{"title":"23 Hippocampal Neurogenesis: Depression and Antidepressant Responses","authors":"Amar Sahay, R. Hen, R. Duman","doi":"10.1101/087969784.52.483","DOIUrl":"https://doi.org/10.1101/087969784.52.483","url":null,"abstract":"Basic research and clinical studies have provided evidence that stress and depression can result in structural alterations in limbic brain regions implicated in mood disorders, including atrophy and loss of neurons and glia. These studies also demonstrate that antidepressant (AD) treatments block or reverse these effects. Several mechanisms contribute to the structural alterations and loss of cells in response to stress and depression, but one of intense interest is the involvement of neurogenesis in the adult hippocampal formation. Basic research studies consistently demonstrate that stress and AD treatment exert opposing actions on neurogenesis in the hippocampal dentate gyrus (DG). The study of adult hippocampal neurogenesis has revealed it to be a robust phenomenon that is capable of conferring previously unrecognized forms of plasticity to the DG. The progression from neuronal stem cell to mature dentate granule neuron can be divided into discrete stages, each of which is defined by distinct physiological and morphological properties (Esposito et al. 2005; Song et al. 2005) and is influenced by a plethora of factors comprising growth factors, neurotrophins, and chemokines (Lledo et al. 2006). These factors act in concert with network activity to regulate the balance between proliferation, differentiation, and survival of neuronal stem cells in vivo. It is through this general mechanism that levels of adult hippocampal neurogenesis change in response to aversive and enriching experiences, such as stress and learning, respectively, and the physiological state of the organism. Recent studies relying on experimental approaches that ablate adult hippocampal neurogenesis in rodents have...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1 1","pages":"483-501"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89317358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"9 Genome-wide Views of Aging Gene Networks","authors":"Stuart K. Kim","doi":"10.1101/087969824.51.215","DOIUrl":"https://doi.org/10.1101/087969824.51.215","url":null,"abstract":"Aging is a complex process involving the additive effects of many genetic pathways (Kirkwood and Austad 2000). To embrace the complexity of aging, an attractive approach is to use DNA microarrays to scan the entire genome for genes that change expression as a function of age or under conditions when longevity is extended. The list of age-regulated genes provides clues about genetic pathways and mechanisms that underlie the aging process. In addition to single-gene analysis, the combined transcriptional profile of aging can act as a molecular phenotype of old age. During the last 20 years, there has been a great deal of effort to search for biomarkers of aging, and recent studies have shown that expression profiles of aging derived from DNA microarray experiments may provide this long-desired goal. A gene expression signature for aging is a quantitative phenotype that gives a high-resolution view of the aging process, much like using transcriptional profiles of cancer to inform about their severity or malignancy. Previously, one could recognize old versus young individuals in a photograph, or old versus young tissue on a microscope slide. Now it is possible to recognize old versus young genetic networks by analyzing expression levels of the entire set of age-regulated genes (Fig. 1). Unlike photographs or micrographs, expression data from DNA microarrays are quantitative, and thus it is possible to compare age-related transcriptional profiles between different tissues, between different conditions that affect longevity, and even between diverse species. Such comparisons are not possible by browsing images of...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"94 1","pages":"215-235"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87595083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"17 Molecular Mechanisms of Aging: Insights from Budding Yeast","authors":"Su-Ju Lin, D. Sinclair","doi":"10.1101/087969824.51.483","DOIUrl":"https://doi.org/10.1101/087969824.51.483","url":null,"abstract":"Until the late 1980s, the prevailing view among researchers was that life span of any organism, even yeast, could not be regulated, let alone by just a few genes. The view was based on the fact that aging is an incredibly complex process that is affected by thousands of genes. Then, in just a few years, genetic studies in model organisms such as Saccharomyces cerevisiae and Caenorhabditis elegans uncovered numerous single-gene mutations that extend life span (Jazwinski et al. 1993; Kenyon et al. 1993; Kennedy et al. 1995). What had researchers overlooked prior to 1990? The major oversight appears to have been the failure to foresee that organisms have evolved to promote their survival, and hence longevity, during times of adversity. Longevity regulation, as it has come to be known, is now thought of as a highly adaptive biological trait that is conserved all the way from yeast to mammals (Kirkwood and Holliday 1979; Kenyon 2001). When Andrew Barton first proposed in 1950 that S. cerevisiae might serve as a model for aging, he was met with considerable skepticism (Barton 1950). It was difficult for most researchers to accept that a simple unicellular organism could provide any information about aging. But we have since learned never to underestimate a fungus. Today, S. cerevisiae is one of the most highly utilized models for aging, and dozens of longevity genes have been identified. Translating these findings to mammals is one of the major challenges for researchers during the next decade. BIOLOGY OF...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"42 1","pages":"483-516"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83554508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"3 Detection and Phenotypic Characterization of Adult Neurogenesis","authors":"H. Kuhn, D. Peterson","doi":"10.1101/087969784.52.25","DOIUrl":"https://doi.org/10.1101/087969784.52.25","url":null,"abstract":"Advances in our understanding of the extent and regulation of adult neurogenesis have been dependent on continued improvements in the detection and quantification of critical events in neurogenesis. To date, no specific and exclusive stem cell marker has been described that would allow for prospective studies of neurogenesis. As a result, detection of neurogenic events has depended on a combination of labeling approaches that document the two critical events in neurogenesis: the generation of new cells and their subsequent progression through lineage commitment to a mature neuron. Detection of neurogenesis in vivo requires the ability to image at a cellular resolution. Although advances in noninvasive imaging approaches, such as magnetic resonance imaging (MRI), show promise for longitudinal studies of neurogenesis, the lack of suitable resolution to characterize individual cells limits the information that can be obtained. In vivo microscopy, using deeply penetrating UV illumination with mulitphoton microscopy or by the recently available endoscopic confocal microscopy, may provide new opportunities for longitudinal studies of neurogenesis in the living animal with single-cell resolution. These latter microscopy approaches are particularly compelling when coupled with transgenic mice expressing phenotype-specific fluorescent reporter genes. However, at present, the predominant approach for studies of neurogenesis relies on traditional histological methods of fixation, production of tissue sections, staining, and microscopic analysis. This chapter discusses methodological considerations for in vivo detection of neurogenesis in the adult brain according to our current state of knowledge. First, detection of newly generated cells is evaluated and the strengths of using exogenous or...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"41 1","pages":"25-47"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78932661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"11 Yeast, a Feast: The Fruit Fly Drosophila as a Model Organism for Research into Aging","authors":"L. Partridge, J. Tower","doi":"10.1101/087969824.51.267","DOIUrl":"https://doi.org/10.1101/087969824.51.267","url":null,"abstract":"Research into aging has been galvanized by the discovery of mutations in single genes that extend life span and evolutionary conservation of their effects. An environmental intervention—dietary restriction—also extends life span in evolutionarily diverse animals. These discoveries have opened the way to using laboratory model organisms to understand human aging. Invertebrate species, budding yeast Saccharomyces cerevisiae , the nematode worm Caenorhabditis elegans , and the fruit fly Drosophila melanogaster , have a vital role in this process of discovery. Their ease of culture and handling in the laboratory and short life spans (~3 days in yeast, ~3 weeks in the worm, and ~3 months in Drosophila ) mean that much more rapid progress can be made than in the mouse, whose life spans are about 3 years. Completion of the genome sequences for the invertebrates and their closely related species, together with the development of many genetic and other resources, also make them powerful experimental systems. Each of these organisms has strengths and weaknesses for research into aging. We highlight here some of the particular strengths of Drosophila and uses to which they have been put and could be put in the future. The jaw-dropping genetics applied to a complex tissue structure approaching that of vertebrates leaves Drosophila flying at the front edge of aging research. The time has long passed when a full review of the biology of aging in the fruit fly D. melanogaster could be usefully accommodated in a single chapter. Drosophila has been an established model organism for...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"47 1","pages":"267-308"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87023685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"10 Adult Subventricular Zone and Olfactory Bulb Neurogenesis","authors":"D. Lim, Yin-Cheng Huang, A. Álvarez-Buylla","doi":"10.1101/087969784.52.175","DOIUrl":"https://doi.org/10.1101/087969784.52.175","url":null,"abstract":"In the adult mammalian brain, new neurons are added to the olfactory bulb (OB) throughout life. In rodents, the adult germinal region for OB neurogenesis is the subventricular zone (SVZ), a layer of cells found along the walls of the brain lateral ventricles (for review, see Alvarez-Buylla and Garcia-Verdugo 2002). Neuroblasts born in the SVZ migrate a relatively long distance into the OB where they then disperse radially and differentiate into interneurons. Most of these new OB neurons integrate into functional circuits (Belluzzi et al. 2003; Carleton et al. 2003), and about half survive long-term (Petreanu and Alvarez-Buylla 2002). SVZ cell proliferation is lifelong (Kuhn et al. 1996; Goldman et al. 1997; Molofsky et al. 2006), with thousands of new neurons generated daily for the mouse OB (Lois and Alvarez-Buylla 1994). The adult SVZ is also the birthplace of oligodendrocytes in both normal and diseased brain (Nait-Oumesmar et al. 1999; Picard-Riera et al. 2002; Menn et al. 2006; Parent et al. 2006). This profound level of continuous neurogenesis and concomitant oligodendrogliogenesis argues for the existence of a self-renewing multipotent precursor cell—or, neural stem cell (NSC)—within the SVZ. The SVZ-OB system is an attractive model in which to study neurogenesis and neuronal replacement as it includes the basic processes of NSC maintenance, progenitor cell-fate specification, migration, differentiation, and survival/death of newly born neurons. The enduring quality and stable cytoarchitecture of adult SVZ-OB neurogenesis may make these complex biological processes experimentally more tractable in comparison to studies of embryonic brain...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"34 1","pages":"175-206"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81473467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"9 TGF-β Signaling from Receptors to Smads","authors":"C. Heldin","doi":"10.1101/087969752.50.259","DOIUrl":"https://doi.org/10.1101/087969752.50.259","url":null,"abstract":"Binding of transforming growth factor-β (TGF-β) family members to their heteromeric complexes of type I and type II serine-threonine kinase receptors makes it possible for the type II receptor to phosphorylate and activate the type I receptor (see Chapter 6). Although several substrates for the type I receptor kinases have been identified, the most important ones for the transmission of the intracellular signals are members of the Smad family of signal transducers. The receptor-activated (R-) Smads (Smad1, Smad5, and Smad8, for bone morphogenic proteins [BMPs] and Smad2 and 3 for TGF-βs and activins) are phosphorylated by the type I receptors and then form hetero-oligomeric complexes with the common mediator (co-) Smad (only one co-Smad in humans, Smad4), which are translocated to the nucleus where they regulate the transcription of specific genes. The third Smad subfamily is represented by the inhibitory (I-) Smads, that is, Smad6 and Smad7, which, on the one hand, inhibit signaling via heteromeric serine-threonine kinase receptor complexes in a feedback mechanism and, on the other hand, promote certain non-Smad signaling pathways. The inhibitory Smads are discussed in Chapter 12 and are not covered in this chapter. The aim of this chapter is to review the mechanism whereby Smads are activated by receptors, how they are translocated to the nucleus, and how their activities are modulated by posttranslational modifications. The role of Smad complexes as transcriptional regulators in the nucleus is not discussed here (see Chapter 10). THE SMAD FAMILY Discovery of the Smads The Smad family was...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"34 1","pages":"259-285"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85058039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"1 Adult Neurogenesis: A Prologue","authors":"F. Gage, Hongjun Song, G. Kempermann","doi":"10.1101/087969784.52.1","DOIUrl":"https://doi.org/10.1101/087969784.52.1","url":null,"abstract":"New ideas pass through a series of stages from initial rejection to skepticism, to reluctant acceptance (without true belief in its importance), to a final casual acknowledgment of the obvious. It is fair to say that the acceptance of the idea that new neurons are generated in the adult brain of all mammals has been a slow process, and along the way, the idea has been met with skepticism and resistance. It is still not yet casually accepted as obvious. Rather, adult neurogenesis remains in the stage of reluctant acceptance, without a clear understanding of its importance, but the search for its function is in full gear. Joseph Altman’s original observations in the 1960s were met with significant reservation, as were attempted confirmations by a handful of investigators in the next 20 years. Somehow, Fernando Nottebohm and Steve Goldman’s observation of neurogenesis in the brains of adult canaries was received more positively but—because it took place in birds—was not considered as much of a threat to the prevailing belief (often even termed “dogma”) that there are no new neurons in the adult mammalian brain. Why this resistance to the capacity of the adult brain to generate new neurons? It was well accepted that other systems, like blood, liver, and skin, could generate new cells, so why not the brain? The most straightforward explanation is that the brain is not just any organ. At a philosophical and metaphysical level, the brain is thought to be the place where the...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"114 1","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88074610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"27 The TGF-β Family in the Reproductive Tract","authors":"S. Pangas, M. Matzuk","doi":"10.1101/087969752.50.861","DOIUrl":"https://doi.org/10.1101/087969752.50.861","url":null,"abstract":"The influence of the transforming growth factor-β (TGF-β) family on fertility and reproduction is impressive. This is true for diverse organisms from flies to humans. In Drosophila melanogaster , for example, oogenesis requires the bone morphogenetic protein (BMP)-2/4 homolog, Decapentaplegic, to maintain germ-line stem cells in the ovary (Xie and Spradling 1998) and, at later stages, for proper egg shape and polarity (Twombly et al. 1996). In mammals, various members of this family are involved from the very early stages of reproductive development, including specification of the male and female germ line and sexual differentiation. In the adult, TGF-β-related proteins govern the growth and differentiation of somatic cells as well as germ cells within the gonads. In the female, TGF-β family ligands are intricately involved in the control of ovulation and fertilization. Several of these growth factors also serve as endocrine hormones to integrate the reproductive status of the gonad to the physiological condition of the organism. Many transgenic and knockout mouse models have been created that display reproductive pathologies and highlight the importance of this family in maintaining reproductive homeostasis. These models have contributed significantly to the understanding of this protein family in reproductive processes (Matzuk et al. 1996; Elvin and Matzuk 1998; Chang et al. 2002). This chapter focuses on recent progress made in mammalian male and female reproductive biology using genetic models for the ligands, receptors, and signaling proteins of the TGF-β family. PRIMORDIAL GERM CELL DEVELOPMENT Specification of the germ cell lineage in mammals begins in early...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1 1","pages":"861-888"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86833217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"33 BMP-based Therapeutics and the BMP Signaling Pathways","authors":"G. Bain, A. Celeste, J. Wozney","doi":"10.1101/087969752.50.1063","DOIUrl":"https://doi.org/10.1101/087969752.50.1063","url":null,"abstract":"The bone morphogenetic proteins (BMPs) were originally identified as molecules responsible for the bone-inductive activity present within bone matrix (Wozney et al. 1988). Now known to be a family of proteins within the larger transforming growth factor-β (TGF-β) family, the BMPs have a wide range of activities on various cell types (see Chapter 5). As discussed elsewhere in this volume, the BMP signaling system parallels, but is distinct from, that of TGF-β. BMP signaling is tightly controlled by a range of extracellular, intracellular, and nuclear modulators, suggesting many targets for pharmaceutical intervention. In this chapter, we discuss some of the potential therapeutic applications of the BMPs and locations in the BMP pathway that may lend themselves to development of therapeutics. Depending on the biology of the BMP, stimulation of the pathway, for example, by supplying exogenous ligand or by increasing endogenous expression, may provide a therapeutic; alternatively, suppression of the pathway via inhibition may be the desired therapeutic approach. In the latter part of the chapter, we give two examples of development of pharmaceuticals. In one case, the therapeutic is the BMP ligand itself; in the other, an inhibitor of the ligand is being evaluated. POTENTIAL THERAPEUTIC APPLICATIONS OF THE BMPS The BMPs are a family of growth and differentiation factors, some of which are expressed in almost every cell type. They have autocrine, paracrine, and perhaps even endocrine functions. Most are believed to be locally acting factors, but some circulate and have been reported to have systemic activities. The...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"72 1","pages":"1063-1093"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86264639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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