{"title":"21 Neurogenesis and Hippocampal Memory System","authors":"D. Abrous, J. Wojtowicz","doi":"10.1101/087969784.52.445","DOIUrl":"https://doi.org/10.1101/087969784.52.445","url":null,"abstract":"When discussing a brain function such as memory, one should relate it to brain plasticity. One definition of plasticity is an alternative way of performing the same function. Anecdotal evidence suggests that the human brain can perform amazing memory feats in unexpected, alternative ways. For example, the established ability of savants (individuals with partial brain damage) to memorize events, sequences of numbers, letters, or musical notes, and to perform arithmetical calculations, suggests that compensatory rewiring of brain circuits after injury can affect learning. Which particular form of brain plasticity could be responsible for such astounding learning abilities as those seen in Kim Peek (“Rain Man”) and Daniel Tammet (“Brainman”), two individuals diagnosed as autistic savants (www.savantsyndrome.com)? In this chapter, we describe a radical form of plasticity, adult neurogenesis, in hippocampal formation (HF). The discovery of adult neurogenesis (production of new neurons in adult brain) has radically changed our ideas of how the brain can adapt to physiological and environmental challenges. The process of neuronal production is highly regulated and is involved in hippocampal functions under physiological conditions. In some cases, neurogenesis can respond to hippocampus-related pathologies such as epilepsy, ischemia, mood disorders, and addiction. Understanding neurogenesis, along with other forms of brain plasticity, may help us to understand normal memory and perhaps the enhanced memory such as that seen in individuals with the Savant Syndrome (Treffert and Christensen 2005). LESIONS OF THE NEUROGENIC REGION The HF is part of an integrated network involved in learning and memory (Eichenbaum 2000, 2001;...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"23 1","pages":"445-461"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72989256","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":"20 Telomeres and Telomerase in Aging and Cancer","authors":"J. Shay, W. Wright","doi":"10.1101/087969824.51.575","DOIUrl":"https://doi.org/10.1101/087969824.51.575","url":null,"abstract":"The role of telomeres in maintaining chromosomal integrity was proposed by Barbara McClintock (for review, see Blackburn 2006). Studying telomeres in maize chromosomes, McClintock observed that if not capped by telomeres, the ends of chromosomes had a tendency to fuse. Her observations were confirmed 50 years later in yeast and mice when it was demonstrated that without telomeric ends, chromosomes undergo aberrant end-to-end fusions, forming multicentric chromosomes with a propensity to break during mitosis, activating DNA-damage checkpoints and, in some cases, leading to widespread cell death (Zakian 1989). It is now known that the shortening of telomeres due to cell divisions forms the basis of replicative aging, the growth arrest originally described by Hayflick and Moorhead (1961). Aging is associated with the gradual decline in the performance of organ systems, resulting in the loss of reserve capacity, leading to an increased chance of death (Gompertz 1825). In some organ systems, this loss of reserve capacity with increasing age can be attributed to the loss of cell function (Martin et al. 1970). Chronic localized stress to specific tissues/cell types may result in increased cell turnover, and it has been hypothesized that this may lead to focal areas of replicative senescence (Hayflick and Moorhead 1961), followed by alterations in patterns of gene expression (West 1994;West et al. 1996). This could result in reduced tissue regeneration, culminating in some of the clinical pathologies that are often associated with increased age. In addition to replicative aging, a variety of mechanisms can induce an irreversible...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"70 1","pages":"575-597"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74726494","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":"2 TGF-β and the TGF-β Family","authors":"R. Derynck, K. Miyazono","doi":"10.1101/087969752.50.29","DOIUrl":"https://doi.org/10.1101/087969752.50.29","url":null,"abstract":"As outlined in the previous chapter, the biochemical characterization of human transforming growth factor-β (TGF-β), now known as TGF-β1, and the determination of its sequence through cDNA cloning provided the basis for identification of TGF-β as structurally distinct from TGF-α. The most striking characteristic that set it apart from TGF-α at that time was that TGF-β was a 25-kD disulfide-linked dimer that was reduced to a 12.5-kD band on gel following treatment with β-mercaptoethanol (Roberts et al. 1983). Following its cDNA cloning (Derynck et al. 1985), it became apparent that TGF-β did not at all resemble TGF-α to which it had been functionally compared thus far and that its polypeptide sequence was unrelated to anything known before. The predicted polypeptide sequence also clearly showed that the mature TGF-β monomer corresponded to only the carboxy-terminal third of a much larger precursor, thus requiring proteolytic cleavage (see Fig. 3 of Chapter 1). Subsequent cDNA cloning demonstrated that the polypeptide chains that define the heteromeric disulfide-linked inhibin are structurally related to TGF-β (Mason et al. 1985; Vale et al. 1986). These polypeptides are, similarly to TGF-β, encoded as carboxy-terminal polypeptides of larger precursors, and only the carboxy-terminal mature polypeptides show structural similarity with TGF-β. Thus was born the realization that there may be a family of secreted disulfide-linked dimeric polypeptides encoded as carboxy-terminal segments of larger secreted polypeptides. This realization was further borne out by the cDNA cloning of bone morphogenetic protein-2A (BMP-2A) and BMP-2B, now known as BMP-2 and BMP-4, respectively (Wozney...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"8 1","pages":"29-43"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74277648","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":"20 Adult Neurogenesis in the Olfactory Bulb","authors":"P. Lledo","doi":"10.1101/087969784.52.425","DOIUrl":"https://doi.org/10.1101/087969784.52.425","url":null,"abstract":"Most organisms rely on an olfactory system to detect and analyze chemical cues from the external world in the context of essential behavior. From worms to vertebrates, chemicals are detected by odorant receptors expressed by olfactory sensory neurons, which send an axon to the primary processing center—the olfactory bulb, in vertebrates. Within this relay, sensory neurons form excitatory synapses with projection neurons and with inhibitory interneurons. Thus, due to complex synaptic interactions in the olfactory bulb circuit, the output of a given projection neuron is determined not only by the sensory input, but also by the activity of local inhibitory interneurons that are concerned by adult neurogenesis throughout life. Recent studies have provided clues about how these new neurons incorporate into preexisting networks, how they survive or die once integrated into proper microcircuits, and how basic network functions are maintained despite the continual renewal of a large percentage of neurons. We know that external influences modulate the process of late neurogenesis at various stages. Thus, this process is probably flexible, allowing brain performance to be optimized for its environment. But optimized how? And why? This chapter describes the adaptation of new interneuron production to experience-induced plasticity. In particular, how the survival of newly generated neurons is highly sensitive not only to the level of sensory inputs, but also to the behavioral context is discussed. Also discussed is how neurogenesis may finely tune the functioning of the neural network, optimizing the processing of sensory information. Adult neurogenesis maintains continual turnover...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"28 1","pages":"425-443"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73235502","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":"8 Monolayer Cultures of Neural Stem/Progenitor Cells","authors":"J. Ray","doi":"10.1101/087969784.52.135","DOIUrl":"https://doi.org/10.1101/087969784.52.135","url":null,"abstract":"The central dogma in neuroscience “no new neurons after birth” existed for almost a century. Only in recent years was it believed that neurons are generated exclusively during the prenatal phase of development. The study of adult neurogenesis was started in earnest in 1990s, and it has now become clear that active neurogenesis, a process of generating functionally integrated neurons from undifferentiated multipotent stem or progenitor cells, continues in discrete regions of the adult CNS throughout the life of mammals, including humans. During development, nerve cells in the mammalian CNS are generated by the proliferation of multipotent stem/progenitor cells that migrate, find their site of final destination, and ultimately terminally differentiate. Owing to their relative rarity and lack of specific phenotypic markers, putative stem cells have been characterized based on their functional criteria. The discovery of putative stem cells in a given tissue is usually contingent on the development of in vitro culture conditions enabling a rigorous characterization. According to these criteria, stem cells must demonstrate the ability to proliferate, self-renew over an extended period of time, and generate a large number of progeny (progenitor or precursor cells) that can differentiate into the primary cell types of the tissue from which it was generated (Gage 1998; Temple 2001a,b). The in vitro culture consists of both stem and progenitor cells, and the terms “stem, progenitor, and precursor cells” have been used interchangeably in the literature. In this chapter, I use the term “stem/progenitor cells.” The molecular specification of neural stem/progenitor cells...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"51 1","pages":"135-157"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74485612","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":"18 TGF-β Family Signaling in the Nematode C. elegans","authors":"G. Patterson, R. W. Padgett","doi":"10.1101/087969752.50.527","DOIUrl":"https://doi.org/10.1101/087969752.50.527","url":null,"abstract":"In the nematode Caenorhabditis elegans , there are two distinct transforming growth factor-β (TGF-β) family signaling pathways with their typical core signaling components, that is, ligands, type I and type II serine-threonine kinase receptors, and Smads (Fig. 1). One of these, the dauer signaling pathway, controls an alternate third larval stage of C. elegans that forms in response to harsh environmental conditions (Riddle and Albert 1997) and feeding behavior, fat metabolism, egg laying, and thermotolerance. The other one, the body size pathway, regulates cell size, male tail development, and immunity (Patterson and Padgett 2000; Kurz and Tan 2004; Nicholas and Hodgkin 2004). DISCOVERY OF TGF-β FAMILY SIGNALING IN C. ELEGANS Genes that encode components of a TGF-β family signaling pathway were identified as mutants with defects in the regulation of the dauer decision (for a schematic presentation of the pathway, see Fig. 1B). The dauer stage is an alternate third larval stage of C. elegans (Fig. 2), in which the worm “hibernates” in response to environmental conditions that are unfavorable for growth and reproduction (Albert and Riddle 1997). Mutations in the ligand, receptors, or putative receptor-activated Smads (R-Smads) in the dauer pathway result in a dauer-constitutive phenotype, in which the worms enter and maintain growth arrest under conditions that, in wild-type worms, lead to continued growth. The first gene that was identified in the dauer pathway was daf-1 , which encodes a type I TGF-β family receptor (Georgi et al. 1990). Its identity as a TGF-β family receptor was not appreciated at...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"25 1","pages":"527-545"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80299845","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":"26 Neurogenesis following Stroke Affecting the Adult Brain","authors":"O. Lindvall, Z. Kokaia","doi":"10.1101/087969784.52.549","DOIUrl":"https://doi.org/10.1101/087969784.52.549","url":null,"abstract":"Stroke is caused by occlusion of a cerebral artery, which gives rise to focal ischemia with irreversible injury in a core region and partially reversible damage in the surrounding penumbra zone. In another type of insult, abrupt and near-total interruption of cerebral blood flow as a consequence of cardiac arrest or coronary artery occlusion leads to global ischemia and selective death of certain vulnerable neuronal populations such as the pyramidal neurons of hippocampal CA1. During the last decade, these ischemic insults have been reported to induce the formation of new neurons in the adult rodent brain from neural stem cells (NSCs) located in two regions: the subventricular zone (SVZ), lining the lateral ventricle, and the subgranular zone (SGZ) in the dentate gyrus (DG). Ischemia-induced neurogenesis is triggered both in areas where new neurons are normally formed, such as the DG, and in areas that are nonneurogenic in the intact brain, e.g., the striatum. These findings have raised several important issues: (1) Is the evidence for the formation of new neurons really solid or could there be other interpretations such as aberrant DNA synthesis caused by the ischemic insult in already existing, mature neurons? (2) What are the functional consequences of ischemia-induced neurogenesis? (3) Because the neurogenic response is minor and recovery after stroke incomplete, how can this presumed self-repair mechanism be boosted? In this chapter, we summarize the current status of research on neurogenesis after stroke. We also discuss the basic scientific problems that need to be addressed before this...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"33 1","pages":"549-570"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85494859","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":"18 Regulation of Hippocampal Neurogenesis by Systemic Factors Including Stress, Glucocorticoids, Sleep, and Inflammation","authors":"P. Lucassen, C. Oomen, A. Dam, B. Czéh","doi":"10.1101/087969784.52.363","DOIUrl":"https://doi.org/10.1101/087969784.52.363","url":null,"abstract":"This chapter summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation. THE CONCEPT OF STRESS Ever present as stress may be in the modern Western society, it represents an old, yet essential, alarm system for an organism. By definition, stress systems are activated whenever a discrepancy occurs between an organism’s expectations and the reality it encounters, particularly when it involves a threat to the organism’s homeostasis, well-being, or health. Lack of information, loss of control, unpredictability, and uncertainty when faced with predator threat in animals or psychosocial demands in humans can all produce stress signals. The same holds for perturbations of a physical or biological nature, such as food shortage, injury, or inflammation. Various sensory and cognitive signals converge to activate a stress response that triggers several adaptive processes in the body and brain aimed to restore homeostasis. THE STRESS RESPONSE In mammals, the stress response develops in a stereotypic manner through three phases: (1) an initial alarm reaction, (2) resistance, and, only after prolonged exposure, (3) exhaustion. The first phase largely involves activation of the sympathoadrenal system through the rapid release of epinephrine and norepinephrine from the adrenal medulla; these hormones elevate basal metabolic rate and increase blood flow to vital organs such as the heart and muscles. At a later stage, the limbic hypothalamus-pituitary-adrenal (HPA) system is activated, i.e., a classic neuroendocrine circuit in which...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"14 1","pages":"363-395"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88703981","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":"15 Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus","authors":"J. Bischofberger, A. F. Schinder","doi":"10.1101/087969784.52.299","DOIUrl":"https://doi.org/10.1101/087969784.52.299","url":null,"abstract":"The hippocampus, located within the medial temporal lobe of the cerebral cortex, is critically important for the formation of semantic and episodic memory (Squire et al. 2004). As with other cortical circuits, the hippocampal network (Fig. 1) is highly dynamic and has the capacity to modify its connectivity by changing the number and strength of synaptic contacts in an activity-dependent manner. Synaptic connections can be added, strengthened, weakened, or eliminated in response to neuronal activity, a phenomenon called synaptic plasticity. The plasticity of specific hippocampal synapses has a significant role in memory formation and learning of hippocampus-dependent tasks (Nakazawa et al. 2004; Whitlock et al. 2006). The dentate gyrus (DG) of the adult hippocampus has the additional capacity of modifying the circuitry by the addition of new neurons. Thus, network remodeling is not limited to synapses, but also includes the incorporation of new functional units (neurons) that provide an additional dimension of plasticity to the existing hippocampal circuitry (Schinder and Gage 2004; Song et al. 2005; Lledo et al. 2006; Piatti et al. 2006). The biological significance of adult hippocampal neurogenesis depends on the extent to which adult-born neurons can participate in signal processing in the hippocampal network. The impact of new neurons on the adult neuronal circuitry will be highly determined by how they become engaged in network activity and how their intrinsic properties and connectivities compare to those of existing dentate granule cells (GCs) that were generated during development. To list some possibilities, adult-born neurons could be continuously...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"121 1","pages":"299-319"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86974139","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":"13 Proneuronal Genes Drive Neurogenesis on the Road from Development to Adulthood","authors":"Elizabeth T. Buchen, S. Pleasure","doi":"10.1101/087969784.52.267","DOIUrl":"https://doi.org/10.1101/087969784.52.267","url":null,"abstract":"The ongoing production of neurons in selected areas of the adult mammalian brain is tantalizing and has become an active area of research for many investigators. It is exciting to consider the functional importance of adding new neurons to mature circuits, as well as the intricate biological processes regulating their production (Meltzer et al. 2005; Ming and Song 2005; Lledo et al. 2006). Many investigators are also fascinated by the potential of repairing the injured nervous system with adult-generated neurons, those either produced in specialized adult neurogenic niches or induced in regions where little (if any) neurogenesis normally persists, such as the spinal cord or neocortex. Whether the inspiration is systems neuroscience, basic biology, or biomedical applications, the advancement of the field of neurogenesis depends on understanding the underlying molecular mechanisms regulating this process. When considering this central issue, most investigators have posited that molecular pathways important for development must have similar roles in the adult (Deisseroth et al. 2004; Meltzer et al. 2005; Ming and Song 2005). It is important to realize, however, that the number of studies demonstrating a required and specific role for any developmental regulators in adult neurogenesis is quite small. Adult neurogenesis is contingent on the functioning of the neurogenic niche, which must be produced during development, maintained during postnatal life, and regulated during adulthood. This presents a significant barrier for interpreting most genetic manipulations, as it is virtually impossible to distinguish adult requirements from developmental insults in most studies examining these pathways. To establish...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"6 1","pages":"267-282"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82186499","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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