippocampal neurogenesis. We performed lateral fluid percussion injury (LFPI) in adult mice and transplanted embryonic stem cell-derived neural progenitor cells (NPC). Our data confirm an injury-induced cognitive deficit in novel object recognition, a hippocampal-dependent learning task, which is reversed one week after NPC transplantation. While LFPI alone promotes hippocampal neurogenesis, as revealed by doublecortin immunolabeling of immature neurons, subsequent NPC transplantation prevents increased neurogenesis and is not associated with morphological maturation of endogenous injury-induced immature neurons. Thus, NPC transplantation enhances cognitive recovery early after LFPI without a concomitant increase in neuron numbers or maturation. PMID:29531536

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

PubMed Central

Mohammad, H; Marchisella, F; Ortega-Martinez, S; Hollos, P; Eerola, K; Komulainen, E; Kulesskaya, N; Freemantle, E; Fagerholm, V; Savontous, E; Rauvala, H; Peterson, B D; van Praag, H; Coffey, E T

2018-01-01

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders. PMID:27843149

Increased radial glia quiescence, decreased reactivation upon injury and unaltered neuroblast behavior underlie decreased neurogenesis in the aging zebrafish telencephalon.

PubMed

Edelmann, Kathrin; Glashauser, Lena; Sprungala, Susanne; Hesl, Birgit; Fritschle, Maike; Ninkovic, Jovica; Godinho, Leanne; Chapouton, Prisca

2013-09-01

The zebrafish has recently become a source of new data on the mechanisms of neural stem cell (NSC) maintenance and ongoing neurogenesis in adult brains. In this vertebrate, neurogenesis occurs at high levels in all ventricular regions of the brain, and brain injuries recover successfully, owing to the recruitment of radial glia, which function as NSCs. This new vertebrate model of adult neurogenesis is thus advancing our knowledge of the molecular cues in use for the activation of NSCs and fate of their progeny. Because the regenerative potential of somatic stem cells generally weakens with increasing age, it is important to assess the extent to which zebrafish NSC potential decreases or remains unaltered with age. We found that neurogenesis in the ventricular zone, in the olfactory bulb, and in a newly identified parenchymal zone of the telencephalon indeed declines as the fish ages and that oligodendrogenesis also declines. In the ventricular zone, the radial glial cell population remains largely unaltered morphologically but enters less frequently into the cell cycle and hence produces fewer neuroblasts. The neuroblasts themselves do not change their behavior with age and produce the same number of postmitotic neurons. Thus, decreased neurogenesis in the physiologically aging zebrafish brain is correlated with an increasing quiescence of radial glia. After injuries, radial glia in aged brains are reactivated, and the percentage of cell cycle entry is increased in the radial glia population. However, this reaction is far less pronounced than in younger animals, pointing to irreversible changes in aging zebrafish radial glia. Copyright © 2013 Wiley Periodicals, Inc.

Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

PubMed Central

Bond, Allison M.; Ming, Guo-li; Song, Hongjun

2015-01-01

Summary Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID:26431181

Defensive behaviors and prosencephalic neurogenesis in pigeons (Columba livia) are affected by environmental enrichment in adulthood.

PubMed

Melleu, F F; Pinheiro, M V; Lino-de-Oliveira, C; Marino-Neto, J

2016-05-01

Neurogenesis in the adult brain appears to be phylogenetically conserved across the animal kingdom. In pigeons and other adult non-oscine birds, immature neurons are observed in several prosencephalic areas, suggesting that neurogenesis may participate in the control of different behaviors. The mechanisms controlling neurogenesis and its relevance to defensive behaviors in non-oscine birds remain elusive. Herein, the contribution of the environment to behavior and neurogenesis of pigeons was investigated. Adult pigeons (Columba livia, n = 6/group), housed in standard (SE) or enriched environment (EE) for 42 days, were exposed to an unfamiliar environment (UE) followed by presentation to a novel object (NO). Video recordings of UE+NO tests were analyzed and scored for latency, duration and frequency of angular head movements, peeping, grooming, immobility and locomotion. Twenty-four hours later, pigeons were submitted to the tonic immobility test (TI) and number of trials for TI and TI duration were scored, followed by euthanasia 2 h later. Brains were immunohistochemically processed to reveal doublecortin (DCX), a marker for newborn neurons. Compared to those housed in SE, the pigeons housed in EE responded to a NO with more immobility. In addition, the pigeons housed in EE presented longer TI, more DCX-immunoreactive (DCX-ir) cells in the hippocampus and fewer DCX-ir cells in the lateral striatum than those housed in SE. There was no correlation between the number of DCX-ir cells and the scores of immobility in behavioral tests. Together, these data suggest that enrichment favored behavioral inhibition and neurogenesis in the adult pigeons through different, parallel mechanisms.

Stem cells distribution, cellular proliferation and migration in the adult Austrolebias charrua brain.

PubMed

Torres-Pérez, Maximiliano; Rosillo, Juan Carlos; Berrosteguieta, Ines; Olivera-Bravo, Silvia; Casanova, Gabriela; García-Verdugo, José Manuel; Fernández, Anabel Sonia

2017-10-15

Our previous studies demonstrated that Austrolebias charrua annual fish is an excellent model to study adult brain cell proliferation and neurogenesis due to the presence of active and fast neurogenesis in several regions during its short lifespan. Our main goal was to identify and localize the cells that compose the neurogenic areas throughout the Austrolebias brain. To do this, we used two thymidine halogenated analogs to detect cell proliferation at different survival times: 5-chloro-2'-deoxyuridine (CldU) at 1day and 5-iodo-2'-deoxyuridine (IdU) at 30days. Three types of proliferating cells were identified: I - transient amplifying or fast cycling cells that uptake CldU; II - stem cells or slow cycling cells, that were labeled with both CldU and IdU and did not migrate; and III - migrant cells that uptake IdU. Mapping and 3D-reconstruction of labeled nuclei showed that type I and type II cells were preferentially found close to ventricle walls. Type III cells appeared widespread and migrating in tangential and radial routes. Use of proliferation markers together with Vimentin or Nestin evidenced that type II cells are the putative stem cells that are located at the ventricular lumen. Double label cells with IdU+ and NeuN or HuC/D allowed us identify migrant neurons. Quantitation of labeled nuclei indicates that the proportion of putative stem cells is around 10% in all regions of the brain. This percentage of stem cells suggests the existence of a constant brain cell population in Austrolebias charrua that seems functional to the maintainance of adult neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Experimental 'jet lag' inhibits adult neurogenesis and produces long-term cognitive deficits in female hamsters.

PubMed

Gibson, Erin M; Wang, Connie; Tjho, Stephanie; Khattar, Neera; Kriegsfeld, Lance J

2010-12-01

Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. In the present study, we investigated whether experimental 'jet lag' (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.

Influence of long-term social interaction on chirping behavior, steroid levels and neurogenesis in weakly electric fish.

PubMed

Dunlap, Kent D; Chung, Michael; Castellano, James F

2013-07-01

Social interactions dramatically affect the brain and behavior of animals. Studies in birds and mammals indicate that socially induced changes in adult neurogenesis participate in the regulation of social behavior, but little is known about this relationship in fish. Here, we review studies in electric fish (Apteronotus leptorhychus) that link social stimulation, changes in electrocommunication behavior and adult neurogenesis in brain regions associated with electrocommunication. Compared with isolated fish, fish living in pairs have greater production of chirps, an electrocommunication signal, during dyadic interactions and in response to standardized artificial social stimuli. Social interaction also promotes neurogenesis in the periventricular zone, which contributes born cells to the prepacemaker nucleus, the brain region that regulates chirping. Both long-term chirp rate and periventricular cell addition depend on the signal dynamics (amplitude and waveform variation), modulations (chirps) and novelty of the stimuli from the partner fish. Socially elevated cortisol levels and cortisol binding to glucocorticoid receptors mediate, at least in part, the effect of social interaction on chirping behavior and brain cell addition. In a closely related electric fish (Brachyhypopomus gauderio), social interaction enhances cell proliferation specifically in brain regions for electrocommunication and only during the breeding season, when social signaling is most elaborate. Together, these studies demonstrate a consistent correlation between brain cell addition and environmentally regulated chirping behavior across many social and steroidal treatments and suggest a causal relationship.

The birth of new neurons in the maternal brain: hormonal regulation and functional implications

PubMed Central

Leuner, Benedetta; Sabihi, Sara

2016-01-01

The maternal brain is remarkably plastic and exhibits multifaceted neural modifications. Neurogenesis has emerged as one of the mechanisms by which the maternal brain exhibits plasticity. This review highlights what is currently known about peripartum-associated changes in adult neurogenesis and the underlying hormonal mechanisms. We also consider the functional consequences of neurogenesis in the peripartum brain and extent to which this process may play a role in maternal care, cognitive function and postpartum mood. Finally, while most work investigating the effects of parenting on adult neurogenesis has focused on mothers, a few studies have examined fathers and these results are also discussed. PMID:26969795

Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice.

PubMed

Nishijima, Takeshi; Llorens-Martín, María; Tejeda, Gonzalo Sanchez; Inoue, Koshiro; Yamamura, Yuhei; Soya, Hideaki; Trejo, José Luis; Torres-Alemán, Ignacio

2013-05-15

While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4 weeks old) were assigned to one of the following groups, and housed until 21 weeks old; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), housed in a running wheel cage; and (3) exercise-no exercise (Ex-noEx), housed in a running wheel cage for 8 weeks and subsequently in a standard cage. Behavioral evaluations suggested that Ex-noEx mice were more anxious compared to noEx control mice, but no differences were found in depression-like behavior. The number of BrdU-labeled surviving cells in the dentate gyrus was significantly higher in Ex but not in Ex-noEx compared with noEx, indicating that the facilitative effects of exercise on cell survival are reversible. Surprisingly, the ratio of differentiation of BrdU-positive cells to doublecortin-positive immature neurons was significantly lower in Ex-noEx compared to the other groups, suggesting that the cessation of wheel running impairs an important component of hippocampal neurogenesis in mice. These results indicate that hippocampal adaptation to physical inactivity is not simply a return to the conditions present in sedentary mice. As the impaired neurogenesis is predicted to increase a vulnerability to stress-induced mood disorders, the reduction of physical activity may contribute to a greater risk of these disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

APC/C-Cdh1 coordinates neurogenesis and cortical size during development

NASA Astrophysics Data System (ADS)

Delgado-Esteban, Maria; García-Higuera, Irene; Maestre, Carolina; Moreno, Sergio; Almeida, Angeles

2013-12-01

The morphology of the adult brain is the result of a delicate balance between neural progenitor proliferation and the initiation of neurogenesis in the embryonic period. Here we assessed whether the anaphase-promoting complex/cyclosome (APC/C) cofactor, Cdh1—which regulates mitosis exit and G1-phase length in dividing cells—regulates neurogenesis in vivo. We use an embryo-restricted Cdh1 knockout mouse model and show that functional APC/C-Cdh1 ubiquitin ligase activity is required for both terminal differentiation of cortical neurons in vitro and neurogenesis in vivo. Further, genetic ablation of Cdh1 impairs the ability of APC/C to promote neurogenesis by delaying the exit of the progenitor cells from the cell cycle. This causes replicative stress and p53-mediated apoptotic death resulting in decreased number of cortical neurons and cortex size. These results demonstrate that APC/C-Cdh1 coordinates cortical neurogenesis and size, thus posing Cdh1 in the molecular pathogenesis of congenital neurodevelopmental disorders, such as microcephaly.

Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis.

PubMed

Hescham, Sarah; Temel, Yasin; Schipper, Sandra; Lagiere, Mélanie; Schönfeld, Lisa-Maria; Blokland, Arjan; Jahanshahi, Ali

2017-03-01

Deep brain stimulation (DBS) is an established symptomatic treatment modality for movement disorders and constitutes an emerging therapeutic approach for the treatment of memory impairment. In line with this, fornix DBS has shown to ameliorate cognitive decline associated with dementia. Nonetheless, mechanisms mediating clinical effects in demented patients or patients with other neurological disorders are largely unknown. There is evidence that DBS is able to modulate neurophysiological activity in targeted brain regions. We therefore hypothesized that DBS might be able to influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters, which were validated to restore memory loss in a previous behavioral study, we here assessed long-term effects of fornix DBS. To do so, we injected the thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), after DBS and perfused the animals 6.5 weeks later. A week prior to perfusion, memory performance was assessed in the water maze. We found that acute stimulation of the fornix improved spatial memory performance in the water maze when the probe trial was performed 1 h after the last training session. However, no evidence for stimulation-induced neurogenesis was found in fornix DBS rats when compared to sham. Our results suggest that fornix DBS improves memory functions independent of hippocampal neurogenesis, possibly through other mechanisms such as synaptic plasticity and acute neurotransmitter release.

Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze

PubMed Central

Merritt, Jennifer; Rhodes, Justin S.

2014-01-01

Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2 to 5 fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6J, 129S1/SvImJ, B6129SF1/J, DBA/2J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running. PMID:25435316

Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress.

PubMed

Culig, Luka; Surget, Alexandre; Bourdey, Marlene; Khemissi, Wahid; Le Guisquet, Anne-Marie; Vogel, Elise; Sahay, Amar; Hen, René; Belzung, Catherine

2017-11-01

Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis. Copyright © 2017 Elsevier Ltd. All rights

Deletion of TLX and social isolation impairs exercise-induced neurogenesis in the adolescent hippocampus.

PubMed

Kozareva, Danka A; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

2018-01-01

Adolescence is a sensitive period of neurodevelopment during which life experiences can have profound effects on the brain. Hippocampal neurogenesis, the neurodevelopmental process of generating functional new neurons from neural stem cells, occurs throughout the lifespan and has been shown to play a role in learning, memory and in mood regulation. In adulthood it is influenced by extrinsic environmental factors such as exercise and stress. Intrinsic factors that regulate hippocampal neurogenesis include the orphan nuclear receptor TLX (Nr2e1) which is primarily expressed in the neurogenic niches of the brain. While mechanisms regulating adult hippocampal neurogenesis have been widely studied, less is known on how hippocampal neurogenesis is affected during adolescence. The aim of this study was to investigate the influence of both TLX and isolation stress on exercise-induced increases in neurogenesis in running and sedentary conditions during adolescence. Single- (isolation stress) wild type and Nr2e1 -/- mice or pair-housed wild type mice were housed in sedentary conditions or allowed free access to running wheels for 3 weeks during adolescence. A reduction of neuronal survival was evident in mice lacking TLX, and exercise did not increase hippocampal neurogenesis in these Nr2e1 -/- mice. This suggests that TLX is necessary for the pro-neurogenic effects of exercise during adolescence. Interestingly, although social isolation during adolescence did not affect hippocampal neurogenesis, it prevented an exercise-induced increase in neurogenesis in the ventral hippocampus. Together these data demonstrate the importance of intrinsic and extrinsic factors in promoting an exercise-induced increase in neurogenesis at this key point in life. © 2017 Wiley Periodicals, Inc.

Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult rats

PubMed Central

Hamilton, G.F.; Murawski, N.J.; St. Cyr, S.A.; Jablonski, S.A.; Schiffino, F.L.; Stanton, M.E.; Klintsova, A.Y.

2011-01-01

Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: sham-intubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200 mg/kg BrdU. Half of the animals were sacrificed two hours later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ∼PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning. PMID:21816390

Influence of long-term social interaction on chirping behavior, steroid levels and neurogenesis in weakly electric fish

PubMed Central

Dunlap, Kent D.; Chung, Michael; Castellano, James F.

2013-01-01

Summary Social interactions dramatically affect the brain and behavior of animals. Studies in birds and mammals indicate that socially induced changes in adult neurogenesis participate in the regulation of social behavior, but little is known about this relationship in fish. Here, we review studies in electric fish (Apteronotus leptorhychus) that link social stimulation, changes in electrocommunication behavior and adult neurogenesis in brain regions associated with electrocommunication. Compared with isolated fish, fish living in pairs have greater production of chirps, an electrocommunication signal, during dyadic interactions and in response to standardized artificial social stimuli. Social interaction also promotes neurogenesis in the periventricular zone, which contributes born cells to the prepacemaker nucleus, the brain region that regulates chirping. Both long-term chirp rate and periventricular cell addition depend on the signal dynamics (amplitude and waveform variation), modulations (chirps) and novelty of the stimuli from the partner fish. Socially elevated cortisol levels and cortisol binding to glucocorticoid receptors mediate, at least in part, the effect of social interaction on chirping behavior and brain cell addition. In a closely related electric fish (Brachyhypopomus gauderio), social interaction enhances cell proliferation specifically in brain regions for electrocommunication and only during the breeding season, when social signaling is most elaborate. Together, these studies demonstrate a consistent correlation between brain cell addition and environmentally regulated chirping behavior across many social and steroidal treatments and suggest a causal relationship. PMID:23761468

Selective impairment of hippocampal neurogenesis by chronic alcoholism: Protective effects of an antioxidant

PubMed Central

Herrera, Daniel G.; Yagüe, Almudena G.; Johnsen-Soriano, Siv; Bosch-Morell, Francisco; Collado-Morente, Lucía; Muriach, Maria; Romero, Francisco J.; García-Verdugo, J. Manuel

2003-01-01

A major pathogenic mechanism of chronic alcoholism involves oxidative burden to liver and other cell types. We show that adult neurogenesis within the dentate gyrus of the hippocampus is selectively impaired in a rat model of alcoholism, and that it can be completely prevented by the antioxidant ebselen. Rats fed for 6 weeks with a liquid diet containing moderate doses of ethanol had a 66.3% decrease in the number of new neurons and a 227–279% increase in cell death in the dentate gyrus as compared with paired controls. Neurogenesis within the olfactory bulb was not affected by alcohol. Our studies indicate that alcohol abuse, even for a short duration, results in the death of newly formed neurons within the adult brain and that the underlying mechanism is related to oxidative or nitrosative stress. Moreover, these findings suggest that the impaired neurogenesis may be a mechanism mediating cognitive deficits observed in alcoholism. PMID:12792022

A weak magnetic field inhibits hippocampal neurogenesis in SD rats

NASA Astrophysics Data System (ADS)

Zhang, B.; Tian, L.; Cai, Y.; Pan, Y.

2017-12-01

Geomagnetic field is an important barrier that protects life forms on Earth from solar wind and radiation. Paleomagnetic data have well demonstrated that the strength of ancient geomagnetic field was dramatically weakened during a polarity transition. Accumulating evidence has shown that weak magnetic field exposures has serious adverse effects on the metabolism and behaviors in organisms. Hippocampal neurogenesis occurs throughout life in mammals' brains which plays a key role in brain function, and can be influenced by animals' age as well as environmental factors, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we have investigated the weak magnetic field effects on hippocampal neurogenesis of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, a weak magnetic field (≤1.3 μT) and the geomagnetic fields (51 μT).The latter is treated as a control condition. SD rats were exposure to the weak magnetic field up to 6 weeks. We measured the changes of newborn nerve cells' proliferation and survival, immature neurons, neurons and apoptosis in the dentate gyrus (DG) of hippocampus in SD rats. Results showed that, the weak magnetic field (≤1.3 μT) inhibited their neural stem cells proliferation and significantly reduced the survival of newborn nerve cells, immature neurons and neurons after 2 or 4 weeks continuous treatment (i.e. exposure to weak magnetic field). Moreover, apoptosis tests indicated the weak magnetic field can promote apoptosis of nerve cells in the hippocampus after 4 weeks treatment. Together, our new data indicate that weak magnetic field decrease adult hippocampal neurogenesis through inhibiting neural stem cells proliferation and promoting apoptosis, which provides useful experimental constraints on better understanding the mechanism of linkage between life and geomagnetic field.

Lasting Adaptations in Social Behavior Produced by Social Disruption and Inhibition of Adult Neurogenesis

PubMed Central

Opendak, Maya; Offit, Lily; Monari, Patrick; Schoenfeld, Timothy J.; Sonti, Anup N.; Cameron, Heather A.

2016-01-01

Research on social instability has focused on its detrimental consequences, but most people are resilient and respond by invoking various coping strategies. To investigate cellular processes underlying such strategies, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Social disruption produced a preference for familiar over novel conspecifics, a change that did not involve global memory impairments or increased anxiety. Using the neuropeptide oxytocin as a tool to increase neurogenesis in the hippocampus of disrupted rats restored preference for novel conspecifics to predisruption levels. Conversely, reducing the number of new neurons by limited inhibition of adult neurogenesis in naive transgenic GFAP–thymidine kinase rats resulted in social behavior similar to disrupted rats. Together, these results provide novel mechanistic evidence that social disruption shapes behavior in a potentially adaptive way, possibly by reducing adult neurogenesis in the hippocampus. SIGNIFICANCE STATEMENT To investigate cellular processes underlying adaptation to social instability, a dominance hierarchy of rats was formed and then destabilized. Regardless of social position, rats from disrupted hierarchies had fewer new neurons in the hippocampus compared with rats from control cages and those from stable hierarchies. Unexpectedly, these changes were accompanied by changes in social strategies without evidence of impairments in cognition or anxiety regulation. Restoring adult neurogenesis in disrupted rats using oxytocin and conditionally suppressing the production of new neurons in socially naive GFAP–thymidine kinase rats showed that loss of 6-week-old neurons may be responsible for adaptive changes in social behavior. PMID:27358459

Decoding Crucial LncRNAs Implicated in Neurogenesis and Neurological Disorders.

PubMed

Ayana, R; Singh, Shailja; Pati, Soumya

2017-04-15

Unraveling transcriptional heterogeneity and the labyrinthine nature of neurodevelopment can probe insights into neuropsychiatric disorders. It is noteworthy that adult neurogenesis is restricted to the subventricular and subgranular zones of the brain. Recent studies suggest long non-coding RNAs (lncRNAs) as an avant-garde class of regulators implicated in neurodevelopment. But, paucity exists in the knowledge regarding lncRNAs in neurogenesis and their associations with neurodevelopmental defects. To address this, we extensively reviewed the existing literature databases as well as performed relevant in-silico analysis. We utilized Allen Brain Atlas (ABA) differential search module and generated a catalogue of ∼30,000 transcripts specific to the neurogenic zones, including coding and non-coding transcripts. To explore the existing lncRNAs reported in neurogenesis, we performed extensive literature mining and identified 392 lncRNAs. These degenerate lncRNAs were mapped onto the ABA transcript list leading to detection of 20 lncRNAs specific to neurogenic zones (Dentate gyrus/Lateral ventricle), among which 10 showed associations to several neurodevelopmental disorders following in-silico mapping onto brain disease databases like Simons Foundation Autism Research Initiative, AutDB, and lncRNADisease. Notably, using ABA correlation module, we could establish lncRNA-to-mRNA coexpression networks for the above 10 candidate lncRNAs. Finally, pathway prediction revealed physical, biochemical, or regulatory interactions for nine lncRNAs. In addition, ABA differential search also revealed 54 novel significant lncRNAs from the null set (∼30,000). Conclusively, this review represents an updated catalogue of lncRNAs in neurogenesis and neurological diseases, and overviews the field of OMICs-based data analysis for understanding lncRNome-based regulation in neurodevelopment.

Enhancement of matrix metalloproteinases 2 and 9 accompanied with neurogenesis following collagen glycosaminoglycan matrix implantation after surgical brain injury.

PubMed

Hsu, Wei-Cherng; Yu, Chun-Hsien; Kung, Woon-Man; Huang, Kuo-Feng

2018-06-01

Surgical brain injury may result in irreversible neurological deficits. Our previous report showed that partial regeneration of a traumatic brain lesion is achieved by implantation of collagen glycosaminoglycan (CGM). Matrix metalloproteinases (MMPs) may play an important role in neurogenesis but there is currently a lack of studies displaying the relationship between the stimulation of MMPs and neurogenesis after collagen glycosaminoglycan implantation following surgical brain trauma. The present study was carried out to further examine the expression of MMP2 and MMP9 after implantation of collagen glycosaminoglycan (CGM) following surgical brain trauma. Using the animal model of surgically induced brain lesion, we implanted CGM into the surgical trauma. Rats were thus divided into three groups: (1) sham operation group: craniotomy only; (2) lesion (L) group: craniotomy + surgical trauma lesion; (3) lesion + CGM (L + CGM) group: CGM implanted following craniotomy and surgical trauma lesion. Cells positive for SOX2 (marker of proliferating neural progenitor cells) and matrix metalloproteinases (MMP2 and MMP9) in the lesion boundary zone were assayed and analyzed by immunofluorescence and ELISA commercial kits, respectively. Our results demonstrated that following implantation of CGM after surgical brain trauma, significant increases in MMP2 + /SOX2 + cells and MMP9 + /SOX2 + cells were seen within the lesion boundary zone in the L + CGM group. Tissue protein concentrations of MMP2 and MMP9 also increased after CGM scaffold implantation. These findings suggest that implantation of a CGM scaffold alone after surgical brain trauma can enhance the expression of MMP2 and MMP9 accompanied by neurogenesis.

Diazepam Binding Inhibitor Promotes Stem Cell Expansion Controlling Environment-Dependent Neurogenesis.

PubMed

Dumitru, Ionut; Neitz, Angela; Alfonso, Julieta; Monyer, Hannah

2017-04-05

Plasticity of adult neurogenesis supports adaptation to environmental changes. The identification of molecular mediators that signal these changes to neural progenitors in the niche has remained elusive. Here we report that diazepam binding inhibitor (DBI) is crucial in supporting an adaptive mechanism in response to changes in the environment. We provide evidence that DBI is expressed in stem cells in all neurogenic niches of the postnatal brain. Focusing on the hippocampal subgranular zone (SGZ) and employing multiple genetic manipulations in vivo, we demonstrate that DBI regulates the balance between preserving the stem cell pool and neurogenesis. Specifically, DBI dampens GABA activity in stem cells, thereby sustaining the proproliferative effect of physical exercise and enriched environment. Our data lend credence to the notion that the modulatory effect of DBI constitutes a general mechanism that regulates postnatal neurogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Adult neurogenesis in the hedgehog (Erinaceus concolor) and mole (Talpa europaea).

PubMed

Bartkowska, K; Turlejski, K; Grabiec, M; Ghazaryan, A; Yavruoyan, E; Djavadian, R L

2010-01-01

We investigated adult neurogenesis in two species of mammals belonging to the superorder Laurasiatheria, the southern white-breasted hedgehog (order Erinaceomorpha, species Erinaceus concolor) from Armenia and the European mole (order Soricomorpha, species Talpa europaea) from Poland. Neurogenesis in the brain of these species was examined immunohistochemically, using the endogenous markers doublecortin (DCX) and Ki-67, which are highly conserved among species. We found that in both the hedgehog and mole, like in the majority of earlier investigated mammals, neurogenesis continues in the subventricular zone (SVZ) of the lateral ventricles and in the dentate gyrus (DG). In the DG of both species, DCX-expressing cells and Ki-67-labeled cells were present in the subgranular and granular layers. In the mole, a strong bundle of DCX-labeled processes, presumably axons of granule cells, was observed in the center of the hilus. Proliferating cells (expressing Ki-67) were identified in the SVZ of lateral ventricles of both species, but neuronal precursor cells (expressing DCX) were also observed in the olfactory bulb (OB). In both species, the vast majority of cells expressing DCX in the OB were granule cells with radially orientated dendrites, although some periglomerular cells surrounding the glomeruli were also labeled. In addition, this paper is the first to show DCX-labeled fibers in the anterior commissure of the hedgehog and mole. These fibers must be axons of new neurons making interhemispheric connections between the two OB or piriform (olfactory) cortices. DCX-expressing neurons were observed in the striatum and piriform cortex of both hedgehog and mole. We postulate that in both species a fraction of cells newly generated in the SVZ migrates along the rostral migratory stream to the piriform cortex. This pattern of migration resembles that of the 'second-wave neurons' generated during embryonal development of the neocortex rather than the pattern observed during

Acute and Fractionated Exposure to High-LET 56Fe HZE-Particle Radiation Both Result in Similar Long-Term Deficits in Adult Hippocampal Neurogenesis

PubMed Central

Rivera, Phillip D.; Shih, Hung-Ying; LeBlanc, Junie A.; Cole, Mara G.; Amaral, Wellington Z.; Mukherjee, Shibani; Zhang, Shichuan; Lucero, Melanie J.; DeCarolis, Nathan A.; Chen, Benjamin P. C.; Eisch, Amelia J.

2014-01-01

Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreERT2/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy 56Fe-particle exposure or five fractionated 20 cGy 56Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of 56Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed. PMID:24320054

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

PubMed

Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

2014-12-15

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis.

PubMed

Hill, Jeremy D; Zuluaga-Ramirez, Viviana; Gajghate, Sachin; Winfield, Malika; Persidsky, Yuri

2018-06-11

The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 receptor (CB 1 R) or cannabinoid 2 receptor (CB 2 R). The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. The effects of GPR55 agonists (LPI, O-1602, ML184) on human NSC proliferation in vitro were assessed by flow cytometry. hNSC differentiation was determined by flow cytometry, qPCR, and immunohistochemistry. Immature neuron formation in the hippocampus of C57BL/6 and GPR55 -/- mice was evaluated by immunohistochemistry. Activation of GPR55 significantly increased proliferation rates of hNSCs in vitro. These effects were attenuated by ML193, a selective GPR55 antagonist. ML184 significantly promoted neuronal differentiation in vitro while ML193 reduced differentiation rates as compared to vehicle treatment. Continuous administration into the hippocampus of O-1602 via cannula connected to osmotic pump resulted in increased Ki67+ cells within the dentate gyrus. O-1602 increased immature neuron generation as assessed by DCX+ and BrdU+ cells as compared to vehicle treated animals. GPR55 -/- animals displayed reduced rates of proliferation and neurogenesis within the hippocampus while O-1602 had no effect as compared to vehicle controls. Together, these findings suggest GPR55 activation as a novel target and strategy to regulate NSC proliferation and adult neurogenesis. This article is protected by copyright. All rights reserved.

Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis.

PubMed

Ehret, Fanny; Vogler, Steffen; Pojar, Sherin; Elliott, David A; Bradke, Frank; Steiner, Barbara; Kempermann, Gerd

2015-03-01

Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL. Copyright © 2014. Published by Elsevier Inc.

Roles of PPAR transcription factors in the energetic metabolic switch occurring during adult neurogenesis

PubMed Central

Cristiano, L.; d'Angelo, M.; Fidoamore, A.; Barone, D.; Moreno, S.; Ippoliti, R.; Cerù, M. P.; Giordano, A.; Cimini, A.

2017-01-01

ABSTRACT PPARs are a class of ligand-activated transcription factors belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids and vitamin D that control the expression of a large number of genes involved in lipid and carbohydrate metabolism and in the regulation of cell proliferation, differentiation and death. The role of PPARs in the CNS has been primarily associated with lipid and glucose metabolism; however, these receptors are also implicated in neural cell differentiation and death, as well as neuronal maturation. Although it has been demonstrated that PPARs play important roles in determining NSCs fate, less is known about their function in regulating NSCs metabolism during differentiation. In order to identify the metabolic events, controlled by PPARs, occurring during neuronal precursor differentiation, the glucose and lipid metabolism was followed in a recognized model of neuronal differentiation in vitro, the SH-SY5Y neuroblastoma cell line. Moreover, PPARs distribution were also followed in situ in adult mouse brains. The concept of adult neurogenesis becomes relevant especially in view of those disorders in which a loss of neurons is described, such as Alzheimer disease, Parkinson disease, brain injuries and other neurological disorders. Elucidating the crucial steps in energetic metabolism and the involvement of PPARγ in NSC neuronal fate (lineage) may be useful for the future design of preventive and/or therapeutic interventions. PMID:27860527

Seasonal variation in cell proliferation and cell migration in the brain of adult red-sided garter snakes (Thamnophis sirtalis parietalis).

PubMed

Maine, Ashley R; Powers, Sean D; Lutterschmidt, Deborah I

2014-01-01

Plasticity in the adult central nervous system has been described in all vertebrate classes as well as in some invertebrate groups. However, the limited taxonomic diversity represented in the current neurogenesis literature limits our ability to assess the functional significance of adult neurogenesis for natural behaviors as well as the evolution of its regulatory mechanisms. In the present study, we used free-ranging red-sided garter snakes (Thamnophis sirtalis parietalis) to test the hypothesis that seasonal shifts in physiology and behavior are associated with seasonal variation in postembryonic neurogenesis. Specifically, we used the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) to determine if the rates of cell proliferation in the adult brain vary between male snakes collected during spring and fall at 1, 5, and 10 days post-BrdU treatment. To assess rates of cell migration within the brain, we further categorized BrdU-labeled cells according to their location within the ventricular zone or parenchymal region. BrdU-labeled cells were localized mainly within the lateral, dorsal, and medial cortex, septal nucleus, nucleus sphericus, preoptic area, and hypothalamus. In all regions, the number of BrdU-labeled cells in the ventricular zone was higher in the fall compared to spring. In the parenchymal region, a significantly higher number of labeled cells was also observed during the fall, but only within the nucleus sphericus and the combined preoptic area/hypothalamus. The immunoreactive cell number did not vary significantly with days post-BrdU treatment in either season or in any brain region. While it is possible that the higher rates of cell proliferation in the fall simply reflect increased growth of all body tissues, including the brain, our data show that seasonal changes in cell migration into the parenchyma are region specific. In red-sided garter snakes and other reptiles, the dorsal and medial cortex is important for spatial navigation and memory

Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats

PubMed Central

Kisel, Alena; Kudabaeva, Marina; Chernysheva, Galina; Smolyakova, Vera; Krutenkova, Elena; Wasserlauf, Irina; Plotnikov, Mark; Yarnykh, Vasily

2018-01-01

A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2′-deoxyuridine was injected at days 8–10 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect. PMID:29304004

Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory.

PubMed

Pristerà, Andrea; Saraulli, Daniele; Farioli-Vecchioli, Stefano; Strimpakos, Georgios; Costanzi, Marco; di Certo, Maria Grazia; Cannas, Sara; Ciotti, Maria Teresa; Tirone, Felice; Mattei, Elisabetta; Cestari, Vincenzo; Canu, Nadia

2013-11-01

Different pathological tau species are involved in memory loss in Alzheimer's disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampus-dependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26-230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase-3-independent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair. Copyright © 2013 Elsevier Inc. All rights reserved.

Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory

PubMed Central

Martel, Guillaume; Uchida, Shusaku; Hevi, Charles; Chévere-Torres, Itzamarie; Fuentes, Ileana; Park, Young Jin; Hafeez, Hannah; Yamagata, Hirotaka; Watanabe, Yoshifumi

2016-01-01

Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an

Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

PubMed Central

Prosper, Boris W.; Marathe, Swanand; Husain, Basma F. A.; Kernie, Steven G.; Bartlett, Perry F.; Vaidya, Vidita A.

2014-01-01

Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis. PMID:24922313

No pain, no gain: lack of exercise obstructs neurogenesis.

PubMed

Watson, Nate; Ji, Xunming; Yasuhara, Takao; Date, Isao; Kaneko, Yuji; Tajiri, Naoki; Borlongan, Cesar V

2015-01-01

Bedridden patients develop atrophied muscles, their daily activities greatly reduced, and some display a depressive mood. Patients who are able to receive physical rehabilitation sometimes show surprising clinical improvements, including reduced depression and attenuation of other stress-related behaviors. Regenerative medicine has advanced two major stem cell-based therapies for CNS disorders, namely, transplantation of exogenous stem cells and amplification of endogenous neurogenesis. The latter strategy embraces a natural way of reinnervating the damaged brain and correcting the neurological impairments. In this study, we discussed how immobilization-induced disuse atrophy, using the hindlimb suspension model, affects neurogenesis in rats. The overarching hypothesis is that immobilization suppresses neurogenesis by reducing the circulating growth or trophic factors, such as vascular endothelial growth factor or brain-derived neurotrophic factor. That immobilization alters neurogenesis and stem cell differentiation in the CNS requires characterization of the stem cell microenvironment by examining the trophic and growth factors, as well as stress-related proteins that have been implicated in exercise-induced neurogenesis. Although accumulating evidence has revealed the contribution of "increased" exercise on neurogenesis, the reverse paradigm involving "lack of exercise," which mimics pathological states (e.g., stroke patients are often immobile), remains underexplored. This novel paradigm will enable us to examine the effects on neurogenesis by a nonpermissive stem cell microenvironment likely produced by lack of exercise. BrdU labeling of proliferative cells, biochemical assays of serum, cerebrospinal fluid and brain levels of trophic factors, growth factors, and stress-related proteins are proposed as indices of neurogenesis, while quantitative measurements of spontaneous movements will reveal psychomotor components of immobilization. Studies designed to

Network modeling of adult neurogenesis: shifting rates of neuronal turnover optimally gears network learning according to novelty gradient.

PubMed

Chambers, R Andrew; Conroy, Susan K

2007-01-01

Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In "adult" networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis-neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders.

No effect of running and laboratory housing on adult hippocampal neurogenesis in wild caught long-tailed wood mouse

PubMed Central

Hauser, Thomas; Klaus, Fabienne; Lipp, Hans-Peter; Amrein, Irmgard

2009-01-01

Background Studies of adult hippocampal neurogenesis (AHN) in laboratory rodents have raised hopes for therapeutic interventions in neurodegenerative diseases and mood disorders, as AHN can be modulated by physical exercise, stress and environmental changes in these animals. Since it is not known whether cell proliferation and neurogenesis in wild living mice can be experimentally changed, this study investigates the responsiveness of AHN to voluntary running and to environmental change in wild caught long-tailed wood mice (Apodemus sylvaticus). Results Statistical analyses show that running had no impact on cell proliferation (p = 0.44), neurogenesis (p = 0.94) or survival of newly born neurons (p = 0.58). Likewise, housing in the laboratory has no effect on AHN. In addition, interindividual differences in the level of neurogenesis are not related to interindividual differences of running wheel performance (rs = -0.09, p = 0.79). There is a correlation between the number of proliferating cells and the number of cells of neuronal lineage (rs = 0.63, p < 0.001) and the number of pyknotic cells (rs = 0.5, p = 0.009), respectively. Conclusion Plasticity of adult neurogenesis is an established feature in strains of house mice and brown rats. Here, we demonstrate that voluntary running and environmental changes which are effective in house mice and brown rats cannot influence AHN in long-tailed wood mice. This indicates that in wild long-tailed wood mice different regulatory mechanisms act on cell proliferation and neurogenesis. If this difference reflects a species-specific adaptation or a broader adaptive strategy to a natural vs. domestic environment is unknown. PMID:19419549

Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia.

PubMed

Kim, Ju Young; Liu, Cindy Y; Zhang, Fengyu; Duan, Xin; Wen, Zhexing; Song, Juan; Feighery, Emer; Lu, Bai; Rujescu, Dan; St Clair, David; Christian, Kimberly; Callicott, Joseph H; Weinberger, Daniel R; Song, Hongjun; Ming, Guo-li

2012-03-02

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Neocortical neurogenesis in humans is restricted to development

PubMed Central

Bhardwaj, Ratan D.; Curtis, Maurice A.; Spalding, Kirsty L.; Buchholz, Bruce A.; Fink, David; Björk-Eriksson, Thomas; Nordborg, Claes; Gage, Fred H.; Druid, Henrik; Eriksson, Peter S.; Frisén, Jonas

2006-01-01

Stem cells generate neurons in discrete regions in the postnatal mammalian brain. However, the extent of neurogenesis in the adult human brain has been difficult to establish. We have taken advantage of the integration of 14C, generated by nuclear bomb tests during the Cold War, in DNA to establish the age of neurons in the major areas of the human cerebral neocortex. Together with the analysis of the neocortex from patients who received BrdU, which integrates in the DNA of dividing cells, our results demonstrate that, whereas nonneuronal cells turn over, neurons in the human cerebral neocortex are not generated in adulthood at detectable levels but are generated perinatally. PMID:16901981

Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

PubMed

Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

2014-06-24

The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

Hypothalamic neurogenesis persists in the aging brain and is controlled by energy-sensing IGF-I pathway.

PubMed

Chaker, Zayna; George, Caroline; Petrovska, Marija; Caron, Jean-Baptiste; Lacube, Philippe; Caillé, Isabelle; Holzenberger, Martin

2016-05-01

Hypothalamic tanycytes are specialized glial cells lining the third ventricle. They are recently identified as adult stem and/or progenitor cells, able to self-renew and give rise to new neurons postnatally. However, the long-term neurogenic potential of tanycytes and the pathways regulating lifelong cell replacement in the adult hypothalamus are largely unexplored. Using inducible nestin-CreER(T2) for conditional mutagenesis, we performed lineage tracing of adult hypothalamic stem and/or progenitor cells (HySC) and demonstrated that new neurons continue to be born throughout adult life. This neurogenesis was targeted to numerous hypothalamic nuclei and produced different types of neurons in the dorsal periventricular regions. Some adult-born neurons integrated the median eminence and arcuate nucleus during aging and produced growth hormone releasing hormone. We showed that adult hypothalamic neurogenesis was tightly controlled by insulin-like growth factors (IGF). Knockout of IGF-1 receptor from hypothalamic stem and/or progenitor cells increased neuronal production and enhanced α-tanycyte self-renewal, preserving this stem cell-like population from age-related attrition. Our data indicate that adult hypothalamus retains the capacity of cell renewal, and thus, a substantial degree of structural plasticity throughout lifespan. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference.

PubMed

Faillace, M P; Zwiller, J; Bernabeu, R O

2015-08-06

Adult neurogenesis occurs in mammals within the dentate gyrus, a hippocampal subarea. It is known to be induced by antidepressant treatment and reduced in response to nicotine administration. We checked here whether the antidepressant fluoxetine would inverse the decrease in hippocampal neurogenesis caused by nicotine. It is shown that repeated, but not a single injection of rats with fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. We measured the expression of several biochemical parameters known to be associated with neurogenesis in the dentate gyrus. Both drugs increased the expression of p75 neurotrophin receptor, which promotes proliferation and early maturation of dentate gyrus cells. Using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Expression of nicotine-induced CPP was accompanied by an increase of phospho-CREB (cyclic AMP-responsive element-binding protein) and HDAC2 (histone deacetylase 2) expression in the nucleus accumbens. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. Since fluoxetine was able to disrupt the association between nicotine and the environment, this antidepressant may be tested as a treatment for nicotine addiction using cue exposure therapy. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress.

PubMed

Ma, Yanbo; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

2017-07-01

Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN-deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress.

Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model

PubMed Central

Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E.; Shi, Yanhong

2014-01-01

The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU+ cells and BrdU+NeuN+ neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory. PMID:24927526

From network structure to network reorganization: implications for adult neurogenesis

NASA Astrophysics Data System (ADS)

Schneider-Mizell, Casey M.; Parent, Jack M.; Ben-Jacob, Eshel; Zochowski, Michal R.; Sander, Leonard M.

2010-12-01

Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells.

TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis

PubMed Central

Islam, Mohammed M.; Zhang, Chun-Li

2014-01-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. PMID:24930777

Neurogenesis and Developmental Anesthetic Neurotoxicity

PubMed Central

Kang, Eunchai; Berg, Daniel A.; Furmanski, Orion; Jackson, William M.; Ryu, Yun Kyoung; Gray, Christy D.; Mintz, C. David

2017-01-01

The mechanism by which anesthetics might act on the developing brain in order to cause long term deficits remains incompletely understood. The hippocampus has been identified as a structure that is likely to be involved, as rodent models show numerous deficits in behavioral tasks of learning that are hippocampal-dependent. The hippocampus is an unusual structure in that it is the site of large amounts of neurogenesis postnatally, particularly in the first year of life in humans, and these newly generated neurons are critical to the function of this structure. Intriguingly, neurogenesis is a major developmental event that occurs during postulated windows of vulnerability to developmental anesthetic neurotoxicity across the different species in which it has been studied. In this review, we examine the evidence for anesthetic effects on neurogenesis in the early postnatal period and ask whether neurogenesis should be studied further as a putative mechanism of injury. Multiple anesthetics are considered, and both in vivo and in vitro work is presented. While there is abundant evidence that anesthetics act to suppress neurogenesis at several different phases, evidence of a causal link between these effects and any change in learning behavior remains elusive. PMID:27751818

Similar GABAergic inputs in dentate granule cells born during embryonic and adult neurogenesis.

PubMed

Laplagne, Diego A; Kamienkowski, Juan E; Espósito, M Soledad; Piatti, Verónica C; Zhao, Chunmei; Gage, Fred H; Schinder, Alejandro F

2007-05-01

Neurogenesis in the dentate gyrus of the hippocampus follows a unique temporal pattern that begins during embryonic development, peaks during the early postnatal stages and persists through adult life. We have recently shown that dentate granule cells born in early postnatal and adult mice acquire a remarkably similar afferent connectivity and firing behavior, suggesting that they constitute a homogeneous functional population [Laplagne et al. (2006)PLoS Biol., 4, e409]. Here we extend our previous study by comparing mature neurons born in the embryonic and adult hippocampus, with a focus on intrinsic membrane properties and gamma-aminobutyric acid (GABA)ergic synaptic inputs. For this purpose, dividing neuroblasts of the ventricular wall were retrovirally labeled with green fluorescent protein at embryonic day 15 (E15), and progenitor cells of the subgranular zone were labeled with red fluorescent protein in the same mice at postnatal day 42 (P42, adulthood). Electrophysiological properties of mature neurons born at either stage were then compared in the same brain slices. Evoked and spontaneous GABAergic postsynaptic responses of perisomatic and dendritic origin displayed similar characteristics in both neuronal populations. Miniature GABAergic inputs also showed similar functional properties and pharmacological profile. A comparative analysis of the present data with our previous observations rendered no significant differences among GABAergic inputs recorded from neurons born in the embryonic, early postnatal and adult mice. Yet, embryo-born neurons showed a reduced membrane excitability, suggesting a lower engagement in network activity. Our results demonstrate that granule cells of different age, location and degree of excitability receive GABAergic inputs of equivalent functional characteristics.

Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

PubMed

Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

2014-07-01

Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis. © 2014 AlphaMed Press.

Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair

PubMed Central

Larson, Tracy A.

2018-01-01

Sex steroidal hormones coordinate the development and maintenance of tissue architecture in many organs, including the central nervous systems (CNS). Within the CNS, sex steroids regulate the morphology, physiology, and behavior of a wide variety of neural cells including, but not limited to, neurons, glia, endothelial cells, and immune cells. Sex steroids spatially and temporally control distinct molecular networks, that, in turn modulate neural activity, synaptic plasticity, growth factor expression and function, nutrient exchange, cellular proliferation, and apoptosis. Over the last several decades, it has become increasingly evident that sex steroids, often in conjunction with neuroinflammation, have profound impact on the occurrence and severity of neuropsychiatric and neurodegenerative disorders. Here, I review the foundational discoveries that established the regulatory role of sex steroids in the CNS and highlight recent advances toward elucidating the complex interaction between sex steroids, neuroinflammation, and CNS regeneration through adult neurogenesis. The majority of recent work has focused on neuroinflammatory responses following acute physical damage, chronic degeneration, or pharmacological insult. Few studies directly assess the role of immune cells in regulating adult neurogenesis under healthy, homeostatic conditions. As such, I also introduce tractable, non-traditional models for examining the role of neuroimmune cells in natural neuronal turnover, seasonal plasticity of neural circuits, and extreme CNS regeneration. PMID:29760681

Network Modeling of Adult Neurogenesis: Shifting Rates of Neuronal Turnover Optimally Gears Network Learning according to Novelty Gradient

PubMed Central

Chambers, R. Andrew; Conroy, Susan K.

2010-01-01

Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In “adult” networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis–neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders. PMID:17214558

Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice.

PubMed

Yang, Miyoung; Kim, Hwanseong; Kim, Juhwan; Kim, Sung-Ho; Kim, Jong-Choon; Bae, Chun-Sik; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

2012-03-01

Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis.

Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis

PubMed Central

Marques, Alessandra Aparecida; Bevilaqua, Mário Cesar do Nascimento; da Fonseca, Alberto Morais Pinto; Nardi, Antonio Egidio; Thuret, Sandrine; Dias, Gisele Pereira

2016-01-01

Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences between male and female rodents with regard to anxiety-related behavior and physiology, with a special focus on AHN. The differences between male and female physiologies are greatly influenced by hormonal differences. Gonadal hormones and their fluctuations during the estrous cycle have often been identified as agents responsible for sexual dimorphism in behavior and AHN. During sexual maturity, hormone levels fluctuate cyclically in females more than in males, increasing the stress response and the susceptibility to anxiety. It is therefore of great importance that future research investigates anxiety and other neurophysiological aspects in the female model, so that results can be more accurately applicable to the female population. PMID:26885403

Movement maintains forebrain neurogenesis via peripheral neural feedback in larval zebrafish

PubMed Central

Hall, Zachary Jonas

2018-01-01

The postembryonic brain exhibits experience-dependent development, in which sensory experience guides normal brain growth. This neuroplasticity is thought to occur primarily through structural and functional changes in pre-existing neurons. Whether neurogenesis also mediates the effects of experience on brain growth is unclear. Here, we characterized the importance of motor experience on postembryonic neurogenesis in larval zebrafish. We found that movement maintains an expanded pool of forebrain neural precursors by promoting progenitor self-renewal over the production of neurons. Physical cues associated with swimming (bodily movement) increase neurogenesis and these cues appear to be conveyed by dorsal root ganglia (DRG) in the zebrafish body: DRG-deficient larvae exhibit attenuated neurogenic responses to movement and targeted photoactivation of DRG in immobilized larvae expands the pallial pool of proliferative cells. Our results demonstrate the importance of movement in neurogenic brain growth and reveal a fundamental sensorimotor association that may couple early motor and brain development. PMID:29528285

Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

PubMed

Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

2016-01-01

The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.

P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice.

PubMed

Kang, Seong Su; Keasey, Matthew Phillip; Hagg, Theo

2013-10-01

Increasing endogenous ciliary neurotrophic factor (CNTF) expression with a pharmacological agent might be beneficial after stroke as CNTF both promotes neurogenesis and, separately, is neuroprotective. P2X7 purinergic receptor inhibition is neuroprotective in rats and increases CNTF release in rat CMT1A Schwann cells. We, first, investigated the role of P2X7 in regulating CNTF and neurogenesis in adult mouse subventricular zone (SVZ). CNTF expression was increased by daily intravenous injections of the P2X7 antagonist Brilliant Blue G (BBG) in naïve C57BL/6 or Balb/c mice over 3 days. Despite the ∼40-60 % increase or decrease in CNTF with BBG or the agonist BzATP, respectively, the number of proliferated BrdU+SVZ nuclei did not change. BBG failed to increase FGF2, which is involved in CNTF-regulated neurogenesis, but induced IL-6, LIF, and EGF, which are known to reduce SVZ proliferation. Injections of IL-6 next to the SVZ induced CNTF and FGF2, but not proliferation, suggesting that IL-6 counteracts their neurogenesis-inducing effects. Following ischemic injury of the striatum by middle cerebral artery occlusion (MCAO), a 3-day BBG treatment increased CNTF in the medial penumbra containing the SVZ. BBG also induced CNTF and LIF, which are known to be protective following stroke, in the whole striatum after MCAO, but not GDNF or BDNF. However, BBG treatment did not reduce the lesion area or apoptosis in the penumbra. Even so, this study shows that P2X7 can be targeted with systemic drug treatments to differentially regulate neurotrophic factors in the brain following stroke.

Use it or lose it: How neurogenesis keeps the brain fit for learning

PubMed Central

Shors, T.J; Anderson, LM; Curlik, D. M.; Nokia, SM

2011-01-01

The presence of new neurons in the adult hippocampus indicates that this structure incorporates new neurons into its circuitry and uses them for some function related to learning and/or related thought processes. Their generation depends on a variety of factors ranging from age to aerobic exercise to sexual behavior to alcohol consumption. However, most of the cells will die unless the animal engages in some kind of effortful learning experience when the cells are about one week of age. If learning does occur, the new cells become incorporated into brain circuits used for learning. In turn, some processes of learning and mental activity appear to depend on their presence. In this review, we discuss the now rather extensive literature showing that new neurons are kept alive by effortful learning, a process that involves concentration in the present moment of experience over some extended period of time. As these thought processes occur, endogenous patterns of rhythmic electrophysiological activity engage the new cells with cell networks that already exist in the hippocampus and at efferent locations. Concurrent and synchronous activity provides a mechanism whereby the new neurons become integrated with the other neurons. This integration allows the present experience to become integrated with memories from the recent past in order to learn and predict when events will occur in the near future. In this way, neurogenesis and learning interact to maintain a fit brain. PMID:21536076

Neurogenesis and developmental anesthetic neurotoxicity.

PubMed

Kang, Eunchai; Berg, Daniel A; Furmanski, Orion; Jackson, William M; Ryu, Yun Kyoung; Gray, Christy D; Mintz, C David

The mechanism by which anesthetics might act on the developing brain in order to cause long term deficits remains incompletely understood. The hippocampus has been identified as a structure that is likely to be involved, as rodent models show numerous deficits in behavioral tasks of learning that are hippocampal-dependent. The hippocampus is an unusual structure in that it is the site of large amounts of neurogenesis postnatally, particularly in the first year of life in humans, and these newly generated neurons are critical to the function of this structure. Intriguingly, neurogenesis is a major developmental event that occurs during postulated windows of vulnerability to developmental anesthetic neurotoxicity across the different species in which it has been studied. In this review, we examine the evidence for anesthetic effects on neurogenesis in the early postnatal period and ask whether neurogenesis should be studied further as a putative mechanism of injury. Multiple anesthetics are considered, and both in vivo and in vitro work is presented. While there is abundant evidence that anesthetics act to suppress neurogenesis at several different phases, evidence of a causal link between these effects and any change in learning behavior remains elusive. Copyright © 2016. Published by Elsevier Inc.

Depression, Antidepressants, and Neurogenesis: A Critical Reappraisal

PubMed Central

Hanson, Nicola D; Owens, Michael J; Nemeroff, Charles B

2011-01-01

The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment. PMID:21937982

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

PubMed

Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

2015-01-01

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Role of adult neurogenesis in hippocampal-cortical memory consolidation

PubMed Central

2014-01-01

Acquired memory is initially dependent on the hippocampus (HPC) for permanent memory formation. This hippocampal dependency of memory recall progressively decays with time, a process that is associated with a gradual increase in dependency upon cortical structures. This process is commonly referred to as systems consolidation theory. In this paper, we first review how memory becomes hippocampal dependent to cortical dependent with an emphasis on the interactions that occur between the HPC and cortex during systems consolidation. We also review the mechanisms underlying the gradual decay of HPC dependency during systems consolidation from the perspective of memory erasures by adult hippocampal neurogenesis. Finally, we discuss the relationship between systems consolidation and memory precision. PMID:24552281

The reduction of adult neurogenesis in depression impairs the retrieval of new as well as remote episodic memory

PubMed Central

Fang, Jing; Demic, Selver; Cheng, Sen

2018-01-01

Major depressive disorder (MDD) is associated with an impairment of episodic memory, but the mechanisms underlying this deficit remain unclear. Animal models of MDD find impaired adult neurogenesis (AN) in the dentate gyrus (DG), and AN in DG has been suggested to play a critical role in reducing the interference between overlapping memories through pattern separation. Here, we study the effect of reduced AN in MDD on the accuracy of episodic memory using computational modeling. We focus on how memory is affected when periods with a normal rate of AN (asymptomatic states) alternate with periods with a low rate (depressive episodes), which has never been studied before. Also, unlike previous models of adult neurogenesis, which consider memories as static patterns, we model episodic memory as sequences of neural activity patterns. In our model, AN adds additional random components to the memory patterns, which results in the decorrelation of similar patterns. Consistent with previous studies, higher rates of AN lead to higher memory accuracy in our model, which implies that memories stored in the depressive state are impaired. Intriguingly, our model makes the novel prediction that memories stored in an earlier asymptomatic state are also impaired by a later depressive episode. This retrograde effect exacerbates with increased duration of the depressive episode. Finally, pattern separation at the sensory processing stage does not improve, but rather worsens, the accuracy of episodic memory retrieval, suggesting an explanation for why AN is found in brain areas serving memory rather than sensory function. In conclusion, while cognitive retrieval biases might contribute to episodic memory deficits in MDD, our model suggests a mechanistic explanation that affects all episodic memories, regardless of emotional relevance. PMID:29879169

The reduction of adult neurogenesis in depression impairs the retrieval of new as well as remote episodic memory.

PubMed

Fang, Jing; Demic, Selver; Cheng, Sen

2018-01-01

Major depressive disorder (MDD) is associated with an impairment of episodic memory, but the mechanisms underlying this deficit remain unclear. Animal models of MDD find impaired adult neurogenesis (AN) in the dentate gyrus (DG), and AN in DG has been suggested to play a critical role in reducing the interference between overlapping memories through pattern separation. Here, we study the effect of reduced AN in MDD on the accuracy of episodic memory using computational modeling. We focus on how memory is affected when periods with a normal rate of AN (asymptomatic states) alternate with periods with a low rate (depressive episodes), which has never been studied before. Also, unlike previous models of adult neurogenesis, which consider memories as static patterns, we model episodic memory as sequences of neural activity patterns. In our model, AN adds additional random components to the memory patterns, which results in the decorrelation of similar patterns. Consistent with previous studies, higher rates of AN lead to higher memory accuracy in our model, which implies that memories stored in the depressive state are impaired. Intriguingly, our model makes the novel prediction that memories stored in an earlier asymptomatic state are also impaired by a later depressive episode. This retrograde effect exacerbates with increased duration of the depressive episode. Finally, pattern separation at the sensory processing stage does not improve, but rather worsens, the accuracy of episodic memory retrieval, suggesting an explanation for why AN is found in brain areas serving memory rather than sensory function. In conclusion, while cognitive retrieval biases might contribute to episodic memory deficits in MDD, our model suggests a mechanistic explanation that affects all episodic memories, regardless of emotional relevance.

Sex and strategy use matters for pattern separation, adult neurogenesis, and immediate early gene expression in the hippocampus.

PubMed

Yagi, Shunya; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

2016-01-01

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation, and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis, and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the eight-arm radial arm maze. Twenty-seven days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore, male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly, neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity. © 2015 Wiley Periodicals, Inc.

Localization and regulation of PML bodies in the adult mouse brain.

PubMed

Hall, Małgorzata H; Magalska, Adriana; Malinowska, Monika; Ruszczycki, Błażej; Czaban, Iwona; Patel, Satyam; Ambrożek-Latecka, Magdalena; Zołocińska, Ewa; Broszkiewicz, Hanna; Parobczak, Kamil; Nair, Rajeevkumar R; Rylski, Marcin; Pawlak, Robert; Bramham, Clive R; Wilczyński, Grzegorz M

2016-06-01

PML is a tumor suppressor protein involved in the pathogenesis of promyelocytic leukemia. In non-neuronal cells, PML is a principal component of characteristic nuclear bodies. In the brain, PML has been implicated in the control of embryonic neurogenesis, and in certain physiological and pathological phenomena in the adult brain. Yet, the cellular and subcellular localization of the PML protein in the brain, including its presence in the nuclear bodies, has not been investigated comprehensively. Because the formation of PML bodies appears to be a key aspect in the function of the PML protein, we investigated the presence of these structures and their anatomical distribution, throughout the adult mouse brain. We found that PML is broadly expressed across the gray matter, with the highest levels in the cerebral and cerebellar cortices. In the cerebral cortex PML is present exclusively in neurons, in which it forms well-defined nuclear inclusions containing SUMO-1, SUMO 2/3, but not Daxx. At the ultrastructural level, the appearance of neuronal PML bodies differs from the classic one, i.e., the solitary structure with more or less distinctive capsule. Rather, neuronal PML bodies have the form of small PML protein aggregates located in the close vicinity of chromatin threads. The number, size, and signal intensity of neuronal PML bodies are dynamically influenced by immobilization stress and seizures. Our study indicates that PML bodies are broadly involved in activity-dependent nuclear phenomena in adult neurons.

Epileptogenesis following Kainic Acid-Induced Status Epilepticus in Cyclin D2 Knock-Out Mice with Diminished Adult Neurogenesis

PubMed Central

Kondratiuk, Ilona; Plucinska, Gabriela; Miszczuk, Diana; Wozniak, Grazyna; Szydlowska, Kinga; Kaczmarek, Leszek; Filipkowski, Robert K.; Lukasiuk, Katarzyna

2015-01-01

The goal of this study was to determine whether a substantial decrease in adult neurogenesis influences epileptogenesis evoked by the intra-amygdala injection of kainic acid (KA). Cyclin D2 knockout (cD2 KO) mice, which lack adult neurogenesis almost entirely, were used as a model. First, we examined whether status epilepticus (SE) evoked by an intra-amygdala injection of KA induces cell proliferation in cD2 KO mice. On the day after SE, we injected BrdU into mice for 5 days and evaluated the number of DCX- and DCX/BrdU-immunopositive cells 3 days later. In cD2 KO control animals, only a small number of DCX+ cells was observed. The number of DCX+ and DCX/BrdU+ cells/mm of subgranular layer in cD2 KO mice increased significantly following SE (p<0.05). However, the number of newly born cells was very low and was significantly lower than in KA-treated wild type (wt) mice. To evaluate the impact of diminished neurogenesis on epileptogenesis and early epilepsy, we performed video-EEG monitoring of wt and cD2 KO mice for 16 days following SE. The number of animals with seizures did not differ between wt (11 out of 15) and cD2 KO (9 out of 12) mice. The median latency to the first spontaneous seizure was 4 days (range 2 – 10 days) in wt mice and 8 days (range 2 – 16 days) in cD2 KO mice and did not differ significantly between groups. Similarly, no differences were observed in median seizure frequency (wt: 1.23, range 0.1 – 3.4; cD2 KO: 0.57, range 0.1 – 2.0 seizures/day) or median seizure duration (wt: 51 s, range 23 – 103; cD2 KO: 51 s, range 23 – 103). Our results indicate that SE-induced epileptogenesis is not disrupted in mice with markedly reduced adult neurogenesis. However, we cannot exclude the contribution of reduced neurogenesis to the chronic epileptic state. PMID:26020770

Huntingtin Acts Non Cell-Autonomously on Hippocampal Neurogenesis and Controls Anxiety-Related Behaviors in Adult Mouse

PubMed Central

Pla, Patrick; Orvoen, Sophie; Benstaali, Caroline; Dodier, Sophie; Gardier, Alain M.; David, Denis J.; Humbert, Sandrine; Saudou, Frédéric

2013-01-01

Huntington’s disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreERT2/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders. PMID:24019939

Insights into neurogenesis and aging: potential therapy for degenerative disease?

PubMed Central

Marr, Robert A; Thomas, Rosanne M; Peterson, Daniel A

2010-01-01

Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age. PMID:20806052

Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice

PubMed Central

Yun, Sanghee; Donovan, Michael H.; Ross, Michele N.; Richardson, Devon R.; Reister, Robin; Farnbauch, Laure A.; Fischer, Stephanie J.; Riethmacher, Dieter; Gershenfeld, Howard K.; Lagace, Diane C.; Eisch, Amelia J.

2016-01-01

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety

Enriched Environment Increases PCNA and PARP1 Levels in Octopus vulgaris Central Nervous System: First Evidence of Adult Neurogenesis in Lophotrochozoa.

PubMed

Bertapelle, Carla; Polese, Gianluca; Di Cosmo, Anna

2017-06-01

Organisms showing a complex and centralized nervous system, such as teleosts, amphibians, reptiles, birds and mammals, and among invertebrates, crustaceans and insects, can adjust their behavior according to the environmental challenges. Proliferation, differentiation, migration, and axonal and dendritic development of newborn neurons take place in brain areas where structural plasticity, involved in learning, memory, and sensory stimuli integration, occurs. Octopus vulgaris has a complex and centralized nervous system, located between the eyes, with a hierarchical organization. It is considered the most "intelligent" invertebrate for its advanced cognitive capabilities, as learning and memory, and its sophisticated behaviors. The experimental data obtained by immunohistochemistry and western blot assay using proliferating cell nuclear antigen and poli (ADP-ribose) polymerase 1 as marker of cell proliferation and synaptogenesis, respectively, reviled cell proliferation in areas of brain involved in learning, memory, and sensory stimuli integration. Furthermore, we showed how enriched environmental conditions affect adult neurogenesis. © 2017 Wiley Periodicals, Inc.

Chronic exposure to WIN55,212-2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis.

PubMed

Abboussi, Oualid; Tazi, Abdelouahhab; Paizanis, Eleni; El Ganouni, Soumaya

2014-05-01

Several epidemiological studies show an increase in cannabis use among adolescents, especially in Morocco for being one of the major producers in the world. The neurobiological consequences of chronic cannabis use are still poorly understood. In addition, brain plasticity linked to ontogeny portrays adolescence as a period of vulnerability to the deleterious effects of drugs. The aim of this study was to investigate the behavioral neurogenic effects of chronic exposure to the cannabinoid agonist WIN55,212-2 during adolescence, by evaluating the emotional and cognitive performances, and the consequences on neurogenesis along the dorso-ventral axis of the hippocampus in adult rats. WIN55,212 was administered intraperitoneally (i.p.) once daily for 20 days to adolescent (27-30 PND) and adult Wistar rats (54-57 PND) at the dose of 1mg/kg. Following a 20 day washout period, emotional and cognitive functions were assessed by the Morris water maze test and the two-way active avoidance test. Twelve hours after, brains were removed and hippocampal neurogenesis was assessed using the doublecortin (DCX) as a marker for cell proliferation. Our results showed that chronic WIN55,212-2 treatment significantly increased thigmotaxis early in the training process whatever the age of treatment, induced spatial learning and memory deficits in adolescent but not adult rats in the Morris water maze test, while it had no significant effect in the active avoidance test during multitrial training in the shuttle box. In addition, the cognitive deficits assessed in adolescent rats were positively correlated to a decrease in the number of newly generated neurons in dorsal hippocampus. These data suggest that long term exposure to cannabinoids may affect more potently spatial learning and memory in adolescent compared to adult rats via a negative action on hippocampal plasticity. Copyright © 2014 Elsevier Inc. All rights reserved.

Developmental and Adult GAP-43 Deficiency in Mice Dynamically Alters Hippocampal Neurogenesis and Mossy Fiber Volume

PubMed Central

Latchney, Sarah E.; Masiulis, Irene; Zaccaria, Kimberly J.; Lagace, Diane C.; Powell, Craig M.; McCasland, James S.; Eisch, Amelia J.

2014-01-01

Growth Associated Protein-43 (GAP-43) is a pre-synaptic protein that plays key roles in axonal growth and guidance and in modulating synapse formation. Previous work has demonstrated that mice lacking one allele of this gene [GAP-43(+/-) mice] exhibit hippocampal structural abnormalities and impaired spatial learning and stress-induced behavioral withdrawal and anxiety (Zaccaria et al., 2010), behaviors that are dependent on proper hippocampal circuitry and function. Given the correlation between hippocampal function, synaptic connectivity, and neurogenesis, we tested if behaviorally-naïve GAP-43(+/-) mice had alterations in either neurogenesis or synaptic connectivity in the hippocampus during early postnatal development and young adulthood, and following behavior testing in older adults. To test our hypothesis, we examined hippocampal cell proliferation (Ki67), number of immature neuroblasts (DCX), and mossy fiber volume (synaptoporin) in behaviorally-naïve postnatal (P) day 9 (P9), P26, and behaviorally-experienced 5-7 month old GAP-43(+/-) and (+/+) littermate mice. P9 GAP-43(+/-) mice had fewer Ki67+ and DCX+ cells compared to (+/+) mice, particularly in the posterior dentate gyrus, and smaller mossy fiber volume in the same region. In young adulthood, however, male GAP-43(+/-) mice had more Ki67+ and DCX+ cells and greater mossy fiber volume in the posterior dentate gyrus relative to male (+/+). These increases were not seen in females. In 5-7 month old GAP-43(+/-) mice whose behaviors were the focus of our prior publication (Zaccaria et al., 2010), there was no global change in number of proliferating or immature neurons relative to (+/+) mice. However, more detailed analysis revealed fewer proliferative DCX+ cells in the anterior dentate gyrus of male GAP-43(+/-) mice compared to male (+/+) mice. This reduction was not observed in females. These results suggest that young GAP-43(+/-) mice have decreased hippocampal neurogenesis and synaptic connectivity

Neurogenesis Interferes with the Retrieval of Remote Memories: Forgetting in Neurocomputational Terms

ERIC Educational Resources Information Center

Weisz, Victoria I.; Argibay, Pablo F.

2012-01-01

In contrast to models and theories that relate adult neurogenesis with the processes of learning and memory, almost no solid hypotheses have been formulated that involve a possible neurocomputational influence of adult neurogenesis on forgetting. Based on data from a previous study that implemented a simple but complete model of the main…

TLX: A master regulator for neural stem cell maintenance and neurogenesis.

PubMed

Islam, Mohammed M; Zhang, Chun-Li

2015-02-01

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests that the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity. This article is part of a Special Issue entitled: Nuclear receptors in animal development. Copyright © 2014 Elsevier B.V. All rights reserved.

Cytoarchitecture and Ultrastructure of Neural Stem Cell Niches and Neurogenic Complexes Maintaining Adult Neurogenesis in the Olfactory Midbrain of Spiny Lobsters, Panulirus argus

PubMed Central

Schmidt, Manfred; Derby, Charles D.

2013-01-01

New interneurons are continuously generated in small proliferation zones within neuronal somata clusters in the olfactory deutocerebrum of adult decapod crustaceans. Each proliferation zone is connected to a clump of cells containing one neural stem cell (i.e., adult neuroblast), thus forming a “neurogenic complex.” Here we provide a detailed analysis of the cytoarchitecture of neurogenic complexes in adult spiny lobsters, Panulirus argus, based on transmission electron microscopy and labeling with cell-type-selective markers. The clump of cells is composed of unique bipolar clump-forming cells that collectively completely envelop the adult neuroblast and are themselves ensheathed by a layer of processes of multipolar cell body glia. An arteriole is attached to the clump of cells, but dye perfusion experiments show that hemolymph has no access to the interior of the clump of cells. Thus, the clump of cells fulfills morphological criteria of a protective stem cell niche, with clump-forming cells constituting the adult neuroblast’s microenvironment together with the cell body glia processes separating it from other tissue components. Bromodeoxyuridine pulse-chase experiments with short survival times suggest that adult neuroblasts are not quiescent but rather cycle actively during daytime. We propose a cell lineage model in which an asymmetrically dividing adult neuroblast repopulates the pool of neuronal progenitor cells in the associated proliferation zone. In conclusion, as in mammalian brains, adult neurogenesis in crustacean brains is fueled by neural stem cells that are maintained by stem cell niches that preserve elements of the embryonic microenvironment and contain glial and vascular elements. PMID:21523781

Cytoarchitecture and ultrastructure of neural stem cell niches and neurogenic complexes maintaining adult neurogenesis in the olfactory midbrain of spiny lobsters, Panulirus argus.

PubMed

Schmidt, Manfred; Derby, Charles D

2011-08-15

New interneurons are continuously generated in small proliferation zones within neuronal somata clusters in the olfactory deutocerebrum of adult decapod crustaceans. Each proliferation zone is connected to a clump of cells containing one neural stem cell (i.e., adult neuroblast), thus forming a "neurogenic complex." Here we provide a detailed analysis of the cytoarchitecture of neurogenic complexes in adult spiny lobsters, Panulirus argus, based on transmission electron microscopy and labeling with cell-type-selective markers. The clump of cells is composed of unique bipolar clump-forming cells that collectively completely envelop the adult neuroblast and are themselves ensheathed by a layer of processes of multipolar cell body glia. An arteriole is attached to the clump of cells, but dye perfusion experiments show that hemolymph has no access to the interior of the clump of cells. Thus, the clump of cells fulfills morphological criteria of a protective stem cell niche, with clump-forming cells constituting the adult neuroblast's microenvironment together with the cell body glia processes separating it from other tissue components. Bromodeoxyuridine pulse-chase experiments with short survival times suggest that adult neuroblasts are not quiescent but rather cycle actively during daytime. We propose a cell lineage model in which an asymmetrically dividing adult neuroblast repopulates the pool of neuronal progenitor cells in the associated proliferation zone. In conclusion, as in mammalian brains, adult neurogenesis in crustacean brains is fueled by neural stem cells that are maintained by stem cell niches that preserve elements of the embryonic microenvironment and contain glial and vascular elements. Copyright © 2011 Wiley-Liss, Inc.

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease.

PubMed

Donovan, Michael H; Yazdani, Umar; Norris, Rebekah D; Games, Dora; German, Dwight C; Eisch, Amelia J

2006-03-01

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies. J. Comp. Neurol. 495:70-83, 2006. (c) 2006 Wiley-Liss, Inc.

Organotypic Slice Cultures for Studies of Postnatal Neurogenesis

PubMed Central

Mosa, Adam J.; Wang, Sabrina; Tan, Yao Fang; Wojtowicz, J. Martin

2015-01-01

Here we describe a technique for studying hippocampal postnatal neurogenesis in the rodent brain using the organotypic slice culture technique. This method maintains the characteristic topographical morphology of the hippocampus while allowing direct application of pharmacological agents to the developing hippocampal dentate gyrus. Additionally, slice cultures can be maintained for up to 4 weeks and thus, allow one to study the maturation process of newborn granule neurons. Slice cultures allow for efficient pharmacological manipulation of hippocampal slices while excluding complex variables such as uncertainties related to the deep anatomic location of the hippocampus as well as the blood brain barrier. For these reasons, we sought to optimize organotypic slice cultures specifically for postnatal neurogenesis research. PMID:25867138

Responses of neurogenesis and neuroplasticity related genes to elevated CO2 levels in the brain of three teleost species.

PubMed

Lai, Floriana; Fagernes, Cathrine E; Bernier, Nicholas J; Miller, Gabrielle M; Munday, Philip L; Jutfelt, Fredrik; Nilsson, Göran E

2017-08-01

The continuous increase of anthropogenic CO 2 in the atmosphere resulting in ocean acidification has been reported to affect brain function in some fishes. During adulthood, cell proliferation is fundamental for fish brain growth and for it to adapt in response to external stimuli, such as environmental changes. Here we report the first expression study of genes regulating neurogenesis and neuroplasticity in brains of three-spined stickleback ( Gasterosteus aculeatus ), cinnamon anemonefish ( Amphiprion melanopus ) and spiny damselfish ( Acanthochromis polyacanthus ) exposed to elevated CO 2 The mRNA expression levels of the neurogenic differentiation factor (NeuroD) and doublecortin (DCX) were upregulated in three-spined stickleback exposed to high-CO 2 compared with controls, while no changes were detected in the other species. The mRNA expression levels of the proliferating cell nuclear antigen (PCNA) and the brain-derived neurotrophic factor (BDNF) remained unaffected in the high-CO 2 exposed groups compared to the control in all three species. These results indicate a species-specific regulation of genes involved in neurogenesis in response to elevated ambient CO 2 levels. The higher expression of NeuroD and DCX mRNA transcripts in the brain of high-CO 2 -exposed three-spined stickleback, together with the lack of effects on mRNA levels in cinnamon anemonefish and spiny damselfish, indicate differences in coping mechanisms among fish in response to the predicted-future CO 2 level. © 2017 The Author(s).

Neurogenesis Inhibition Prevents Enriched Environment to Prolong and Strengthen Social Recognition Memory, But Not to Increase BDNF Expression.

PubMed

Pereira-Caixeta, Ana Raquel; Guarnieri, Leonardo O; Pena, Roberta R; Dias, Thomáz L; Pereira, Grace Schenatto

2017-07-01

Hippocampus-dependent memories, such as social recognition (SRM), are modulated by neurogenesis. However, the precise role of newborn neurons in social memory processing is still unknown. We showed previously that 1 week of enriched environment (EE) is sufficient to increase neurogenesis in the hippocampus (HIP) and the olfactory bulb (OB) of mice. Here, we tested the hypothesis that 1 week of EE would enhance SRM persistence and strength. In addition, as brain-derived neurotrophic factor (BDNF) may mediate some of the neurogenesis effects on memory, we also tested if 1 week of EE would increase BDNF expression in the HIP and OB. We also predicted that neurogenesis inhibition would block the gain of function caused by EE on both SRM and BDNF expression. We found that EE increased BDNF expression in the HIP and OB of mice; at the same time, it allowed SRM to last longer. In addition, mice on EE had their SRM unaffected by memory consolidation interferences. As we predicted, treatment with the anti-mitotic drug AraC blocked EE effects on SRM. Surprisingly, neurogenesis inhibition did not affect the BDNF expression, increased by EE. Together, our results suggest that newborn neurons improve SRM persistence through a BDNF-independent mechanism. Interestingly, this study on social memory uncovered an unexpected dissociation between the effect of adult neurogenesis and BDNF expression on memory persistence, reassuring the idea that not all neurogenesis effects on memory are BDNF-dependent.

The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

PubMed

Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

2013-11-27

The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Running throughout middle-age improves memory function, hippocampal neurogenesis and BDNF levels in female C57Bl/6J mice

PubMed Central

Marlatt, Michael W.; Potter, Michelle C.; Lucassen, Paul J.; van Praag, Henriette

2012-01-01

Age-related memory loss is considered to commence at middle-age and coincides with reduced adult hippocampal neurogenesis and neurotrophin levels. Consistent physical activity at midlife may preserve brain-derived neurotrophic factor (BDNF) levels, new cell genesis and learning. In the present study, 9-month-old female C57Bl/6J mice were housed with or without a running wheel and injected with bromodeoxyuridine (BrdU) to label newborn cells. Morris water maze learning, open field activity and rotarod behavior were tested 1 and 6 months after exercise onset. Here we show that long-term running improved retention of spatial memory and modestly enhanced rotarod performance at 15 months of age. Both hippocampal neurogenesis and mature BDNF peptide levels were elevated after long-term running. Thus, regular exercise from the onset and during middle-age may maintain brain function. PMID:22252978

Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents

PubMed Central

Cavegn, Nicole; van Dijk, R. Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T.; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

2013-01-01

Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups. PMID:23616743

Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function

PubMed Central

Garza-Lombó, Carla; Gonsebatt, María E.

2016-01-01

The kinase mammalian target of rapamycin (mTOR) integrates signals triggered by energy, stress, oxygen levels, and growth factors. It regulates ribosome biogenesis, mRNA translation, nutrient metabolism, and autophagy. mTOR participates in various functions of the brain, such as synaptic plasticity, adult neurogenesis, memory, and learning. mTOR is present during early neural development and participates in axon and dendrite development, neuron differentiation, and gliogenesis, among other processes. Furthermore, mTOR has been shown to modulate lifespan in multiple organisms. This protein is an important energy sensor that is present throughout our lifetime its role must be precisely described in order to develop therapeutic strategies and prevent diseases of the central nervous system. The aim of this review is to present our current understanding of the functions of mTOR in neural development, the adult brain and aging. PMID:27378854

Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

PubMed

Val-Laillet, David; Guérin, Sylvie; Coquery, Nicolas; Nogret, Isabelle; Formal, Michèle; Romé, Véronique; Le Normand, Laurence; Meurice, Paul; Randuineau, Gwénaëlle; Guilloteau, Paul; Malbert, Charles-Henri; Parnet, Patricia; Lallès, Jean-Paul; Segain, Jean-Pierre

2018-04-01

Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neurocognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus ( P = 0.003), increased hippocampal granular cell layer volume ( P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon-like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals ( P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.-Val-Laillet, D., Guérin, S., Coquery, N., Nogret, I., Formal, M., Romé, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.-H., Parnet, P., Lallès, J.-P., Segain, J.-P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

Role of Cyclic Nucleotide-Gated Channels in the Modulation of Mouse Hippocampal Neurogenesis

PubMed Central

Podda, Maria Vittoria; Piacentini, Roberto; Barbati, Saviana Antonella; Mastrodonato, Alessia; Puzzo, Daniela; D’Ascenzo, Marcello; Leone, Lucia; Grassi, Claudio

2013-01-01

Neural stem cells generate neurons in the hippocampal dentate gyrus in mammals, including humans, throughout adulthood. Adult hippocampal neurogenesis has been the focus of many studies due to its relevance in processes such as learning and memory and its documented impairment in some neurodegenerative diseases. However, we are still far from having a complete picture of the mechanism regulating this process. Our study focused on the possible role of cyclic nucleotide-gated (CNG) channels. These voltage-independent channels activated by cyclic nucleotides, first described in retinal and olfactory receptors, have been receiving increasing attention for their involvement in several brain functions. Here we show that the rod-type, CNGA1, and olfactory-type, CNGA2, subunits are expressed in hippocampal neural stem cells in culture and in situ in the hippocampal neurogenic niche of adult mice. Pharmacological blockade of CNG channels did not affect cultured neural stem cell proliferation but reduced their differentiation towards the neuronal phenotype. The membrane permeant cGMP analogue, 8-Br-cGMP, enhanced neural stem cell differentiation to neurons and this effect was prevented by CNG channel blockade. In addition, patch-clamp recording from neuron-like differentiating neural stem cells revealed cGMP-activated currents attributable to ion flow through CNG channels. The current work provides novel insights into the role of CNG channels in promoting hippocampal neurogenesis, which may prove to be relevant for stem cell-based treatment of cognitive impairment and brain damage. PMID:23991183

Oxytocin stimulates hippocampal neurogenesis via oxytocin receptor expressed in CA3 pyramidal neurons.

PubMed

Lin, Yu-Ting; Chen, Chien-Chung; Huang, Chiung-Chun; Nishimori, Katsuhiko; Hsu, Kuei-Sen

2017-09-14

In addition to the regulation of social and emotional behaviors, the hypothalamic neuropeptide oxytocin has been shown to stimulate neurogenesis in adult dentate gyrus; however, the mechanisms underlying the action of oxytocin are still unclear. Taking advantage of the conditional knockout mouse model, we show here that endogenous oxytocin signaling functions in a non-cell autonomous manner to regulate survival and maturation of newly generated dentate granule cells in adult mouse hippocampus via oxytocin receptors expressed in CA3 pyramidal neurons. Through bidirectional chemogenetic manipulations, we also uncover a significant role for CA3 pyramidal neuron activity in regulating adult neurogenesis in the dentate gyrus. Retrograde neuronal tracing combined with immunocytochemistry revealed that the oxytocin neurons in the paraventricular nucleus project directly to the CA3 region of the hippocampus. Our findings reveal a critical role for oxytocin signaling in adult neurogenesis.Oxytocin (OXT) has been implicated in adult neurogenesis. Here the authors show that CA3 pyramidal cells in the adult mouse hippocampus express OXT receptors and receive inputs from hypothalamic OXT neurons; activation of OXT signaling in CA3 pyramidal cells promotes the survival and maturation of newborn neurons in the dentate gyrus in a non-cell autonomous manner.

Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion.

PubMed

Nakano, Tomonori; Kurimoto, Shigeru; Kato, Shuichi; Asano, Kenichi; Hirata, Takuma; Kiyama, Hiroshi; Hirata, Hitoshi

2018-06-01

Neurogenesis in the adult peripheral nervous system remains to be demonstrated. We transplanted embryonic neural stem cells into a Wallerian degenerating nerve graft and observed development of a nodular structure consisting of neurons, glia, and Schwann cells. Histological analysis revealed a structure loosely resembling the spinal cord, including a synaptic network that formed along the neuron. Furthermore, the new axons reinnervated the paralysed muscle, forming both de novo and revived neuromuscular junctions. Reinnervation of the paralysed muscle resulted in significantly greater mean wet muscle weight and muscle fibre cross-sectional area on the cell transplantation side than on the surgical control side (body weight 0.071 ± 0.011% vs. 0.051 ± 0.007%, p = .006; area 355.6 ± 345.2 vs. 114.0 ± 132.0 μm 2 , p < .001). Electrophysiological experiments demonstrated a functional connection between the neurons and muscle; hence, we identified this nodule as an ectopic ganglion. Surprisingly, in green rat experiments, most of these glial cells, but none of the neurons, expressed enhanced green fluorescent protein, suggesting that the cells constituting the ectopic ganglion were derived from both transplanted stem cells and endogenous stem cells. Such adult neurogenesis in a peripheral nerve related to neural stem cell transplantation has not been reported previously, and these results form the basis for a novel regenerative medicine approach in paralysed muscle. Copyright © 2018 John Wiley & Sons, Ltd.

Repeated exposure of the developing rat brain to magnetic resonance imaging did not affect neurogenesis, cell death or memory function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu, Changlian; Department of Pediatrics, The Third Affiliated Hospital, Zhengzhou University; Gao, Jianfeng

2011-01-07

Research highlights: {yields} The effect of MRI on the developing brain is a matter of debate. {yields} Repeated exposure to MRI did not affect neurogenesis. {yields} Memory function was not affected by repeated MRI during development. {yields} Neither late gestation nor young postnatal brains were affected by MRI. {yields} Repeated MRI did not cause cell death in the neurogenic region of the hippocampus. -- Abstract: The effect of magnetic fields on the brain is a matter of debate. The objective of this study was to investigate whether repeated exposure to strong magnetic fields, such as during magnetic resonance imaging (MRI),more » could elicit changes in the developing rat brain. Embryonic day 15 (E15) and postnatal day 14 (P14) rats were exposed to MRI using a 7.05 T MR system. The animals were anesthetized and exposed for 35 min per day for 4 successive days. Control animals were anesthetized but no MRI was performed. Body temperature was maintained at 37 {sup o}C. BrdU was injected after each session (50 mg/kg). One month later, cell proliferation, neurogenesis and astrogenesis in the dentate gyrus were evaluated, revealing no effects of MRI, neither in the E15, nor in the P14 group. DNA damage in the dentate gyrus in the P14 group was evaluated on P18, 1 day after the last session, using TUNEL staining. There was no difference in the number of TUNEL-positive cells after MRI compared with controls, neither in mature neurons, nor in newborn progenitors (BrdU/TUNEL double-labeled cells). Novel object recognition was performed to assess memory function 1 month after MRI. There was no difference in the recognition index observed after MRI compared with the control rats, neither for the E15, nor for the P14 group. In conclusion, repeated exposure to MRI did not appear to affect neurogenesis, cell death or memory function in rats, neither in late gestation (E15-E18) nor in young postnatal (P14-P17) rats.« less

Brain tumor - primary - adults

MedlinePlus

... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

Extremely weak magnetic field exposure may inhibit hippocampal neurogenesis of Sprague Dawley rats

NASA Astrophysics Data System (ADS)

Zhang, B.; Tian, L.; Cai, Y.; Xu, H.; Pan, Y.

2016-12-01

Hippocampal neurogenesis occurs throughout life in mammals brains and can be influenced by animals' age as well as environmental factors. Lines of evidences have shown that the magnetic field is an important physics environmental factor influencing many animals' growth and development, and extremely weak magnetic field exposures have been proved having serious adverse effects on the metabolism and behaviors in some animals, but few studies have examined the response of hippocampal neurogenesis to it. In the present study, we experimentally examined the extremely weak magnetic field effects on neurogenesis of the dentate gyrus (DG) of hippocampus of adult Sprague Dawley (SD) rats. Two types of magnetic fields were used, an extremely weak magnetic field (≤ 0.5μT) and the geomagnetic fields (strength 31-58μT) as controls. Thirty-two SD rats (3-weeks old) were used in this study. New cell survival in hippocampus was assessed at 0, 14, 28, and 42 days after a 7-day intraperitoneal injections of 5-bromo-2'-deoxyuridine (BrdU). Meanwhile, the amounts of immature neurons and mature neurons which are both related to hippocampal neurogenesis, as documented by labeling with doublecortin (DCX) and neuron (NeuN), respectively, were also analyzed at 0, 14, 28, and 42 days. Compared with geomagnetic field exposure groups, numbers of BrdU-, DCX-positive cells of DG of hippocampus in tested rats reduces monotonously and more rapidly after 14 days, and NeuN-positive cells significantly decreases after 28days when exposed in the extremely weak magnetic field condition. Our data suggest that the exposure to an extremely weak magnetic field may suppress the neurogenesis in DG of SD rats.

Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

PubMed Central

Juliandi, Berry; Tanemura, Kentaro; Igarashi, Katsuhide; Tominaga, Takashi; Furukawa, Yusuke; Otsuka, Maky; Moriyama, Noriko; Ikegami, Daigo; Abematsu, Masahiko; Sanosaka, Tsukasa; Tsujimura, Keita; Narita, Minoru; Kanno, Jun; Nakashima, Kinichi

2015-01-01

Summary Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running. PMID:26677766

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ji, Jian-feng; Ji, Sheng-jun; Sun, Rui

Highlights: •Forced exercise can ameliorate WBI induced cognitive impairment in our rat model. •Mature BDNF plays an important role in the effects of forced exercise. •Exercise may be a possible treatment of the radiation-induced cognitive impairment. -- Abstract: Cranial radiotherapy induces progressive and debilitating cognitive deficits, particularly in long-term cancer survivors, which may in part be caused by the reduction of hippocampal neurogenesis. Previous studies suggested that voluntary exercise can reduce the cognitive impairment caused by radiation therapy. However, there is no study on the effect of forced wheel exercise and little is known about the molecular mechanisms mediating themore » effect of exercise. In the present study, we investigated whether the forced running exercise after irradiation had the protective effects of the radiation-induced cognitive impairment. Sixty-four Male Sprague–Dawley rats received a single dose of 20 Gy or sham whole-brain irradiation (WBI), behavioral test was evaluated using open field test and Morris water maze at 2 months after irradiation. Half of the rats accepted a 3-week forced running exercise before the behavior detection. Immunofluorescence was used to evaluate the changes in hippocampal neurogenesis and Western blotting was used to assess changes in the levels of mature brain-derived neurotrophic factor (BDNF), phosphorylated tyrosine receptor kinase B (TrkB) receptor, protein kinase B (Akt), extracellular signal-regulated kinase (ERK), calcium-calmodulin dependent kinase (CaMKII), cAMP-calcium response element binding protein (CREB) in the BDNF–pCREB signaling. We found forced running exercise significantly prevented radiation-induced cognitive deficits, ameliorated the impairment of hippocampal neurogenesis and attenuated the down-regulation of these proteins. Moreover, exercise also increased behavioral performance, hippocampal neurogenesis and elevated BDNF–pCREB signaling in non

α2δ ligands act as positive modulators of adult hippocampal neurogenesis and prevent depression-like behavior induced by chronic restraint stress.

PubMed

Valente, Maria Maddalena; Bortolotto, Valeria; Cuccurazzu, Bruna; Ubezio, Federica; Meneghini, Vasco; Francese, Maria Teresa; Canonico, Pier Luigi; Grilli, Mariagrazia

2012-08-01

Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the α2δ1 subunit and the nuclear factor-κB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression.

MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

PubMed

Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

2017-03-15

Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

PubMed Central

Ko, Hyoung-Gon; Jang, Deok-Jin; Son, Junehee; Kwak, Chuljung; Choi, Jun-Hyeok; Ji, Young-Hoon; Lee, Yun-Sil; Son, Hyeon; Kaang, Bong-Kiun

2009-01-01

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory. PMID:19138433

Reactive Neuroblastosis in Huntington’s Disease: A Putative Therapeutic Target for Striatal Regeneration in the Adult Brain

PubMed Central

Kandasamy, Mahesh; Aigner, Ludwig

2018-01-01

The cellular and molecular mechanisms underlying the reciprocal relationship between adult neurogenesis, cognitive and motor functions have been an important focus of investigation in the establishment of effective neural replacement therapies for neurodegenerative disorders. While neuronal loss, reactive gliosis and defects in the self-repair capacity have extensively been characterized in neurodegenerative disorders, the transient excess production of neuroblasts detected in the adult striatum of animal models of Huntington’s disease (HD) and in post-mortem brain of HD patients, has only marginally been addressed. This abnormal cellular response in the striatum appears to originate from the selective proliferation and ectopic migration of neuroblasts derived from the subventricular zone (SVZ). Based on and in line with the term “reactive astrogliosis”, we propose to name the observed cellular event “reactive neuroblastosis”. Although, the functional relevance of reactive neuroblastosis is unknown, we speculate that this process may provide support for the tissue regeneration in compensating the structural and physiological functions of the striatum in lieu of aging or of the neurodegenerative process. Thus, in this review article, we comprehend different possibilities for the regulation of striatal neurogenesis, neuroblastosis and their functional relevance in the context of HD. PMID:29593498

Notch Receptor Expression in Neurogenic Regions of the Adult Zebrafish Brain

PubMed Central

de Oliveira-Carlos, Vanessa; Ganz, Julia; Hans, Stefan; Kaslin, Jan; Brand, Michael

2013-01-01

The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches. PMID:24039926

Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases.

PubMed

Zhang, Kuan; Zhu, Lingling; Fan, Ming

2011-01-01

Oxygen is vital to maintain the normal functions of almost all the organs, especially for brain which is one of the heaviest oxygen consumers in the body. The important roles of oxygen on the brain are not only reflected in the development, but also showed in the pathological processes of many cerebral diseases. In the current review, we summarized the oxygen levels in brain tissues tested by real-time measurements during the embryonic and adult neurogenesis, the cerebral diseases, or in the hyperbaric/hypobaric oxygen environment. Oxygen concentration is low in fetal brain (0.076-7.6 mmHg) and in adult brain (11.4-53.2 mmHg), decreased during stroke, and increased in hyperbaric oxygen environment. In addition, we reviewed the effects of oxygen tensions on the behaviors of neural stem cells (NSCs) in vitro cultures at different oxygen concentration (15.2-152 mmHg) and in vivo niche during different pathological states and in hyperbaric/hypobaric oxygen environment. Moderate hypoxia (22.8-76 mmHg) can promote the proliferation of NSCs and enhance the differentiation of NSCs into the TH-positive neurons. Next, we briefly presented the oxygen-sensitive molecular mechanisms regulating NSCs proliferation and differentiation recently found including the Notch, Bone morphogenetic protein and Wnt pathways. Finally, the future perspectives about the roles of oxygen on brain and NSCs were given.

A role for adult TLX-positive neural stem cells in learning and behaviour.

PubMed

Zhang, Chun-Li; Zou, Yuhua; He, Weimin; Gage, Fred H; Evans, Ronald M

2008-02-21

Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

Chronic Exposure to Uranium from Gestation: Effects on Behavior and Neurogenesis in Adulthood

PubMed Central

Dinocourt, Céline; Culeux, Cécile; Legrand, Marie; Elie, Christelle; Lestaevel, Philippe

2017-01-01

Uranium exposure leads to cerebral dysfunction involving for instance biochemical, neurochemical and neurobehavioral effects. Most studies have focused on mechanisms in uranium-exposed adult animals. However, recent data on developing animals have shown that the developing brain is also sensitive to uranium. Models of uranium exposure during brain development highlight the need to improve our understanding of the effects of uranium. In a model in which uranium exposure began from the first day of gestation, we studied the neurobehavioral consequences as well as the progression of hippocampal neurogenesis in animals from dams exposed to uranium. Our results show that 2-month-old rats exposed to uranium from gestational day 1 displayed deficits in special memory and a prominent depressive-like phenotype. Cell proliferation was not disturbed in these animals, as shown by 5-bromo-2′deoxyuridine (BrdU)/neuronal specific nuclear protein (NeuN) immunostaining in the dentate gyrus. However, in some animals, the pyramidal cell layer was dispersed in the CA3 region. From our previous results with the same model, the hypothesis of alterations of neurogenesis at prior stages of development is worth considering, but is probably not the only one. Therefore, further investigations are needed to correlate cerebral dysfunction and its underlying mechanistic pathways. PMID:28513543

Chronic Exposure to Uranium from Gestation: Effects on Behavior and Neurogenesis in Adulthood.

PubMed

Dinocourt, Céline; Culeux, Cécile; Legrand, Marie; Elie, Christelle; Lestaevel, Philippe

2017-05-17

Uranium exposure leads to cerebral dysfunction involving for instance biochemical, neurochemical and neurobehavioral effects. Most studies have focused on mechanisms in uranium-exposed adult animals. However, recent data on developing animals have shown that the developing brain is also sensitive to uranium. Models of uranium exposure during brain development highlight the need to improve our understanding of the effects of uranium. In a model in which uranium exposure began from the first day of gestation, we studied the neurobehavioral consequences as well as the progression of hippocampal neurogenesis in animals from dams exposed to uranium. Our results show that 2-month-old rats exposed to uranium from gestational day 1 displayed deficits in special memory and a prominent depressive-like phenotype. Cell proliferation was not disturbed in these animals, as shown by 5-bromo-2'deoxyuridine (BrdU)/neuronal specific nuclear protein (NeuN) immunostaining in the dentate gyrus. However, in some animals, the pyramidal cell layer was dispersed in the CA3 region. From our previous results with the same model, the hypothesis of alterations of neurogenesis at prior stages of development is worth considering, but is probably not the only one. Therefore, further investigations are needed to correlate cerebral dysfunction and its underlying mechanistic pathways.

Adolescent social isolation stress unmasks the combined effects of adolescent exercise and adult inflammation on hippocampal neurogenesis and behavior.

PubMed

Hueston, Cara M; Cryan, John F; Nolan, Yvonne M

2017-12-04

Hippocampal neurogenesis and associated cognitive behaviors are regulated by a number of factors including stress, inflammation, and exercise. However, the interplay between these factors remains relatively unexplored, especially across the lifespan. In the current study, the effect of social isolation stress during the adolescent period on neurogenesis and hippocampal-dependent cognitive behaviors was examined. This period of the lifespan has been demonstrated to be an important time for hippocampal growth and plasticity, during which changes to hippocampal neurogenesis may have long lasting effects. Additionally, we aimed to determine whether a 'dual-hit' of adolescent stress and adult chronic neuroinflammation would potentiate any negative effects of either insult alone. Lastly, the potential positive effects of exercise during adolescence was examined to determine whether exercise could attenuate any negative impacts of these insults on hippocampal neurogenesis and behavior. The results from the current study demonstrate that social isolation stress during adolescence followed by intra-hippocampal exposure to the pro-inflammatory cytokine IL-1β in early adulthood produces deficits in both spontaneous alternations and novel object recognition. Exercise attenuated deficits in neurogenesis and novel object recognition in mice that had been exposed to the 'dual-hit' of stress and neuroinflammation. These findings indicate that adolescence represents a key period of the lifespan during which external factors such as stress and exercise can impact on hippocampal development, and may alter the response to challenges such as neuroinflammation in later life. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice.

PubMed

Monteiro, Brisa M M; Moreira, Fabrício A; Massensini, André R; Moraes, Márcio F D; Pereira, Grace S

2014-02-01

Social memory consists of the information necessary to identify and recognize cospecifics and is essential to many forms of social interaction. Social memory persistence is strongly modulated by the animal's experiences. We have shown in previous studies that social isolation (SI) in adulthood impairs social memory persistence and that an enriched environment (EE) prevents this impairment. However, the mechanisms involved in the effects of SI and EE on social memory persistence remain unknown. We hypothesized that the mechanism by which SI and EE affect social memory persistence is through their modulation of neurogenesis. To investigate this hypothesis, adult mice were submitted to 7 days of one of the following conditions: group-housing in a standard (GH) or enriched environment (GH+EE); social isolation in standard (SI) or enriched environment (SI+EE). We observed an increase in the number of newborn neurons in the dentate gyrus of the hippocampus (DG) and glomerular layer of the olfactory bulb (OB) in both GH+EE and SI+EE mice. However, this increase of newborn neurons in the granule cell layer of the OB was restricted to the GH+EE group. Furthermore, both SI and SI+EE groups showed less neurogenesis in the mitral layer of the OB. Interestingly, the performance of the SI mice in the buried food-finding task was inferior to that of the GH mice. To further analyze whether increased neurogenesis is in fact the mechanism by which the EE improves social memory persistence in SI mice, we administered the mitotic inhibitor AraC or saline directly into the lateral ventricles of the SI+EE mice. We found that the AraC treatment decreased cell proliferation in both the DG and OB, and impaired social memory persistence in the SI+EE mice. Taken together, our results strongly suggest that neurogenesis is what supports social memory persistence in socially isolated mice. © 2013 Wiley Periodicals, Inc.

CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy.

PubMed

Zhou, Zhike; Liu, Tingting; Sun, Xiaoyu; Mu, Xiaopeng; Zhu, Gang; Xiao, Ting; Zhao, Mei; Zhao, Chuansheng

2017-03-30

It has been showed that enriched environment (EE) enhances the hippocampal neurogenesis and improves the cognitive impairments, accompanied by the increased expressions of stromal cell-derived factor-1 (SDF-1) in adult rats of temporal lobe epilepsy (TLE). We examined whether the enhanced neurogenesis and improved cognitive functions induced by EE following seizures were mediated by SDF-1/CXCR4 pathway. Therefore, we investigated the effects of the EE combined with CXCR4 antagonist AMD3100 on neurogenesis, cognitive functions and the long-term seizure activity in the TLE model. Adult rats were randomly assigned as control rats, rats treated with EE, rats subjected to status epilepticus (SE), post-SE rats treated with EE, AMD3100 or EE combined with AMD3100 respectively. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the frequency and mean duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze test. EE treatment significantly, as well as improved cognitive impairments and decreased long-term seizure activity, and that these effects might be mediated through SDF-1/CXCR4 pathway during the chronic stage of TLE. Although AMD3100 reversed the effect of EE on neurogenesis, it did not abolish the cognitive improvement induced by EE following seizures. More importantly, EE combined with AMD3100 treatment significantly suppressed long-term seizure activity, which provided promising evidences to treat TLE. Copyright © 2017 Elsevier B.V. All rights reserved.

Oxotremorine treatment restores hippocampal neurogenesis and ameliorates depression-like behaviour in chronically stressed rats.

PubMed

Veena, J; Srikumar, B N; Mahati, K; Raju, T R; Shankaranarayana Rao, B S

2011-09-01

Chronic stress results in cognitive impairment, affects hippocampal neurogenesis and is known to precipitate affective disorders such as depression. In addition to stress, neurotransmitters such as acetylcholine (ACh) modulate adult neurogenesis. Earlier, we have shown that oxotremorine, a cholinergic muscarinic agonist, ameliorates stress-induced cognitive impairment and restores cholinergic function. In the current study, we have looked into the possible involvement of adult neurogenesis in cognitive restoration by oxotremorine. Further, we have assessed the effect of oxotremorine treatment on depression-like behaviour and hippocampal volumes in stressed animals. Chronic restraint stressed rats were treated with either vehicle or oxotremorine. For neurogenesis studies, proliferation, survival and differentiation of the progenitor cells in the hippocampus were examined using 5'-bromo-2-deoxyuridine immunohistochemistry. Depression-like behaviour was evaluated using forced swim test (FST) and sucrose consumption test (SCT). Volumes were estimated using Cavalieri's estimator. Hippocampal neurogenesis was severely decreased in stressed rats. Ten days of oxotremorine treatment to stressed animals partially restored proliferation and survival, while it completely restored the differentiation of the newly formed cells. Stressed rats showed increased immobility and decreased sucrose preference in the FST and SCT, respectively, and oxotremorine ameliorated this depression-like behaviour. In addition, oxotremorine treatment recovered the stress-induced decrease in hippocampal volume. These results indicate that the restoration of impaired neurogenesis and hippocampal volume could be associated with the behavioural recovery by oxotremorine. Our results imply the muscarinic regulation of adult neurogenesis and incite the potential utility of cholinomimetics in ameliorating cognitive dysfunction in stress-related disorders.

Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus

PubMed Central

Hassouna, I; Ott, C; Wüstefeld, L; Offen, N; Neher, R A; Mitkovski, M; Winkler, D; Sperling, S; Fries, L; Goebbels, S; Vreja, I C; Hagemeyer, N; Dittrich, M; Rossetti, M F; Kröhnert, K; Hannke, K; Boretius, S; Zeug, A; Höschen, C; Dandekar, T; Dere, E; Neher, E; Rizzoli, S O; Nave, K-A; Sirén, A-L; Ehrenreich, H

2016-01-01

Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of ~20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a 15N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated 15N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration. PMID:26809838

Organotypic hippocampal slice culture from the adult mouse brain: a versatile tool for translational neuropsychopharmacology.

PubMed

Kim, Hyunjeong; Kim, Eosu; Park, Minsun; Lee, Eun; Namkoong, Kee

2013-03-05

One of the most significant barriers towards translational neuropsychiatry would be an unavailability of living brain tissues. Although organotypic brain tissue culture could be a useful alternative enabling observation of temporal changes induced by various drugs in living brain tissues, a proper method to establish a stable organotypic brain slice culture system using adult (rather than neonatal) hippocampus has been still elusive. In this study, we evaluated our simple method using the serum-free culture medium for successful adult organotypic hippocampal slice culture. Several tens of hippocampal slices from a single adult mouse (3-5 months old) were cultured in serum-free versus serum-containing conventional culture medium for 30 days and underwent various experiments to validate the effects of the existence of serum in the culture medium. Neither the excessive regression of neuronal viability nor metabolic deficiency was observed in the serum-free medium culture in contrast to the serum-containing medium culture. Despite such viability, newly generated immature neurons were scarcely detected in the serum-free culture, suggesting that the original neurons in the brain slice persist rather than being replaced by neurogenesis. Key structural features of in vivo neural tissue constituting astrocytes, neural processes, and pre- and post-synapses were also well preserved in the serum-free culture. In conclusion, using the serum-free culture medium, the adult hippocampal slice culture system will serve as a promising ex vivo tool for various fields of neuroscience, especially for studies on aging-related neuropsychiatric disorders or for high throughput screening of potential agents working against such disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Understanding How the Subcommissural Organ and Other Periventricular Secretory Structures Contribute via the Cerebrospinal Fluid to Neurogenesis

PubMed Central

Guerra, Maria M.; González, César; Caprile, Teresa; Jara, Maryoris; Vío, Karin; Muñoz, Rosa I.; Rodríguez, Sara; Rodríguez, Esteban M.

2015-01-01

The dynamic and molecular composition of the cerebrospinal fluid (CSF) and, consequently, the CSF physiology is much more complex and fascinating than the simplistic view held for decades. Signal molecules either transported from blood to CSF or secreted into the CSF by circumventricular organs and CSF-contacting neurons, use the CSF to reach their targets in the brain, including the pre- and postnatal neurogenic niche. The subcommissural organ (SCO), a highly conserved brain gland present throughout the vertebrate phylum, is one of the sources for signals, as well as the choroid plexus, tanycytes and CSF-contacting neurons. The SCO secretes into the fetal and adult CSF SCO-spondin, transthyretin, and basic fibroblast growth factor. These proteins participate in certain aspects of neurogenesis, such as cell cycle of neural stem cells, neuronal differentiation, and axon pathfinding. Through the CSF, the SCO-secretory proteins may reach virtually any target in the embryonic and adult central nervous system. Since the SCO continues to secrete throughout life span, it seems likely that the neurogenetic property of the SCO compounds would be targeted to the niches where neurogenesis continues in adulthood. This review is aimed to bring into discussion early and new evidence concerning the role(s) of the SCO, and the probable mechanisms by which SCO compounds can readily reach the neurogenic niche of the subventricular zone flowing with the CSF to participate in the regulation of the neurogenic niche. As we unfold the multiples trans-fluid talks between discrete brain domains we will have more tools to influence such talks. PMID:26778959

The Neurogenesis Actuator and NR2B/NMDA Receptor Antagonist Ro25-6981 Consistently Improves Spatial Memory Retraining Via Brain Region-Specific Gene Expression.

PubMed

Gruden, Marina A; Ratmirov, Alexander M; Storozheva, Zinaida I; Solovieva, Olga A; Sherstnev, Vladimir V; Sewell, Robert D E

2018-05-22

NR2B-containing NMDA (NR2B/NMDA) receptors are important in controlling neurogenesis and are involved in generating spatial memory. Ro25-6981 is a selective antagonist at these receptors and actuates neurogenesis and spatial memory. Inter-structural neuroanatomical profiles of gene expression regulating adult neurogenesis and neuroapoptosis require examination in the context of memory retrieval and reversal learning. The aim was to investigate spatial memory retrieval and reversal learning in relation to gene expression-linked neurogenetic processes following blockade of NR2B/NMDA receptors by Ro25-6981. Rats were trained in Morris water maze (MWM) platform location for 5 days. Ro25-6981 was administered (protocol days 6-7) followed by retraining (days 15-18 or 29-32). Platform location was tested (on days 19 or 33) then post-mortem brain tissue sampling (on days 20 or 34). The expression of three genes known to regulate cell proliferation (S100a6), differentiation (Ascl1), and apoptosis (Casp-3) were concomitantly evaluated in the hippocampus, prefrontal cortex, and cerebellum in relation to the MWM performance protocol. Following initial training, Ro25-6981 enhanced visuospatial memory retrieval performance during further retraining (protocol days 29-32) but did not influence visuospatial reversal learning (day 33). Hippocampal Ascl1 and Casp-3 expressions were correspondingly increased and decreased while cerebellar S100a6 and Casp-3 activities were decreased and increased respectively 27 days after Ro25-6981 treatment. Chronological analysis indicated a possible involvement of new mature neurons in the reconfiguration of memory processes. This was attended by behavioral/gene correlations which revealed direct links between spatial memory retrieval enhancement and modified gene activity induced by NR2B/NMDA receptor blockade and upregulation.

Oxygen, a Key Factor Regulating Cell Behavior during Neurogenesis and Cerebral Diseases

PubMed Central

Zhang, Kuan; Zhu, Lingling; Fan, Ming

2011-01-01

Oxygen is vital to maintain the normal functions of almost all the organs, especially for brain which is one of the heaviest oxygen consumers in the body. The important roles of oxygen on the brain are not only reflected in the development, but also showed in the pathological processes of many cerebral diseases. In the current review, we summarized the oxygen levels in brain tissues tested by real-time measurements during the embryonic and adult neurogenesis, the cerebral diseases, or in the hyperbaric/hypobaric oxygen environment. Oxygen concentration is low in fetal brain (0.076–7.6 mmHg) and in adult brain (11.4–53.2 mmHg), decreased during stroke, and increased in hyperbaric oxygen environment. In addition, we reviewed the effects of oxygen tensions on the behaviors of neural stem cells (NSCs) in vitro cultures at different oxygen concentration (15.2–152 mmHg) and in vivo niche during different pathological states and in hyperbaric/hypobaric oxygen environment. Moderate hypoxia (22.8–76 mmHg) can promote the proliferation of NSCs and enhance the differentiation of NSCs into the TH-positive neurons. Next, we briefly presented the oxygen-sensitive molecular mechanisms regulating NSCs proliferation and differentiation recently found including the Notch, Bone morphogenetic protein and Wnt pathways. Finally, the future perspectives about the roles of oxygen on brain and NSCs were given. PMID:21503147

Hippocampal neurogenesis and volume in migrating and wintering semipalmated sandpipers (Calidris pusilla)

PubMed Central

de Morais Magalhães, Nara Gyzely; Guerreiro Diniz, Daniel; Pereira Henrique, Ediely; Corrêa Pereira, Patrick Douglas; Matos Moraes, Isis Ananda; Damasceno de Melo, Mauro André; Sherry, David Francis; Wanderley Picanço Diniz, Cristovam

2017-01-01

Long distance migratory birds find their way by sensing and integrating information from a large number of cues in their environment. These cues are essential to navigate over thousands of kilometers and reach the same breeding, stopover, and wintering sites every year. The semipalmated sandpiper (Calidris pusilla) is a long-distance migrant that breeds in the arctic tundra of Canada and Alaska and winters on the northeast coast of South America. Its fall migration includes a 5,300-kilometer nonstop flight over the Atlantic Ocean. The avian hippocampus has been proposed to play a central role in the integration of multisensory spatial information for navigation. Hippocampal neurogenesis may contribute to hippocampal function and a variety of factors including cognitive activity, exercise, enrichment, diet and stress influence neurogenesis in the hippocampus. We quantified hippocampal neurogenesis and volume in adult migrating and wintering semipalmated sandpipers using stereological counts of doublecortin (DCX) immunolabeled immature neurons. We found that birds captured in the coastal region of Bragança, Brazil during the wintering period had more DCX positive neurons and larger volume in the hippocampus than individuals captured in the Bay of Fundy, Canada during fall migration. We also estimate the number of NeuN immunolabeled cells in migrating and wintering birds and found no significant differences between them. These findings suggest that, at this time window, neurogenesis just replaced neurons that might be lost during the transatlantic flight. Our findings also show that in active fall migrating birds, a lower level of adult hippocampal neurogenesis is associated with a smaller hippocampal formation. High levels of adult hippocampal neurogenesis and a larger hippocampal formation found in wintering birds may be late occurring effects of long distance migratory flight or the result of conditions the birds experienced while wintering. PMID:28591201

Hippocampal neurogenesis and volume in migrating and wintering semipalmated sandpipers (Calidris pusilla).

PubMed

de Morais Magalhães, Nara Gyzely; Guerreiro Diniz, Cristovam; Guerreiro Diniz, Daniel; Pereira Henrique, Ediely; Corrêa Pereira, Patrick Douglas; Matos Moraes, Isis Ananda; Damasceno de Melo, Mauro André; Sherry, David Francis; Wanderley Picanço Diniz, Cristovam

2017-01-01

Long distance migratory birds find their way by sensing and integrating information from a large number of cues in their environment. These cues are essential to navigate over thousands of kilometers and reach the same breeding, stopover, and wintering sites every year. The semipalmated sandpiper (Calidris pusilla) is a long-distance migrant that breeds in the arctic tundra of Canada and Alaska and winters on the northeast coast of South America. Its fall migration includes a 5,300-kilometer nonstop flight over the Atlantic Ocean. The avian hippocampus has been proposed to play a central role in the integration of multisensory spatial information for navigation. Hippocampal neurogenesis may contribute to hippocampal function and a variety of factors including cognitive activity, exercise, enrichment, diet and stress influence neurogenesis in the hippocampus. We quantified hippocampal neurogenesis and volume in adult migrating and wintering semipalmated sandpipers using stereological counts of doublecortin (DCX) immunolabeled immature neurons. We found that birds captured in the coastal region of Bragança, Brazil during the wintering period had more DCX positive neurons and larger volume in the hippocampus than individuals captured in the Bay of Fundy, Canada during fall migration. We also estimate the number of NeuN immunolabeled cells in migrating and wintering birds and found no significant differences between them. These findings suggest that, at this time window, neurogenesis just replaced neurons that might be lost during the transatlantic flight. Our findings also show that in active fall migrating birds, a lower level of adult hippocampal neurogenesis is associated with a smaller hippocampal formation. High levels of adult hippocampal neurogenesis and a larger hippocampal formation found in wintering birds may be late occurring effects of long distance migratory flight or the result of conditions the birds experienced while wintering.

Therapeutic application of neural stem cells and adult neurogenesis for neurodegenerative disorders: regeneration and beyond.

PubMed

Latchney, Sarah E; Eisch, Amelia J

With the growth of the aging population and increasing life expectancy, the diagnosis of age-related neurodegenerative diseases is predicted to increase 12% by 2030. There is urgent need to develop better and novel treatments for disorders like Alzheimer's, Huntington's, and Parkinson's diseases. As these neurodegenerative diseases are customarily defined by the progressive loss of neurons, treatment strategies have traditionally focused on replacing neurons lost during disease progression. To this end, the self-renewing and multipotent properties of neural stem/precursor cells (NSPCs) that exist in the adult brain suggest that NSPCs could contribute to a therapy for replacement of damaged or lost neurons. Although a wealth of research demonstrates the proof-of-concept that NSPC transplantation has therapeutic potential, there are considerable barriers between the theory of cell transplantation and clinical implementation. However, a new view on harnessing the power of NSPC for treatment of neurodegenerative disorders has emerged, and focuses on treating neuropathological aspects of the disease prior to the appearance of overt neuronal loss. For example, rather than merely replacing lost neurons, NSPCs are now being considered for their ability to provide trophic support. Here we review the evolution of how the field has considered application of NSPCs for treatment of neurodegeneration disorders. We discuss the challenges posed by the "traditional" view of neurodegeneration - overt cell loss - for utilization of NSPCs for treatment of these disorders. We also review the emergence of an alternative strategy that involves fine-tuning the neurogenic capacity of existing adult NSPCs so that they are engineered to address disease-specific pathologies at specific time points during the trajectory of disease. We conclude with our opinion that for this strategy to become a translational reality, it requires a thorough understanding of NSPCs, the dynamic process of adult

Effects of Extremely Low-Frequency Electromagnetic Fields on Neurogenesis and Cognitive Behavior in an Experimental Model of Hippocampal Injury

PubMed Central

Sakhaie, Mohammad Hassan; Pourheydar, Bagher; Majd, Zahra; Atefimanesh, Pezhman

2017-01-01

Exposure to extremely low-frequency electromagnetic fields may induce constant modulation in neuronal plasticity. In recent years, tremendous efforts have been made to design a suitable strategy for enhancing adult neurogenesis, which seems to be deterred due to brain senescence and several neurodegenerative diseases. In this study, we evaluated the effects of ELF-EMF on neurogenesis and memory, following treatment with trimethyltin chloride (TMT) as a neurotoxicant. The mice in all groups (n = 56) were injected with BrdU during the experiment for seven consecutive days to label newborn cells. Spatial memory was assessed by the Morris water maze (MWM) test. By the end of the experiment, neurogenesis and neuronal differentiation were assessed in the hippocampus, using immunohistochemistry and Western blot analysis. Based on the findings, exposure to ELF-EMF enhanced spatial learning and memory in the MWM test. ELF-EMF exposure significantly enhanced the number of BrdU+ and NeuN+ cells in the dentate gyrus of adult mice (P < 0.001 and P < 0.05, resp.). Western blot analysis revealed significant upregulation of NeuroD2 in ELF-EMF-exposed mice compared to the TMT-treated group (P < 0.05). These findings suggest that ELF-EMF might have clinical implications for the improvement of neurodegenerative processes and could help develop a novel therapeutic approach in regenerative medicine. PMID:29259353

Cellular Composition and Organization of the Subventricular Zone and Rostral Migratory Stream in the Adult and Neonatal Common Marmoset Brain

PubMed Central

Sawamoto, Kazunobu; Hirota, Yuki; Alfaro-Cervello, Clara; Soriano-Navarro, Mario; He, Xiaoping; Hayakawa-Yano, Yoshika; Yamada, Masayuki; Hikishima, Keigo; Tabata, Hidenori; Iwanami, Akio; Nakajima, Kazunori; Toyama, Yoshiaki; Itoh, Toshio; Alvarez-Buylla, Arturo; Garcia-Verdugo, Jose Manuel; Okano, Hideyuki

2014-01-01

The adult subventricular zone (SVZ) of the lateral ventricle contains neural stem cells. In rodents, these cells generate neuroblasts that migrate as chains toward the olfactory bulb along the rostral migratory stream (RMS). The neural-stem-cell niche at the ventricular wall is conserved in various animal species, including primates. However, it is unclear how the SVZ and RMS organization in nonhuman primates relates to that of rodents and humans. Here we studied the SVZ and RMS of the adult and neonatal common marmoset (Callithrix jacchus), a New World primate used widely in neuroscience, by electron microscopy, and immunohistochemical detection of cell-type-specific markers. The marmoset SVZ contained cells similar to type B, C, and A cells of the rodent SVZ in their marker expression and morphology. The adult marmoset SVZ had a three-layer organization, as in the human brain, with ependymal, hypocellular, and astro-cyte-ribbon layers. However, the hypocellular layer was very thin or absent in the adult-anterior and neonatal SVZ. Anti-PSA-NCAM staining of the anterior SVZ in whole-mount ventricular wall preparations of adult marmosets revealed an extensive network of elongated cell aggregates similar to the neuroblast chains in rodents. Time-lapse recordings of marmoset SVZ explants cultured in Matrigel showed the neuroblasts migrating in chains, like rodent type A cells. These results suggest that some features of neurogenesis and neuronal migration in the SVZ are common to marmosets, humans, and rodents. This basic description of the adult and neonatal marmoset SVZ will be useful for future studies on adult neurogenesis in primates. PMID:21246550

Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels.

PubMed

Vignisse, Julie; Sambon, Margaux; Gorlova, Anna; Pavlov, Dmitrii; Caron, Nicolas; Malgrange, Brigitte; Shevtsova, Elena; Svistunov, Andrey; Anthony, Daniel C; Markova, Natalyia; Bazhenova, Natalyia; Coumans, Bernard; Lakaye, Bernard; Wins, Pierre; Strekalova, Tatyana; Bettendorff, Lucien

2017-07-01

Thiamine is essential for normal brain function and its deficiency causes metabolic impairment, specific lesions, oxidative damage and reduced adult hippocampal neurogenesis (AHN). Thiamine precursors with increased bioavailability, especially benfotiamine, exert neuroprotective effects not only for thiamine deficiency (TD), but also in mouse models of neurodegeneration. As it is known that AHN is impaired by stress in rodents, we exposed C57BL6/J mice to predator stress for 5 consecutive nights and studied the proliferation (number of Ki67-positive cells) and survival (number of BrdU-positive cells) of newborn immature neurons in the subgranular zone of the dentate gyrus. In stressed mice, the number of Ki67- and BrdU-positive cells was reduced compared to non-stressed animals. This reduction was prevented when the mice were treated (200mg/kg/day in drinking water for 20days) with thiamine or benfotiamine, that were recently found to prevent stress-induced behavioral changes and glycogen synthase kinase-3β (GSK-3β) upregulation in the CNS. Moreover, we show that thiamine and benfotiamine counteract stress-induced bodyweight loss and suppress stress-induced anxiety-like behavior. Both treatments induced a modest increase in the brain content of free thiamine while the level of thiamine diphosphate (ThDP) remained unchanged, suggesting that the beneficial effects observed are not linked to the role of this coenzyme in energy metabolism. Predator stress increased hippocampal protein carbonylation, an indicator of oxidative stress. This effect was antagonized by both thiamine and benfotiamine. Moreover, using cultured mouse neuroblastoma cells, we show that in particular benfotiamine protects against paraquat-induced oxidative stress. We therefore hypothesize that thiamine compounds may act by boosting anti-oxidant cellular defenses, by a mechanism that still remains to be unveiled. Our study demonstrates, for the first time, that thiamine and benfotiamine prevent

Neuroprotection and enhanced neurogenesis by extract from the tropical plant Knema laurina after inflammatory damage in living brain tissue.

PubMed

Häke, Ines; Schönenberger, Silvia; Neumann, Jens; Franke, Katrin; Paulsen-Merker, Katrin; Reymann, Klaus; Ismail, Ghazally; Bin Din, Laily; Said, Ikram M; Latiff, A; Wessjohann, Ludger; Zipp, Frauke; Ullrich, Oliver

2009-01-03

Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic survey, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that alcoholic extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly anti-inflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protected living brain tissue from microglia-mediated inflammatory damage at a concentration of 30 microg/ml. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, IkB-phosphorylation and subsequently NF-kB-translocation in microglia cells. K. laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from K. laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from K. laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury.

Seasonal variation in telencephalon cell proliferation in adult female tsinling dwarf skinks (Scincella tsinlingensis).

PubMed

Yang, Chun; Wang, Limin; Xing, Xiangyang; Gao, Yanyan; Guo, Li

2017-05-01

In adult mammals, neurogenesis is limited to specific niches in the brain, but considerable adult neurogenesis occurs in many brain regions in non-mammalian vertebrates. Non-mammalian vertebrates provide invaluable comparative material for understanding the core mechanisms of adult neural stem cell maintenance and fate, but phylogenetic differences in adult neurogenesis remain poorly understood. Here we examine cell proliferation seasonality in the telencephalon of adult female tsinling dwarf skinks (Scincella tsinlingensis) by injecting wild animals caught in summer, autumn and spring, and animals caught in autumn and raised under winter conditions, with 5-Bromo-2'-deoxyuridine (BrdU). Then, 24h, 7d and 28d after BrdU administration we examined brain tissue and quantified BrdU-labeled cells as a marker of neuronal proliferation. The highest number of labeled cells in the telencephalon was found in the 7d group. BrdU-positive cells were widely distributed in the anterior olfactory nucleus (AON), medial cortex (MC), dorsal cortex (DC), lateral cortex (LC), dorsal ventricular ridge (DVR), septum (SP), striatum (STR) and nucleus sphericus (NS). No BrdU-positive cells were detected in olfactory bulbs or elsewhere in the telencephalon. The highest proliferative levels were found in the AON in autumn. The NS exhibited relatively high levels of cell proliferation. The proliferative rate in the AON fluctuated seasonally as autumn>summer>spring>winter. Glial fibrillary acidic protein-positive cells were widely distributed in the telencephalon and their fibrous processes extended into brain parenchyma and anchored in the meninges. Doublecortin-positive newborn neurons of the subventricular zone appeared to migrate into the cerebral cortex via the radial migratory stream. Cell proliferation in the telencephalon of adult female S. tsinlingensis fluctuates seasonally, especially in regions related to olfactory memory. This is the first demonstration of proliferative activity in

Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity

PubMed Central

Pohodich, Amy E; Yalamanchili, Hari; Raman, Ayush T; Wan, Ying-Wooi; Gundry, Michael; Hao, Shuang; Jin, Haijing; Tang, Jianrong; Liu, Zhandong

2018-01-01

Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer’s patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17–24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders. PMID:29570050

The Coumarin Derivative Osthole Stimulates Adult Neural Stem Cells, Promotes Neurogenesis in the Hippocampus, and Ameliorates Cognitive Impairment in APP/PS1 Transgenic Mice.

PubMed

Kong, Liang; Hu, Yu; Yao, Yingjia; Jiao, Yanan; Li, Shaoheng; Yang, Jingxian

2015-01-01

It is believed that neuronal death caused by abnormal deposition of amyloid-beta peptide is the major cause of the cognitive decline in Alzheimer's disease. Adult neurogenesis plays a key role in the rescue of impaired neurons and amelioration of cognitive impairment. In the present study, we demonstrated that osthole, a natural coumarin derivative, was capable of promoting neuronal stem cell (NSC) survival and inducing NSC proliferation in vitro. In osthole-treated APP/PS1 transgenic mice, a significant improvement in learning and memory function was seen, which was associated with a significant increase in the number of new neurons (Ki67(+)/NF-M(+)) and a decrease in apoptotic cells in the hippocampal region of the brain. These observations suggested that osthole promoted NSC proliferation, supported neurogenesis, and thus efficiently rescued impaired neurons in the hippocampus and ameliorated cognitive impairment. We also found that osthole treatment activated the Notch pathway and upregulated the expression of self-renewal genes Notch 1 and Hes 1 mRNA in NSCs. However, when Notch activity was blocked by the γ-secretase inhibitor DAPT, the augmentation of Notch 1 and Hes 1 protein was ameliorated, and the proliferation-inducing effect of osthole was abolished, suggesting that the effects of osthole are at least in part mediated by activation of the Notch pathway.

Engraftment of enteric neural progenitor cells into the injured adult brain.

PubMed

Belkind-Gerson, Jaime; Hotta, Ryo; Whalen, Michael; Nayyar, Naema; Nagy, Nandor; Cheng, Lily; Zuckerman, Aaron; Goldstein, Allan M; Dietrich, Jorg

2016-01-25

A major area of unmet need is the development of strategies to restore neuronal network systems and to recover brain function in patients with neurological disease. The use of cell-based therapies remains an attractive approach, but its application has been challenging due to the lack of suitable cell sources, ethical concerns, and immune-mediated tissue rejection. We propose an innovative approach that utilizes gut-derived neural tissue for cell-based therapies following focal or diffuse central nervous system injury. Enteric neuronal stem and progenitor cells, able to differentiate into neuronal and glial lineages, were isolated from the postnatal enteric nervous system and propagated in vitro. Gut-derived neural progenitors, genetically engineered to express fluorescent proteins, were transplanted into the injured brain of adult mice. Using different models of brain injury in combination with either local or systemic cell delivery, we show that transplanted enteric neuronal progenitor cells survive, proliferate, and differentiate into neuronal and glial lineages in vivo. Moreover, transplanted cells migrate extensively along neuronal pathways and appear to modulate the local microenvironment to stimulate endogenous neurogenesis. Our findings suggest that enteric nervous system derived cells represent a potential source for tissue regeneration in the central nervous system. Further studies are needed to validate these findings and to explore whether autologous gut-derived cell transplantation into the injured brain can result in functional neurologic recovery.

Pretreatment with minocycline restores neurogenesis in the subventricular zone and subgranular zone of the hippocampus after ketamine exposure in neonatal rats.

PubMed

Lu, Yang; Giri, P K; Lei, Shan; Zheng, Juan; Li, Weisong; Wang, Ning; Chen, Xinlin; Lu, Haixia; Zuo, Zhiyi; Liu, Yong; Zhang, Pengbo

2017-06-03

Ketamine is commonly used for anesthesia in pediatric patients. Recent studies indicated that ketamine exposure in the developing brain can induce neuroapoptosis and disturb normal neurogenesis, which will result in long-lasting cognitive impairment. Minocycline exerts neuroprotection against a wide range of toxic insults in neurodegenerative disease models. In the present study, we investigated whether the disturbed neurogenesis and behavioral deficits after ketamine neonatal exposure could be alleviated by minocycline. Postnatal day (PND)7 Sprague-Dawley rat pups randomly received either normal saline, ketamine, or minocycline 30min prior to ketamine administration, respectively. The rats were decapitated at PND14 for the detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. The protein expression of p-Akt, p-GSK-3β in the SVZ and SGZ at 12h after anesthesia, PND10 and PND14 were assessed by western blotting analysis. At PND 42-47, spatial learning and memory abilities were measured by the Morris water maze in all groups. Our data showed that ketamine exposure in neonatal rats resulted in neurogenetic damage and persistent cognitive deficits, and that pretreatment with minocycline eliminated the brain development damage and improved the behavioral function in adult rats. Moreover, the protection of minocycline is associated with the PI3K/Akt signaling pathway. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response.

PubMed

Klempin, Friederike; Mosienko, Valentina; Matthes, Susann; Villela, Daniel C; Todiras, Mihail; Penninger, Josef M; Bader, Michael; Santos, Robson A S; Alenina, Natalia

2018-04-20

Physical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1-7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1-7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism.

A Neuroprotective Brain-penetrating Endopeptidase Fusion Protein Ameliorates Alzheimer Disease Pathology and Restores Neurogenesis*

PubMed Central

Spencer, Brian; Verma, Inder; Desplats, Paula; Morvinski, Dinorah; Rockenstein, Ed; Adame, Anthony; Masliah, Eliezer

2014-01-01

Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials. PMID:24825898

Progranulin regulates neurogenesis in the developing vertebrate retina.

PubMed

Walsh, Caroline E; Hitchcock, Peter F

2017-09-01

We evaluated the expression and function of the microglia-specific growth factor, Progranulin-a (Pgrn-a) during developmental neurogenesis in the embryonic retina of zebrafish. At 24 hpf pgrn-a is expressed throughout the forebrain, but by 48 hpf pgrn-a is exclusively expressed by microglia and/or microglial precursors within the brain and retina. Knockdown of Pgrn-a does not alter the onset of neurogenic programs or increase cell death, however, in its absence, neurogenesis is significantly delayed-retinal progenitors fail to exit the cell cycle at the appropriate developmental time and postmitotic cells do not acquire markers of terminal differentiation, and microglial precursors do not colonize the retina. Given the link between Progranulin and cell cycle regulation in peripheral tissues and transformed cells, we analyzed cell cycle kinetics among retinal progenitors following Pgrn-a knockdown. Depleting Pgrn-a results in a significant lengthening of the cell cycle. These data suggest that Pgrn-a plays a dual role during nervous system development by governing the rate at which progenitors progress through the cell cycle and attracting microglial progenitors into the embryonic brain and retina. Collectively, these data show that Pgrn-a governs neurogenesis by regulating cell cycle kinetics and the transition from proliferation to cell cycle exit and differentiation. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 77: 1114-1129, 2017. © 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc.

Adult Neurogenesis in the Mammalian Hippocampus: Why the Dentate Gyrus?

ERIC Educational Resources Information Center

Drew, Liam J.; Fusi, Stefano; Hen, René

2013-01-01

In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity…

The effect of phloretin on synaptic proteins and adult hippocampal neurogenesis in Aβ (1-42)-injected male Wistar rats.

PubMed

Ghumatkar, Priya; Peshattiwar, Vaibhavi; Patil, Sachin; Muke, Suraj; Whitfield, David; Howlett, David; Francis, Paul; Sathaye, Sadhana

2018-04-23

Considering the deleterious effect of Aβ1-42, a study was designed to evaluate the effect of phloretin on altered synaptic proteins and adult hippocampal neurogenesis in Aβ1-42-injected Wistar rats. The rats were pretreated with 5 mg/kg p.o dose of phloretin and donepezil (positive control) for 28 days, followed by intrahippocampal injections of aggregated Aβ1-42. After termination, perfused brains were isolated and subjected to Western blot and immunohistochemistry (IHC) analysis. The Western blot revealed that Aβ1-42-injected rats had significantly low levels of synaptophysin as compared to sham control. Phloretin pretreatment significantly protected the presynaptic protein synaptophysin against the effects of Aβ1-42. There were no significant changes in the levels of PSD95 between different groups. The IHC findings showed that Aβ1-42 significantly reduced the Ki67 and DCX in the dentate gyrus as compared to sham control. However, phloretin significantly improved the number of Ki67- and DCX-positive neurons in the dentate gyrus region as compared to Aβ1-42 group. This study demonstrated the protective effect of phloretin on synaptophysin and adult neuronal proliferating cells in Aβ1-42-injected rats. The encouraging findings highlight the potential of phloretin as a dietary supplement targeting key therapeutic mechanisms in neurodegenerative disorders such as AD. © 2018 Royal Pharmaceutical Society.

Mouse embryonic stem cell-derived cells reveal niches that support neuronal differentiation in the adult rat brain.

PubMed

Maya-Espinosa, Guadalupe; Collazo-Navarrete, Omar; Millán-Aldaco, Diana; Palomero-Rivero, Marcela; Guerrero-Flores, Gilda; Drucker-Colín, René; Covarrubias, Luis; Guerra-Crespo, Magdalena

2015-02-01

A neurogenic niche can be identified by the proliferation and differentiation of its naturally residing neural stem cells. However, it remains unclear whether "silent" neurogenic niches or regions suitable for neural differentiation, other than the areas of active neurogenesis, exist in the adult brain. Embryoid body (EB) cells derived from embryonic stem cells (ESCs) are endowed with a high potential to respond to specification and neuralization signals of the embryo. Hence, to identify microenvironments in the postnatal and adult rat brain with the capacity to support neuronal differentiation, we transplanted dissociated EB cells to conventional neurogenic and non-neurogenic regions. Our results show a neuronal differentiation pattern of EB cells that was dependent on the host region. Efficient neuronal differentiation of EB cells occurred within an adjacent region to the rostral migratory stream. EB cell differentiation was initially patchy and progressed toward an even distribution along the graft by 15-21 days post-transplantation, giving rise mostly to GABAergic neurons. EB cells in the striatum displayed a lower level of neuronal differentiation and derived into a significant number of astrocytes. Remarkably, when EB cells were transplanted to the striatum of adult rats after a local ischemic stroke, increased number of neuroblasts and neurons were observed. Unexpectedly, we determined that the adult substantia nigra pars compacta, considered a non-neurogenic area, harbors a robust neurogenic environment. Therefore, neurally uncommitted cells derived from ESCs can detect regions that support neuronal differentiation within the adult brain, a fundamental step for the development of stem cell-based replacement therapies. © 2014 AlphaMed Press.

Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior

PubMed Central

Sah, A; Schmuckermair, C; Sartori, S B; Gaburro, S; Kandasamy, M; Irschick, R; Klimaschewski, L; Landgraf, R; Aigner, L; Singewald, N

2012-01-01

Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety. PMID:23047242

Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model.

PubMed

Guidi, Sandra; Stagni, Fiorenza; Bianchi, Patrizia; Ciani, Elisabetta; Giacomini, Andrea; De Franceschi, Marianna; Moldrich, Randal; Kurniawan, Nyoman; Mardon, Karine; Giuliani, Alessandro; Calzà, Laura; Bartesaghi, Renata

2014-02-01

Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators

PubMed Central

Hueston, C M; Cryan, J F; Nolan, Y M

2017-01-01

Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators.

PubMed

Hueston, C M; Cryan, J F; Nolan, Y M

2017-04-04

Adolescence is a critical period for brain maturation. Deciphering how disturbances to the central nervous system at this time affect structure, function and behavioural outputs is important to better understand any long-lasting effects. Hippocampal neurogenesis occurs during development and continues throughout life. In adulthood, integration of these new cells into the hippocampus is important for emotional behaviour, cognitive function and neural plasticity. During the adolescent period, maturation of the hippocampus and heightened levels of hippocampal neurogenesis are observed, making alterations to neurogenesis at this time particularly consequential. As stress negatively affects hippocampal neurogenesis, and adolescence is a particularly stressful time of life, it is important to investigate the impact of stressor exposure at this time on hippocampal neurogenesis and cognitive function. Adolescence may represent not only a time for which stress can have long-lasting effects, but is also a critical period during which interventions, such as exercise and diet, could ameliorate stress-induced changes to hippocampal function. In addition, intervention at this time may also promote life-long behavioural changes that would aid in fostering increased hippocampal neurogenesis and cognitive function. This review addresses both the acute and long-term stress-induced alterations to hippocampal neurogenesis and cognition during the adolescent period, as well as changes to the stress response and pubertal hormones at this time which may result in differential effects than are observed in adulthood. We hypothesise that adolescence may represent an optimal time for healthy lifestyle changes to have a positive and long-lasting impact on hippocampal neurogenesis, and to protect against stress-induced deficits. We conclude that future research into the mechanisms underlying the susceptibility of the adolescent hippocampus to stress, exercise and diet and the consequent effect

A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis.

PubMed

Spencer, Brian; Verma, Inder; Desplats, Paula; Morvinski, Dinorah; Rockenstein, Ed; Adame, Anthony; Masliah, Eliezer

2014-06-20

Alzheimer disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-β peptide (Aβ) in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intracranial viral vector delivery or ex vivo manipulated intracranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v. infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38-amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t½ of 24 h and accumulated to 1.7% of injected dose at 24 h following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses, and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of C-terminal neuropeptide Y fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis.

PubMed

Hua, Yao; Huang, Xin-Yan; Zhou, Li; Zhou, Qi-Gang; Hu, Yao; Luo, Chun-Xia; Li, Fei; Zhu, Dong-Ya

2008-10-01

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. Our recent study shows that endogenous nitric oxide (NO) contributes to chronic mild stress (CMS)-induced depression by suppressing hippocampal neurogenesis. The aim of this study was to investigate the effects of exogenous NO in CMS-induced depression in young adult mice. In normal mice, administration of a pure NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate; 0.4 mg/kg, i.p., for 7 days) produced an antidepressant-like effect and significantly increased hippocampal neurogenesis. The mice exposed to CMS exhibited behavioral changes typical of depression and impaired neurogenesis in the hippocampus. Treatment with DETA/NONOate (0.4 mg/kg, i.p., for 7 days) reversed CMS-induced behavioral despair and hippocampal neurogenesis impairment. We treated mice with a telomerase inhibitor 3'-azido-deoxythymidine (AZT; 100 mg/kg, i.p., for 14 days) to disrupt neurogenesis. From day 4 to day 11 of AZT treatment, mice were injected with DETA/NONOate (0.4 mg/kg, i.p., for 7 days). Disrupting hippocampal neurogenesis blocked the antidepressant effect of DETA/NONOate. Our findings suggest that exogenous NO benefits chronic stress-induced depression by stimulating hippocampal neurogenesis and may represent a novel approach for the treatment of depressive disorders.

Derivation of Neural Stem Cells from Human Adult Peripheral CD34+ Cells for an Autologous Model of Neuroinflammation

PubMed Central

Wang, Tongguang; Choi, Elliot; Monaco, Maria Chiara G.; Campanac, Emilie; Medynets, Marie; Do, Thao; Rao, Prashant; Johnson, Kory R.; Elkahloun, Abdel G.; Von Geldern, Gloria; Johnson, Tory; Subramaniam, Sriram; Hoffman, Dax; Major, Eugene; Nath, Avindra

2013-01-01

Proinflammatory factors from activated T cells inhibit neurogenesis in adult animal brain and cultured human fetal neural stem cells (NSC). However, the role of inhibition of neurogenesis in human neuroinflammatory diseases is still uncertain because of the difficulty in obtaining adult NSC from patients. Recent developments in cell reprogramming suggest that NSC may be derived directly from adult fibroblasts. We generated NSC from adult human peripheral CD34+ cells by transfecting the cells with Sendai virus constructs containing Sox2, Oct3/4, c-Myc and Klf4. The derived NSC could be differentiated to glial cells and action potential firing neurons. Co-culturing NSC with activated autologous T cells or treatment with recombinant granzyme B caused inhibition of neurogenesis as indicated by decreased NSC proliferation and neuronal differentiation. Thus, we have established a unique autologous in vitro model to study the pathophysiology of neuroinflammatory diseases that has potential for usage in personalized medicine. PMID:24303066

Absence of the neurogenesis-dependent nuclear receptor TLX induces inflammation in the hippocampus.

PubMed

Kozareva, Danka A; Hueston, Cara M; Ó'Léime, Ciarán S; Crotty, Suzanne; Dockery, Peter; Cryan, John F; Nolan, Yvonne M

2017-08-20

The orphan nuclear receptor TLX (Nr2e1) is a key regulator of hippocampal neurogenesis. Impaired adult hippocampal neurogenesis has been reported in neurodegenerative and psychiatric conditions including dementia and stress-related depression. Neuroinflammation is also implicated in the neuropathology of these disorders, and has been shown to negatively affect hippocampal neurogenesis. To investigate a role for TLX in hippocampal neuroinflammation, we assessed microglial activation in the hippocampus of mice with a spontaneous deletion of TLX. Results from our study suggest that a lack of TLX is implicated in deregulation of microglial phenotype and that consequently, the survival and function of newborn cells in the hippocampus is impaired. TLX may be an important target in understanding inflammatory-associated impairments in neurogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Adult neural stem cells: The promise of the future

PubMed Central

Taupin, Philippe

2007-01-01

Stem cells are self-renewing undifferentiated cells that give rise to multiple types of specialized cells of the body. In the adult, stem cells are multipotents and contribute to homeostasis of the tissues and regeneration after injury. Until recently, it was believed that the adult brain was devoid of stem cells, hence unable to make new neurons and regenerate. With the recent evidences that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS), the adult brain has the potential to regenerate and may be amenable to repair. The function(s) of NSCs in the adult CNS remains the source of intense research and debates. The promise of the future of adult NSCs is to redefine the functioning and physiopathology of the CNS, as well as to treat a broad range of CNS diseases and injuries. PMID:19300610

Neuronal survival in the brain: neuron type-specific mechanisms.

PubMed

Pfisterer, Ulrich; Khodosevich, Konstantin

2017-03-02

Neurogenic regions of mammalian brain produce many more neurons that will eventually survive and reach a mature stage. Developmental cell death affects both embryonically produced immature neurons and those immature neurons that are generated in regions of adult neurogenesis. Removal of substantial numbers of neurons that are not yet completely integrated into the local circuits helps to ensure that maturation and homeostatic function of neuronal networks in the brain proceed correctly. External signals from brain microenvironment together with intrinsic signaling pathways determine whether a particular neuron will die. To accommodate this signaling, immature neurons in the brain express a number of transmembrane factors as well as intracellular signaling molecules that will regulate the cell survival/death decision, and many of these factors cease being expressed upon neuronal maturation. Furthermore, pro-survival factors and intracellular responses depend on the type of neuron and region of the brain. Thus, in addition to some common neuronal pro-survival signaling, different types of neurons possess a variety of 'neuron type-specific' pro-survival constituents that might help them to adapt for survival in a certain brain region. This review focuses on how immature neurons survive during normal and impaired brain development, both in the embryonic/neonatal brain and in brain regions associated with adult neurogenesis, and emphasizes neuron type-specific mechanisms that help to survive for various types of immature neurons. Importantly, we mainly focus on in vivo data to describe neuronal survival specifically in the brain, without extrapolating data obtained in the PNS or spinal cord, and thus emphasize the influence of the complex brain environment on neuronal survival during development.

Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis.

PubMed

Mouri, Akihiro; Ukai, Mayu; Uchida, Mizuki; Hasegawa, Sho; Taniguchi, Masayuki; Ito, Takahiro; Hida, Hirotake; Yoshimi, Akira; Yamada, Kiyofumi; Kunimoto, Shohko; Ozaki, Norio; Nabeshima, Toshitaka; Noda, Yukihiro

2018-05-01

Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis

PubMed Central

Tosetti, Valentina; Sassone, Jenny; Ferri, Anna L. M.; Taiana, Michela; Bedini, Gloria; Nava, Sara; Brenna, Greta; Di Resta, Chiara; Pareyson, Davide; Di Giulio, Anna Maria; Carelli, Stephana

2017-01-01

The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT. PMID:28704421

Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.

PubMed

Tosetti, Valentina; Sassone, Jenny; Ferri, Anna L M; Taiana, Michela; Bedini, Gloria; Nava, Sara; Brenna, Greta; Di Resta, Chiara; Pareyson, Davide; Di Giulio, Anna Maria; Carelli, Stephana; Parati, Eugenio A; Gorio, Alfredo

2017-01-01

The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR) is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA) Sox2 overlapping transcript (Sox2OT) plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE), and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.

Evaluating the functional state of adult-born neurons in the adult dentate gyrus of the hippocampus: from birth to functional integration.

PubMed

Aguilar-Arredondo, Andrea; Arias, Clorinda; Zepeda, Angélica

2015-01-01

Hippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function.

Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice.

PubMed

Kuzumaki, Naoko; Ikegami, Daigo; Imai, Satoshi; Narita, Michiko; Tamura, Rie; Yajima, Marie; Suzuki, Atsuo; Miyashita, Kazuhiko; Niikura, Keiichi; Takeshima, Hideyuki; Ando, Takayuki; Ushijima, Toshikazu; Suzuki, Tsutomu; Narita, Minoru

2010-09-01

A variety of mechanisms that contribute to the accumulation of age-related damage and the resulting brain dysfunction have been identified. Recently, decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. However, the molecular mechanism of decreased neurogenesis with aging is still unclear. In the present study, we investigated whether aging decreases neurogenesis accompanied by the activation of microglia and astrocytes, which increases the expression of IL-1beta in the hippocampus, and whether in vitro treatment with IL-1beta in neural stem cells directly impairs neurogenesis. Ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were increased in the dentate gyrus of the hippocampus of 28-month-old mice. Furthermore, the mRNA level of IL-1beta was significantly increased without related histone modifications. Moreover, a significant increase in lysine 9 on histone H3 (H3K9) trimethylation at the promoter of NeuroD (a neural progenitor cell marker) was observed in the hippocampus of aged mice. In vitro treatment with IL-1beta in neural stem cells prepared from whole brain of E14.5 mice significantly increased H3K9 trimethylation at the NeuroD promoter. These findings suggest that aging may decrease hippocampal neurogenesis via epigenetic modifications accompanied by the activation of microglia and astrocytes with the increased expression of IL-1beta in the hippocampus.

Left Brain/Right Brain Learning for Adult Education.

ERIC Educational Resources Information Center

Garvin, Barbara

1986-01-01

Contrasts and compares the theory and practice of adult education as it relates to the issue of right brain/left brain learning. The author stresses the need for a whole-brain approach to teaching and suggests that adult educators, given their philosophical directions, are the perfect potential users of this integrated system. (Editor/CT)

Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals.

PubMed

Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth; Miller, Elaine; Ariza, Jeanelle; Kienzle, Devon; Plank, Kaela; Noctor, Stephen C; Van de Water, Judy

2016-01-01

Autism spectrum disorders (ASDs) affect up to 1 in 68 children. Autism-specific autoantibodies directed against fetal brain proteins have been found exclusively in a subpopulation of mothers whose children were diagnosed with ASD or maternal autoantibody-related autism. We tested the impact of autoantibodies on brain development in mice by transferring human antigen-specific IgG directly into the cerebral ventricles of embryonic mice during cortical neurogenesis. We show that autoantibodies recognize radial glial cells during development. We also show that prenatal exposure to autism-specific maternal autoantibodies increased stem cell proliferation in the subventricular zone (SVZ) of the embryonic neocortex, increased adult brain size and weight, and increased the size of adult cortical neurons. We propose that prenatal exposure to autism-specific maternal autoantibodies directly affects radial glial cell development and presents a viable pathologic mechanism for the maternal autoantibody-related prenatal ASD risk factor. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Genetic Approaches to Reveal the Connectivity of Adult-Born Neurons

PubMed Central

Arenkiel, Benjamin R.

2011-01-01

Much has been learned about the environmental and molecular factors that influence the division, migration, and programmed cell death of adult-born neurons in the mammalian brain. However, detailed knowledge of the mechanisms that govern the formation and maintenance of functional circuit connectivity via adult neurogenesis remains elusive. Recent advances in genetic technologies now afford the ability to precisely target discrete brain tissues, neuronal subtypes, and even single neurons for vital reporter expression and controlled activity manipulations. Here, I review current viral tracing methods, heterologous receptor expression systems, and optogenetic technologies that hold promise toward elucidating the wiring diagrams and circuit properties of adult-born neurons. PMID:21519388

Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation.

PubMed

Ryan, Sinead M; O'Keeffe, Gerard W; O'Connor, Caitriona; Keeshan, Karen; Nolan, Yvonne M

2013-10-01

Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features. Copyright © 2013 Elsevier Inc. All rights reserved.

Dose-response and relative biological effectiveness of fast neutrons: induction of apoptosis and inhibition of neurogenesis in the hippocampus of adult mice.

PubMed

Yang, Miyoung; Kim, Joong-Sun; Song, Myoung-Sub; Kim, Jong-Choon; Shin, Taekyun; Lee, Seung-Sook; Kim, Sung-Ho; Moon, Changjong

2010-06-01

Our study compared the effects of high linear energy transfer (LET) fast neutrons on the induction of apoptosis and reduction of neurogenesis in the hippocampus of adult ICR mice with those of low-LET (60)Co gamma-rays, to evaluate the relative biological effectiveness (RBE) of fast neutrons in the adult hippocampal dentate gyrus (DG). The mice were exposed to 35 MeV fast neutrons or (60)Co gamma-rays. We evaluated acutely the incidence of apoptosis and expression of Ki-67 (a protein marker for cell proliferation originally defined by the monoclonal antibody Kiel-67) and doublecortin (DCX: an immature progenitor neuron marker) in the hippocampus after a single whole-body irradiation. The number of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling (TUNEL)-positive apoptotic nuclei in the DG increased and both Ki-67- and DCX-positive cells declined in a dose-dependent pattern, with fast neutrons or gamma-rays. In the hippocampus, which showed an apoptosis frequency between 2 and 8 per DG, the RBE of fast neutrons was approximately 1.9. Additionally, the inhibitory effects of fast neutrons on the expression frequencies of Ki-67 (4-8) and DCX (8-32) were approximately 3.2 and 2.5 times, respectively, the effects of gamma-rays at the same dose. Increased apoptotic cell death and decreased neurogenesis in the hippocampal DG were seen in a dose-dependent pattern after exposure to fast neutrons and gamma-rays. In addition, the different rate of hippocampal neurogenesis between different radiation qualities may be an index of RBE.

Neurogenesis as a new target for the development of antidepressant drugs.

PubMed

Pascual-Brazo, Jesus; Baekelandt, Veerle; Encinas, Juan Manuel

2014-01-01

Thirteen years have passed since the neurogenic hypothesis of depression was postulated. One of its aspects, that decreased neurogenesis could be causative of the onset of depression has been difficult to prove. Another aspect, the prediction that increasing neurogenesis would not only be supportive but also required to produce clinical results by antidepressants has gathered experimental validation. Thus a question arises: should new antidepressant strategies based solely on increasing neurogenesis be pursued? At the risk of disappointing the audience, we will not provide a straight answer to this question in this review, but we do hope to enlighten the reader regarding what is known about adult hippocampal neurogenesis, the indications and evidence of its involvement in the onset and treatment of depression, and the advances that have been made in the field in recent years. As we will recount here, the main body of support in favor of the neurogenic hypothesis of depression is based more on intimation than actual proof. However the rare examples that provide support are sufficiently robust to justify investment of resources and effort to clarify the issue, even if the involvement of neurogenesis, both in the etiology and the treatment of depression, is only partial and comprises only subtle components of this complex mental disorder.

PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats

PubMed Central

Winocur, Gordon; Wojtowicz, J. Martin; Shevtsova, Olga; Fuller, Steven; Ghanbari, Hossein A.

2018-01-01

Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals. PAN-811 in saline was delivered through i.p. injection, 10 min following each saline (Saline+PAN-811 group) or MTX/5-FU (Chemo+PAN-811 group) treatment, while equal volumes of saline were delivered to Saline and Chemo groups. Over Days 31–66, rats were administered tests of spatial memory, nonmatching-to-sample rule learning, and discrimination learning, which are sensitive to dysfunction in hippocampus, frontal lobe and striatum, respectively. On Day 97, neurogenesis was immnunohistochemically evaluated by counting doublecortin-positive (DCX+) cells in the dentate gyrus (DG). The results demonstrated that the Chemo group was impaired on the three cognitive tasks, but co-administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. In addition, MTX/5-FU reduced DCX+ cells to 67% of that in Saline control rats, an effect that was completely blocked by PAN-811 co-administration. Overall, we present the first evidence that PAN-811 protects cognitive functions and preserves neurogenesis from deleterious effects of MTX/5-FU. The current findings provide a basis for rapid clinical translation to determine the effect of PAN-811 on CICI in human. PMID:29370277

Salvianolic acid A alleviates ischemic brain injury through the inhibition of inflammation and apoptosis and the promotion of neurogenesis in mice.

PubMed

Chien, Mei-Yin; Chuang, Cheng-Hung; Chern, Chang-Ming; Liou, Kou-Tong; Liu, Der-Zen; Hou, Yu-Chang; Shen, Yuh-Chiang

2016-10-01

Salvianolic acid A (SalA), a chemical type of caffeic acid trimer, has drawn great attention for its potent bioactivities against ischemia-induced injury both in vitro and in vivo. In this study, we evaluated SalA's protective effects against acute ischemic stroke by inducing middle cerebral artery occlusion/reperfusion (MCAO) injuries in mice. Treatment of the mice with SalA (50 and 100μg/kg, i.v.) at 2h after MCAO enhanced their survival rate, improved their moving activity, and ameliorated the severity of brain infarction and apoptosis seen in the mice by diminishing pathological changes such as the extensive breakdown of the blood-brain barrier (BBB), nitrosative stress, and the activation of an inflammatory transcriptional factor p65 nuclear factor-kappa B (NF-κB) and a pro-apoptotic kinase p25/Cdk5. SalA also intensively limited cortical infarction and promoted the expression of neurogenesis protein near the peri-infarct cortex and subgranular zone of the hippocampal dentate gyrus by compromising the activation of GSK3β and p25/Cdk5, which in turn upregulated β-catenin, doublecortin (DCX), and Bcl-2, most possibly through the activation of PI3K/Akt signaling via the upregulation of brain-derived neurotrophic factor. We conclude that SalA blocks inflammatory responses by impairing NF-κB signaling, thereby limiting inflammation/nitrosative stress and preserving the integrity of the BBB; SalA also concomitantly promotes neurogenesis-related protein expression by compromising GSK3β/Cdk5 activity to enhance the expression levels of β-catenin/DCX and Bcl-2 for neuroprotection. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurogenesis-mediated forgetting minimizes proactive interference.

PubMed

Epp, Jonathan R; Silva Mera, Rudy; Köhler, Stefan; Josselyn, Sheena A; Frankland, Paul W

2016-02-26

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting.

Neurogenesis-mediated forgetting minimizes proactive interference

PubMed Central

Epp, Jonathan R.; Silva Mera, Rudy; Köhler, Stefan; Josselyn, Sheena A.; Frankland, Paul W.

2016-01-01

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting. PMID:26917323

Paradox of pattern separation and adult neurogenesis: A dual role for new neurons balancing memory resolution and robustness.

PubMed

Johnston, Stephen T; Shtrahman, Matthew; Parylak, Sarah; Gonçalves, J Tiago; Gage, Fred H

2016-03-01

Hippocampal adult neurogenesis is thought to subserve pattern separation, the process by which similar patterns of neuronal inputs are transformed into distinct neuronal representations, permitting the discrimination of highly similar stimuli in hippocampus-dependent tasks. However, the mechanism by which immature adult-born dentate granule neurons cells (abDGCs) perform this function remains unknown. Two theories of abDGC function, one by which abDGCs modulate and sparsify activity in the dentate gyrus and one by which abDGCs act as autonomous coding units, are generally suggested to be mutually exclusive. This review suggests that these two mechanisms work in tandem to dynamically regulate memory resolution while avoiding memory interference and maintaining memory robustness. Copyright © 2015 Elsevier Inc. All rights reserved.

Can adult neural stem cells create new brains? Plasticity in the adult mammalian neurogenic niches: realities and expectations in the era of regenerative biology.

PubMed

Kazanis, Ilias

2012-02-01

Since the first experimental reports showing the persistence of neurogenic activity in the adult mammalian brain, this field of neurosciences has expanded significantly. It is now widely accepted that neural stem and precursor cells survive during adulthood and are able to respond to various endogenous and exogenous cues by altering their proliferation and differentiation activity. Nevertheless, the pathway to therapeutic applications still seems to be long. This review attempts to summarize and revisit the available data regarding the plasticity potential of adult neural stem cells and of their normal microenvironment, the neurogenic niche. Recent data have demonstrated that adult neural stem cells retain a high level of pluripotency and that adult neurogenic systems can switch the balance between neurogenesis and gliogenesis and can generate a range of cell types with an efficiency that was not initially expected. Moreover, adult neural stem and precursor cells seem to be able to self-regulate their interaction with the microenvironment and even to contribute to its synthesis, altogether revealing a high level of plasticity potential. The next important step will be to elucidate the factors that limit this plasticity in vivo, and such a restrictive role for the microenvironment is discussed in more details.

Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation

PubMed Central

Lee, Myoung-Hwa; Amin, Niranjana D.; Venkatesan, Arun; Wang, Tongguang; Tyagi, Richa; Pant, Harish C.; Nath, Avindra

2013-01-01

Human immunodeficiency virus (HIV) infection associated neurocognitive disorders (HAND) is accompanied with brain atrophy. In these patients, impairment of adult neurogenesis and neurite outgrowth in the hippocampus may contribute to the cognitive dysfunction. Although running exercises can enhance neurogenesis and normalize neurite outgrowth, the underlying molecular mechanisms are not well understood. The HIV envelope protein, gp120, has been shown to impair neurogenesis. Using a gp120 transgenic mouse model, we demonstrate that exercise stimulated neural progenitor cell (NPC) proliferation in the hippocampal dentate gyrus and increased the survival rate and generation of newborn cells. However sustained exercise activity was necessary since the effects were reversed by detraining. Exercise also normalized dendritic outgrowth of neurons. Furthermore, it also increased the expression of hippocampal brainderived neurotrophic factor (BDNF) and normalized hyperactivation of cyclin-dependent kinase 5 (Cdk5). Hyper-activated Cdk5 or gp120 treatment led to aberrant neurite outgrowth and BDNF treatment normalized the neurite outgrowth in NPC cultures. These results suggest that sustained exercise has trophic activity on the neuronal lineage which is mediated by Cdk5 modulation of the BDNF pathway. PMID:23982957

Studies of HVC Plasticity in Adult Canaries Reveal Social Effects and Sex Differences as Well as Limitations of Multiple Markers Available to Assess Adult Neurogenesis

PubMed Central

Shevchouk, Olesya T.; Ball, Gregory F.; Cornil, Charlotte A.

2017-01-01

In songbirds, neurogenesis in the song control nucleus HVC is sensitive to the hormonal and social environment but the dynamics of this process is difficult to assess with a single exogenous marker of new neurons. We simultaneously used three independent markers to investigate HVC neurogenesis in male and female canaries. Males were castrated, implanted with testosterone and housed either alone (M), with a female (M-F) or with another male (M-M) while females were implanted with 17β-estradiol and housed with a male (F-M). All subjects received injections of the two thymidine analogues, BrdU and of EdU, respectively 21 and 10 days before brain collection. Cells containing BrdU or EdU or expressing doublecortin (DCX), which labels newborn neurons, were quantified. Social context and sex differentially affected total BrdU+, EdU+, BrdU+EdU- and DCX+ populations. M-M males had a higher density of BrdU+ cells in the ventricular zone adjacent to HVC and of EdU+ in HVC than M-F males. M birds had a higher ratio of BrdU+EdU- to EdU+ cells than M-F subjects suggesting higher survival of newer neurons in the former group. Total number of HVC DCX+ cells was lower in M-F than in M-M males. Sex differences were also dependent of the type of marker used. Several technical limitations associated with the use of these multiple markers were also identified. These results indicate that proliferation, recruitment and survival of new neurons can be independently affected by environmental conditions and effects can only be fully discerned through the use of multiple neurogenesis markers. PMID:28141859

Studies of HVC Plasticity in Adult Canaries Reveal Social Effects and Sex Differences as Well as Limitations of Multiple Markers Available to Assess Adult Neurogenesis.

PubMed

Shevchouk, Olesya T; Ball, Gregory F; Cornil, Charlotte A; Balthazart, Jacques

2017-01-01

In songbirds, neurogenesis in the song control nucleus HVC is sensitive to the hormonal and social environment but the dynamics of this process is difficult to assess with a single exogenous marker of new neurons. We simultaneously used three independent markers to investigate HVC neurogenesis in male and female canaries. Males were castrated, implanted with testosterone and housed either alone (M), with a female (M-F) or with another male (M-M) while females were implanted with 17β-estradiol and housed with a male (F-M). All subjects received injections of the two thymidine analogues, BrdU and of EdU, respectively 21 and 10 days before brain collection. Cells containing BrdU or EdU or expressing doublecortin (DCX), which labels newborn neurons, were quantified. Social context and sex differentially affected total BrdU+, EdU+, BrdU+EdU- and DCX+ populations. M-M males had a higher density of BrdU+ cells in the ventricular zone adjacent to HVC and of EdU+ in HVC than M-F males. M birds had a higher ratio of BrdU+EdU- to EdU+ cells than M-F subjects suggesting higher survival of newer neurons in the former group. Total number of HVC DCX+ cells was lower in M-F than in M-M males. Sex differences were also dependent of the type of marker used. Several technical limitations associated with the use of these multiple markers were also identified. These results indicate that proliferation, recruitment and survival of new neurons can be independently affected by environmental conditions and effects can only be fully discerned through the use of multiple neurogenesis markers.

The cellular and molecular basis of cnidarian neurogenesis.

PubMed

Rentzsch, Fabian; Layden, Michael; Manuel, Michaël

2017-01-01

Neurogenesis initiates during early development and it continues through later developmental stages and in adult animals to enable expansion, remodeling, and homeostasis of the nervous system. The generation of nerve cells has been analyzed in detail in few bilaterian model organisms, leaving open many questions about the evolution of this process. As the sister group to bilaterians, cnidarians occupy an informative phylogenetic position to address the early evolution of cellular and molecular aspects of neurogenesis and to understand common principles of neural development. Here we review studies in several cnidarian model systems that have revealed significant similarities and interesting differences compared to neurogenesis in bilaterian species, and between different cnidarian taxa. Cnidarian neurogenesis is currently best understood in the sea anemone Nematostella vectensis, where it includes epithelial neural progenitor cells that express transcription factors of the soxB and atonal families. Notch signaling regulates the number of these neural progenitor cells, achaete-scute and dmrt genes are required for their further development and Wnt and BMP signaling appear to be involved in the patterning of the nervous system. In contrast to many vertebrates and Drosophila, cnidarians have a high capacity to generate neurons throughout their lifetime and during regeneration. Utilizing this feature of cnidarian biology will likely allow gaining new insights into the similarities and differences of embryonic and regenerative neurogenesis. The use of different cnidarian model systems and their expanding experimental toolkits will thus continue to provide a better understanding of evolutionary and developmental aspects of nervous system formation. WIREs Dev Biol 2017, 6:e257. doi: 10.1002/wdev.257 For further resources related to this article, please visit the WIREs website. © 2016 The Authors. WIREs Developmental Biology published by Wiley Periodicals, Inc.

Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion.

PubMed

Liu, Yanqun; Tang, Guanghui; Zhang, Zhijun; Wang, Yongting; Yang, Guo-Yuan

2014-09-05

Current studies demonstrated that metformin is not only a hypoglycemic drug, but also a neuro-protective agent. However, the effect of metformin during ischemic brain injury is unclear. The aim of the present study is to explore the effect of metformin during ischemic brain injury. Adult male CD1 mice underwent 90min transient middle cerebral artery occlusion. Metformin (200mg/kg) was given at the time of reperfusion daily until sacrifice. Results showed that metformin treatment significantly reduced ischemia-induced brain atrophy volume compared to the control (p<0.05). Immunostaining results showed that the microvessel density in the peri-focal region of metformin treated mice was greatly increased compared to the control (p<0.05). Similarly, the numbers of BrdU+/DCX+ and nestin+ cells in the subventricular zone were increased in metformin treated mice compared to the control (p<0.05). Furthermore, we demonstrated that metformin treatment activated AMPK signaling pathway and promoted eNOS phosphorylation. Thus, we concluded that metformin promoted focal angiogenesis and neurogenesis and attenuated ischemia-induced brain injury in mice after middle cerebral artery occlusion, suggesting that metformin is a potential new drug for ischemic stroke therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Genome-wide analysis of the bHLH gene family in planarians identifies factors required for adult neurogenesis and neuronal regeneration.

PubMed

Cowles, Martis W; Brown, David D R; Nisperos, Sean V; Stanley, Brianna N; Pearson, Bret J; Zayas, Ricardo M

2013-12-01

In contrast to most well-studied model organisms, planarians have a remarkable ability to completely regenerate a functional nervous system from a pluripotent stem cell population. Thus, planarians provide a powerful model to identify genes required for adult neurogenesis in vivo. We analyzed the basic helix-loop-helix (bHLH) family of transcription factors, many of which are crucial for nervous system development and have been implicated in human diseases. However, their potential roles in adult neurogenesis or central nervous system (CNS) function are not well understood. We identified 44 planarian bHLH homologs, determined their patterns of expression in the animal and assessed their functions using RNAi. We found nine bHLHs expressed in stem cells and neurons that are required for CNS regeneration. Our analyses revealed that homologs of coe, hes (hesl-3) and sim label progenitors in intact planarians, and following amputation we observed an enrichment of coe(+) and sim(+) progenitors near the wound site. RNAi knockdown of coe, hesl-3 or sim led to defects in CNS regeneration, including failure of the cephalic ganglia to properly pattern and a loss of expression of distinct neuronal subtype markers. Together, these data indicate that coe, hesl-3 and sim label neural progenitor cells, which serve to generate new neurons in uninjured or regenerating animals. Our study demonstrates that this model will be useful to investigate how stem cells interpret and respond to genetic and environmental cues in the CNS and to examine the role of bHLH transcription factors in adult tissue regeneration.

High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention.

PubMed

Kim, Ah Hyun; Chun, Hye Jeong; Lee, Seulah; Kim, Hyung Sik; Lee, Jaewon

2017-08-01

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. Copyright © 2017 Elsevier Ltd. All rights reserved.

Regulation of endogenous neural stem/progenitor cells for neural repair—factors that promote neurogenesis and gliogenesis in the normal and damaged brain

PubMed Central

Christie, Kimberly J.; Turnley, Ann M.

2012-01-01

Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation. PMID:23346046

Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse.

PubMed

García-Fuster, M J; Perez, J A; Clinton, S M; Watson, S J; Akil, H

2010-01-01

Hippocampal plasticity (e.g. neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and 5-bromo-2'-deoxyuridine for older cells born prior to sensitization. Results show that: (i) bHRs exhibited greater psychomotor response to cocaine than bLRs; (ii) acute cocaine did not alter cell proliferation in bLR/bHR rats; (iii) chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence; (iv) neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype; (v) cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine; and (vi) cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR vs. bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs, which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.

Magnolol Enhances Hippocampal Neurogenesis and Exerts Antidepressant-Like Effects in Olfactory Bulbectomized Mice.

PubMed

Matsui, Nobuaki; Akae, Haruka; Hirashima, Nana; Kido, Yuki; Tanabe, Satoshi; Koseki, Mayumi; Fukuyama, Yoshiyasu; Akagi, Masaaki

2016-11-01

Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

PubMed

Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

2014-03-15

A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

TLX-Its Emerging Role for Neurogenesis in Health and Disease.

PubMed

Sobhan, Praveen K; Funa, Keiko

2017-01-01

The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions. Growing evidence suggests that dysregulated TLX acts in the initiation and progression of human disorders of the nervous system. This review describes recent knowledge about TLX expression, structure, targets, and biological functions, relevant to maintaining adult neural stem cells related to both neuropsychiatric conditions and certain nervous system tumours.

Roles of p53 and p27 Kip1 in the regulation of neurogenesis in the murine adult subventricular zone

PubMed Central

Gil-Perotin, Sara; Haines, Jeffery D.; Kaur, Jasbir; Marin-Husstege, Mireya; Spinetta, Michael J.; Kim, Kwi-Hye; Duran-Moreno, Maria; Schallert, Timothy; Zindy, Frederique; Roussel, Martine F.; Garcia-Verdugo, Jose M.; Casaccia, Patrizia

2011-01-01

The tumor suppressor protein p53 (Trp53) and the cell cycle inhibitor p27 Kip1 (Cdknb1) have both been implicated in regulating proliferation of adult subventricular zone (aSVZ) cells. We previously reported that genetic ablation of Trp53 (Trp53 −/−) or Cdknb1 (p27 Kip1−/−) increased proliferation of cells in the aSVZ, but differentially affected the number of adult born neuroblasts. We therefore hypothesized that these molecules might play non-redundant roles. To test this hypothesis we generated mice lacking both genes (Trp53 −/−;p27 Kip1−/−) and analysed the consequences on aSVZ cells and adult neuroblasts. Proliferation and self-renewal of cultured aSVZ cells were increased in the double mutants compared with control, but the mice did not develop spontaneous brain tumors. In contrast, the number of adult-born neuroblasts in the double mutants was similar to wild-type animals and suggested a complementation of the p27 Kip1−/− phenotype due to loss of Trp53. Cellular differences detected in the aSVZ correlated with cellular changes in the olfactory bulb and behavioral data on novel odor recognition. The exploration time for new odors was reduced in p27 Kip1−/− mice, increased in Trp53 −/− mice and normalized in the double Trp53−/−;p27 Kip1−/− mutants. At the molecular level, Trp53 −/− aSVZ cells were characterized by higher levels of NeuroD and Math3 and by the ability to generate neurons more readily. In contrast, p27 Kip1−/− cells generated fewer neurons, due to enhanced proteasomal degradation of pro-neural transcription factors. Together, these results suggest that p27 Kip1 and p53 function non-redundantly to modulate proliferation and self-renewal of aSVZ cells and antagonistically in regulating adult neurogenesis. PMID:21899604

Modeling hippocampal neurogenesis using human pluripotent stem cells.

PubMed

Yu, Diana Xuan; Di Giorgio, Francesco Paolo; Yao, Jun; Marchetto, Maria Carolina; Brennand, Kristen; Wright, Rebecca; Mei, Arianna; McHenry, Lauren; Lisuk, David; Grasmick, Jaeson Michael; Silberman, Pedro; Silberman, Giovanna; Jappelli, Roberto; Gage, Fred H

2014-03-11

The availability of human pluripotent stem cells (hPSCs) offers the opportunity to generate lineage-specific cells to investigate mechanisms of human diseases specific to brain regions. Here, we report a differentiation paradigm for hPSCs that enriches for hippocampal dentate gyrus (DG) granule neurons. This differentiation paradigm recapitulates the expression patterns of key developmental genes during hippocampal neurogenesis, exhibits characteristics of neuronal network maturation, and produces PROX1+ neurons that functionally integrate into the DG. Because hippocampal neurogenesis has been implicated in schizophrenia (SCZD), we applied our protocol to SCZD patient-derived human induced pluripotent stem cells (hiPSCs). We found deficits in the generation of DG granule neurons from SCZD hiPSC-derived hippocampal NPCs with lowered levels of NEUROD1, PROX1, and TBR1, reduced neuronal activity, and reduced levels of spontaneous neurotransmitter release. Our approach offers important insights into the neurodevelopmental aspects of SCZD and may be a promising tool for drug screening and personalized medicine.

Expression and function of orphan nuclear receptor TLX in adult neural stem cells.

PubMed

Shi, Yanhong; Chichung Lie, D; Taupin, Philippe; Nakashima, Kinichi; Ray, Jasodhara; Yu, Ruth T; Gage, Fred H; Evans, Ronald M

2004-01-01

The finding of neurogenesis in the adult brain led to the discovery of adult neural stem cells. TLX was initially identified as an orphan nuclear receptor expressed in vertebrate forebrains and is highly expressed in the adult brain. The brains of TLX-null mice have been reported to have no obvious defects during embryogenesis; however, mature mice suffer from retinopathies, severe limbic defects, aggressiveness, reduced copulation and progressively violent behaviour. Here we show that TLX maintains adult neural stem cells in an undifferentiated, proliferative state. We show that TLX-expressing cells isolated by fluorescence-activated cell sorting (FACS) from adult brains can proliferate, self-renew and differentiate into all neural cell types in vitro. By contrast, TLX-null cells isolated from adult mutant brains fail to proliferate. Reintroducing TLX into FACS-sorted TLX-null cells rescues their ability to proliferate and to self-renew. In vivo, TLX mutant mice show a loss of cell proliferation and reduced labelling of nestin in neurogenic areas in the adult brain. TLX can silence glia-specific expression of the astrocyte marker GFAP in neural stem cells, suggesting that transcriptional repression may be crucial in maintaining the undifferentiated state of these cells.

Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington's Disease

PubMed Central

Velusamy, Thirunavukkarasu; Panneerselvam, Archana S.; Purushottam, Meera; Anusuyadevi, Muthuswamy; Pal, Pramod Kumar; Jain, Sanjeev; Essa, Musthafa Mohamed

2017-01-01

Huntington's disease (HD) is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD. PMID:28168008

Suppression of IGF-I signals in neural stem cells enhances neurogenesis and olfactory function during aging.

PubMed

Chaker, Zayna; Aïd, Saba; Berry, Hugues; Holzenberger, Martin

2015-10-01

Downregulation of insulin-like growth factor (IGF) pathways prolongs lifespan in various species, including mammals. Still, the cellular mechanisms by which IGF signaling controls the aging trajectory of individual organs are largely unknown. Here, we asked whether suppression of IGF-I receptor (IGF-1R) in adult stem cells preserves long-term cell replacement, and whether this may prevent age-related functional decline in a regenerating tissue. Using neurogenesis as a paradigm, we showed that conditional knockout of IGF-1R specifically in adult neural stem cells (NSC) maintained youthful characteristics of olfactory bulb neurogenesis within an aging brain. We found that blocking IGF-I signaling in neural precursors increased cumulative neuroblast production and enhanced neuronal integration into the olfactory bulb. This in turn resulted in neuro-anatomical changes that improved olfactory function. Interestingly, mutants also displayed long-term alterations in energy metabolism, possibly related to IGF-1R deletion in NSCs throughout lifespan. We explored Akt and ERK signaling cascades and revealed differential regulation downstream of IGF-1R, with Akt phosphorylation preferentially decreased in IGF-1R(-/-) NSCs within the niche, and ERK pathway downregulated in differentiated neurons of the OB. These challenging experimental results were sustained by data from mathematical modeling, predicting that diminished stimulation of growth is indeed optimal for tissue aging. Thus, inhibiting growth and longevity gene IGF-1R in adult NSCs induced a gain-of-function phenotype during aging, marked by optimized management of cell renewal, and enhanced olfactory sensory function. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

PubMed

Bulin, Sarah E; Mendoza, Matthew L; Richardson, Devon R; Song, Kwang H; Solberg, Timothy D; Yun, Sanghee; Eisch, Amelia J

2018-03-01

Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. © 2017 Society for the Study of Addiction.

Elevating Integrin-linked Kinase Expression has Rescued Hippocampal Neurogenesis and Memory Deficits in an AD animal Model.

PubMed

Xu, Xu-Feng; Wang, You-Cui; Zong, Liang; Chen, Zhe-Yu; Li, Yan

2018-05-19

Alterations in adult neurogenesis have been regarded as a major cause of cognitive impairment in Alzheimer's disease (AD). The underlying mechanism of neurogenesis deficiency in AD remains unclear. In this study, we reported that Integrin-linked Kinase (ILK) protein levels and phosphorylation were significantly decreased in the hippocampus of APP/PS1 mice. Increased ILK expression of dentate gyrus (DG) rescued the hippocampus-dependent neurogenesis and memory deficits in APP/PS1 mice. Moreover, we demonstrated that the effect of ILK overexpression in the hippocampus was exerted via AKT-GSK3β pathway. Finally, we found that Fluoxetine, a selective serotonin reuptake inhibitor, could improve the impaired hippocampal neurogenesis and memory by enhancing ILK-AKT-GSK3β pathway activity in APP/PS1 mice. Thus, these findings demonstrated the effects of ILK on neurogenesis and memory recovery, suggesting that ILK is an important therapeutic target for AD prevention and treatment. Copyright © 2018. Published by Elsevier B.V.

Selective alteration of adult hippocampal neurogenesis and impaired spatial pattern separation performance in the RSK2-deficient mouse model of Coffin-Lowry syndrome.

PubMed

Castillon, Charlotte; Lunion, Steeve; Desvignes, Nathalie; Hanauer, André; Laroche, Serge; Poirier, Roseline

2018-07-01

Adult neurogenesis is involved in certain hippocampus-dependent cognitive functions and is linked to psychiatric diseases including intellectual disabilities. The Coffin-Lowry syndrome (CLS) is a developmental disorder caused by mutations in the Rsk2 gene and characterized by intellectual disabilities associated with growth retardation. How RSK2-deficiency leads to cognitive dysfunctions in CLS is however poorly understood. Here, using Rsk2 Knock-Out mice, we characterized the impact of RSK2 deficiency on adult hippocampal neurogenesis in vivo. We report that the absence of RSK2 does not affect basal proliferation, differentiation and survival of dentate gyrus adult-born neurons but alters the maturation progression of young immature newborn neurons. Moreover, when RSK2-deficient mice were submitted to spatial learning, in contrast to wild-type mice, proliferation of adult generated neurons was decreased and no pro-survival effect of learning was observed. Thus, learning failed to recruit a selective population of young newborn neurons in association with deficient long-term memory recall. Given the proposed role of the dentate gyrus and of adult-generated newborn neurons in hippocampal-dependent pattern separation function, we explored this function in a delayed non-matching to place task and in an object-place pattern separation task and report severe deficits in spatial pattern separation in Rsk2-KO mice. Together, this study reveals a previously unknown role for RSK2 in the early stages of maturation and learning-dependent involvement of adult-born dentate gyrus neurons. These alterations associated with a deficit in the ability of RSK2-deficient mice to finely discriminate relatively similar spatial configurations, may contribute to cognitive dysfunction in CLS. Copyright © 2018 Elsevier Inc. All rights reserved.

Adult responses to an ischemic stroke in a rat model of neonatal stress and morphine treatment.

PubMed

Hays, Sarah L; Valieva, Olga A; McPherson, Ronald J; Juul, Sandra E; Gleason, Christine A

2013-02-01

Critically ill newborn infants experience stressors that may alter brain development. Using a rodent model, we previously showed that neonatal stress, morphine, and stress plus morphine treatments each influence early gene expression and may impair neurodevelopment and learning behavior. We hypothesized that the combination of neonatal stress with morphine may alter neonatal angiogenesis and/or adult cerebral blood vessel density and thus increase injury after cerebral ischemia in adulthood. To test this, neonatal Lewis rats underwent 8 h/d maternal separation, plus morning/afternoon hypoxia exposure and either saline or morphine treatment (2 mg/kg s.c.) from postnatal day 3-7. A subset received bromodeoxyuridine to track angiogenesis. Adult brains were stained with collagen IV to quantify cerebral blood vessel density. To examine vulnerability to brain injury, postnatal day 80 adult rats underwent right middle cerebral artery occlusion (MCAO) to produce unilateral ischemic lesions. Brains were removed and processed for histology 48 h after injury. Brain injury was assessed by histological evaluation of hematoxylin and eosin, and silver staining. In contrast to our hypothesis, neither neonatal morphine, stress, nor the combination affected cerebral vessel density or MCAO-induced brain injury. Neonatal angiogenesis was not detected in adult rats possibly due to turnover of endothelial cells. Although unrelated to angiogenesis, hippocampal granule cell neurogenesis was detected and there was a trend (P = 0.073) toward increased bromodeoxyuridine incorporation in rats that underwent neonatal stress. These findings are discussed in contrast to other data concerning the effects of morphine on cerebrovascular function, and acute effects of morphine on hippocampal neurogenesis. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Origins of neurogenesis, a cnidarian view.

PubMed

Galliot, Brigitte; Quiquand, Manon; Ghila, Luiza; de Rosa, Renaud; Miljkovic-Licina, Marijana; Chera, Simona

2009-08-01

New perspectives on the origin of neurogenesis emerged with the identification of genes encoding post-synaptic proteins as well as many "neurogenic" regulators as the NK, Six, Pax, bHLH proteins in the Demosponge genome, a species that might differentiate sensory cells but no neurons. However, poriferans seem to miss some key regulators of the neurogenic circuitry as the Hox/paraHox and Otx-like gene families. Moreover as a general feature, many gene families encoding evolutionarily-conserved signaling proteins and transcription factors were submitted to a wave of gene duplication in the last common eumetazoan ancestor, after Porifera divergence. In contrast gene duplications in the last common bilaterian ancestor, Urbilateria, are limited, except for the bHLH Atonal-class. Hence Cnidaria share with Bilateria a large number of genetic tools. The expression and functional analyses currently available suggest a neurogenic function for numerous orthologs in developing or adult cnidarians where neurogenesis takes place continuously. As an example, in the Hydra polyp, the Clytia medusa and the Acropora coral, the Gsx/cnox2/Anthox-2 ParaHox gene likely supports neurogenesis. Also neurons and nematocytes (mechanosensory cells) share in hydrozoans a common stem cell and several regulatory genes indicating that they can be considered as sister cells. Performed in anthozoan and medusozoan species, these studies should tell us more about the way(s) evolution hazards achieved the transition from epithelial to neuronal cell fate, and about the robustness of the genetic circuitry that allowed neuromuscular transmission to arise and be maintained across evolution.

Rho kinase inhibition following traumatic brain injury in mice promotes functional improvement and acute neuron survival but has little effect on neurogenesis, glial responses or neuroinflammation.

PubMed

Bye, Nicole; Christie, Kimberly J; Turbic, Alisa; Basrai, Harleen S; Turnley, Ann M

2016-05-01

Inhibition of the Rho/Rho kinase pathway has been shown to be beneficial in a variety of neural injuries and diseases. In this manuscript we investigate the role of Rho kinase inhibition in recovery from traumatic brain injury using a controlled cortical impact model in mice. Mice subjected to a moderately severe TBI were treated for 1 or 4 weeks with the Rho kinase inhibitor Y27632, and functional outcomes and neuronal and glial cell responses were analysed at 1, 7 and 35 days post-injury. We hypothesised that Y27632-treated mice would show functional improvement, with augmented recruitment of neuroblasts from the SVZ and enhanced survival of newborn neurons in the pericontusional cortex, with protection against neuronal degeneration, neuroinflammation and modulation of astrocyte reactivity and blood-brain-barrier permeability. While Rho kinase inhibition enhanced recovery of motor function after trauma, there were no substantial increases in the recruitment of DCX(+) neuroblasts or the number of BrdU(+) or EdU(+) labelled newborn neurons in the pericontusional cortex of Y27632-treated mice. Inhibition of Rho kinase significantly reduced the number of degenerating cortical neurons at 1day post-injury compared to saline controls but had no longer term effect on neuronal degeneration, with only modest effects on astrocytic reactivity and macrophage/microglial responses. Overall, this study showed that Rho kinase contributes to acute neurodegenerative processes in the injured cortex but does not play a significant role in SVZ neural precursor cell-derived adult neurogenesis, glial responses or blood-brain barrier permeability following a moderately severe brain injury. Copyright © 2016 Elsevier Inc. All rights reserved.

Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis

PubMed Central

Cassano, Paolo; Petrie, Samuel R.; Hamblin, Michael R.; Henderson, Theodore A.; Iosifescu, Dan V.

2016-01-01

Abstract. We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD). While still experimental, preliminary data on the use of PBM for brain disorders are promising. PBM is low-cost with potential for wide dissemination; further research on PBM is sorely needed. We found clinical and preclinical studies via PubMed search (2015), using the following keywords: “near-infrared radiation,” “NIR,” “low-level light therapy,” “low-level laser therapy,” or “LLLT” plus “depression.” We chose clinically focused studies and excluded studies involving near-infrared spectroscopy. In addition, we used PubMed to find articles that examine the link between PBM and relevant biological processes including metabolism, inflammation, oxidative stress, and neurogenesis. Studies suggest the processes aforementioned are potentially effective targets for PBM to treat depression. There is also clinical preliminary evidence suggesting the efficacy of PBM in treating MDD, and comorbid anxiety disorders, suicidal ideation, and traumatic brain injury. Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD. PMID:26989758

Elevation of Hippocampal Neurogenesis Induces a Temporally Graded Pattern of Forgetting of Contextual Fear Memories.

PubMed

Gao, Aijing; Xia, Frances; Guskjolen, Axel J; Ramsaran, Adam I; Santoro, Adam; Josselyn, Sheena A; Frankland, Paul W

2018-03-28

Throughout life neurons are continuously generated in the subgranular zone of the hippocampus. The subsequent integration of newly generated neurons alters patterns of dentate gyrus input and output connectivity, potentially rendering memories already stored in those circuits harder to access. Consistent with this prediction, we previously showed that increasing hippocampal neurogenesis after training induces forgetting of hippocampus-dependent memories, including contextual fear memory. However, the brain regions supporting contextual fear memories change with time, and this time-dependent memory reorganization might regulate the sensitivity of contextual fear memories to fluctuations in hippocampal neurogenesis. By virally expressing the inhibitory designer receptor exclusively activated by designer drugs, hM4Di, we first confirmed that chemogenetic inhibition of dorsal hippocampal neurons impairs retrieval of recent (day-old) but not remote (month-old) contextual fear memories in male mice. We then contrasted the effects of increasing hippocampal neurogenesis at recent versus remote time points after contextual fear conditioning in male and female mice. Increasing hippocampal neurogenesis immediately following training reduced conditioned freezing when mice were replaced in the context 1 month later. In contrast, when hippocampal neurogenesis was increased time points remote to training, conditioned freezing levels were unaltered when mice were subsequently tested. These temporally graded forgetting effects were observed using both environmental and genetic interventions to increase hippocampal neurogenesis. Our experiments identify memory age as a boundary condition for neurogenesis-mediated forgetting and suggest that, as contextual fear memories mature, they become less sensitive to changes in hippocampal neurogenesis levels because they no longer depend on the hippocampus for their expression. SIGNIFICANCE STATEMENT New neurons are generated in the

Phenotypic and Gene Expression Modification with Normal Brain Aging in GFAP-Positive Astrocytes and Neural Stem Cells

PubMed Central

Bernal, Giovanna M.; Peterson, Daniel A.

2011-01-01

Summary Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche, and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked if a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in gene expression of GFAP, VEGF and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits neural stem cell and progenitor cell maintenance and contributes to decreased neurogenesis. PMID:21385309

Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.

PubMed

Zhu, Changlian; Gao, Jianfeng; Karlsson, Niklas; Li, Qian; Zhang, Yu; Huang, Zhiheng; Li, Hongfu; Kuhn, H Georg; Blomgren, Klas

2010-05-01

Isoflurane and related anesthetics are widely used to anesthetize children, ranging from premature babies to adolescents. Concerns have been raised about the safety of these anesthetics in pediatric patients, particularly regarding possible negative effects on cognition. The purpose of this study was to investigate the effects of repeated isoflurane exposure of juvenile and mature animals on cognition and neurogenesis. Postnatal day 14 (P14) rats and mice, as well as adult (P60) rats, were anesthetized with isoflurane for 35 mins daily for four successive days. Object recognition, place learning and reversal learning as well as cell death and cytogenesis were evaluated. Object recognition and reversal learning were significantly impaired in isoflurane-treated young rats and mice, whereas adult animals were unaffected, and these deficits became more pronounced as the animals grew older. The memory deficit was paralleled by a decrease in the hippocampal stem cell pool and persistently reduced neurogenesis, subsequently causing a reduction in the number of dentate gyrus granule cell neurons in isoflurane-treated rats. There were no signs of increased cell death of progenitors or neurons in the hippocampus. These findings show a previously unknown mechanism of neurotoxicity, causing cognitive deficits in a clearly age-dependent manner.

Paracrine control of vascularization and neurogenesis by neurotrophins.

PubMed

Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

2003-10-01

The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

Hard-Diet Feeding Recovers Neurogenesis in the Subventricular Zone and Olfactory Functions of Mice Impaired by Soft-Diet Feeding

PubMed Central

Utsugi, Chizuru; Miyazono, Sadaharu; Osada, Kazumi; Sasajima, Hitoshi; Noguchi, Tomohiro; Matsuda, Mitsuyoshi; Kashiwayanagi, Makoto

2014-01-01

The subventricular zone (SVZ) generates an immense number of neurons even during adulthood. These neurons migrate to the olfactory bulb (OB) and differentiate into granule cells and periglomerular cells. The information broadcast by general odorants is received by the olfactory sensory neurons and transmitted to the OB. Recent studies have shown that a reduction of mastication impairs both neurogenesis in the hippocampus and brain functions. To examine these effects, we first measured the difference in Fos-immunoreactivity (Fos-ir) at the principal sensory trigeminal nucleus (Pr5), which receives intraoral touch information via the trigeminal nerve, when female adult mice ingested a hard or soft diet to explore whether soft-diet feeding could mimic impaired mastication. Ingestion of a hard diet induced greater expression of Fos-ir cells at the Pr5 than did a soft diet or no diet. Bromodeoxyuridine-immunoreactive (BrdU-ir) structures in sagittal sections of the SVZ and in the OB of mice fed a soft or hard diet were studied to explore the effects of changes in mastication on newly generated neurons. After 1 month, the density of BrdU-ir cells in the SVZ and OB was lower in the soft-diet-fed mice than in the hard-diet-fed mice. The odor preferences of individual female mice to butyric acid were tested in a Y-maze apparatus. Avoidance of butyric acid was reduced by the soft-diet feeding. We then explored the effects of the hard-diet feeding on olfactory functions and neurogenesis in the SVZ of mice impaired by soft-diet feeding. At 3 months of hard-diet feeding, avoidance of butyric acid was reversed and responses to odors and neurogenesis were recovered in the SVZ. The present results suggest that feeding with a hard diet improves neurogenesis in the SVZ, which in turn enhances olfactory function at the OB. PMID:24817277