Pub Date : 2008-01-01DOI: 10.1101/087969784.52.445
D. Abrous, J. Wojtowicz
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;...
在讨论诸如记忆之类的大脑功能时，我们应该将其与大脑的可塑性联系起来。可塑性的一个定义是执行相同功能的另一种方式。轶事证据表明，人类大脑可以以意想不到的、不同的方式表现出惊人的记忆壮举。例如，学者(部分脑损伤的个体)记忆事件、数字序列、字母或音符以及进行算术计算的能力表明，损伤后大脑回路的补偿性重新布线会影响学习。哪一种特殊的大脑可塑性会导致金·皮克(“雨人”)和丹尼尔·塔米特(“聪明人”)如此惊人的学习能力，这两个被诊断为自闭症的学者(www.savantsyndrome.com)?在本章中，我们描述了一种根本性的可塑性形式，即海马形成(HF)中的成人神经发生。成人神经发生(在成人大脑中产生新的神经元)的发现从根本上改变了我们对大脑如何适应生理和环境挑战的看法。在生理条件下，神经元的产生过程受到高度调控，并参与海马的功能。在某些情况下，神经发生可以对海马体相关的病理，如癫痫、缺血、情绪障碍和成瘾作出反应。了解神经发生，以及其他形式的大脑可塑性，可能有助于我们理解正常记忆，也许还能帮助我们理解像学者综合症患者那样的增强记忆(Treffert and Christensen 2005)。HF是学习和记忆相关的综合网络的一部分(Eichenbaum 2000,2001;…
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Pub Date : 2008-01-01DOI: 10.1101/087969824.51.575
J. Shay, W. Wright
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...
端粒在维持染色体完整性中的作用是由Barbara McClintock提出的(回顾，见Blackburn 2006)。在研究玉米染色体的端粒时，麦克林托克观察到，如果没有端粒的覆盖，染色体的末端有融合的倾向。50年后，她的观察结果在酵母和小鼠中得到证实，没有端粒末端，染色体会发生异常的端到端融合，形成多中心染色体，在有丝分裂期间容易断裂，激活dna损伤检查点，在某些情况下导致广泛的细胞死亡(Zakian 1989)。现在我们知道，由于细胞分裂导致的端粒缩短形成了复制衰老的基础，这种生长停滞最初是由Hayflick和Moorhead(1961)描述的。衰老与器官系统性能的逐渐下降有关，导致储备能力的丧失，从而导致死亡的机会增加(Gompertz 1825)。在一些器官系统中，随着年龄的增长储备能力的丧失可归因于细胞功能的丧失(Martin et al. 1970)。对特定组织/细胞类型的慢性局部应激可能导致细胞更新增加，据推测，这可能导致复制衰老的焦点区域(Hayflick和Moorhead 1961)，随后是基因表达模式的改变(West 1994;West et al. 1996)。这可能导致组织再生减少，最终导致一些通常与年龄增长相关的临床病理。除复制老化外，多种机制可诱发不可逆的…
{"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}
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...
如前一章所述，人转化生长因子-β (TGF-β，现称为TGF-β1)的生化表征，以及通过cDNA克隆确定其序列，为鉴定TGF-β与TGF-α在结构上的区别提供了依据。当时将其与TGF-α区别开来的最显著特征是TGF-β是一种25kd的二硫键二聚体，在用β-巯基乙醇处理后，在凝胶上被还原为12.5 kd的条带(Roberts et al. 1983)。在cDNA克隆之后(Derynck et al. 1985)，我们发现TGF-β在功能上与TGF-α完全不相似，其多肽序列与之前已知的任何序列都无关。预测的多肽序列也清楚地表明，成熟的TGF-β单体只对应于一个大得多的前体的羧基末端三分之一，因此需要蛋白水解裂解(见第1章图3)。随后的cDNA克隆表明，定义异聚二硫连接抑制素的多肽链在结构上与TGF-β相关(Mason等，1985;Vale et al. 1986)。这些多肽与TGF-β类似，编码为较大前体的羧基端多肽，只有羧基端成熟多肽与TGF-β具有结构相似性。由此产生的认识，可能有一个家族的分泌二硫连接二聚体多肽编码的羧基末端区段较大的分泌多肽。骨形态发生蛋白2a (BMP-2A)和BMP-2B(现在分别称为BMP-2和BMP-4)的cDNA克隆进一步证实了这一认识(Wozney…
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.135
J. Ray
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...
神经科学的中心教条“出生后没有新的神经元”已经存在了将近一个世纪。直到最近几年，人们才相信神经元只在胎儿发育阶段产生。成人神经发生的研究始于20世纪90年代，现在已经很清楚，活跃的神经发生是一种从未分化的多能干细胞或祖细胞产生功能完整的神经元的过程，在包括人类在内的哺乳动物的成年中枢神经系统的离散区域持续存在。在发育过程中，哺乳动物中枢神经系统中的神经细胞是由多能干细胞/祖细胞增殖产生的，这些细胞迁移，找到它们的最终目的地，并最终分化。由于其相对罕见和缺乏特异性表型标记，假定的干细胞已根据其功能标准进行表征。在给定组织中发现假定的干细胞通常取决于能够严格表征的体外培养条件的发展。根据这些标准，干细胞必须表现出增殖能力，在很长一段时间内自我更新，并产生大量的后代细胞(祖细胞或前体细胞)，这些后代细胞可以分化为产生它的组织的原代细胞类型(Gage 1998;寺庙2001 a, b)。体外培养包括干细胞和祖细胞，术语“干细胞、祖细胞和前体细胞”在文献中可互换使用。在本章中，我使用术语“干细胞/祖细胞”。神经干细胞/祖细胞的分子特征…
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.425
P. Lledo
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...
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.527
G. Patterson, R. W. Padgett
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...
在秀丽隐杆线虫中，有两种截然不同的转化生长因子-β (TGF-β)家族信号通路及其典型的核心信号成分，即配体，I型和II型丝氨酸-苏氨酸激酶受体和Smads(图1)。其中一种是dauer信号通路，控制秀丽隐杆线虫在恶劣环境条件下形成的第三个幼虫阶段(Riddle and Albert 1997)，以及摄食行为、脂肪代谢、产卵、和耐热性。另一条是体型通路，调节细胞大小、雄性尾巴发育和免疫(Patterson and Padgett 2000;Kurz and Tan 2004;尼古拉斯和霍奇金2004)。编码TGF-β家族信号通路组分的基因被鉴定为在决策调控中存在缺陷的突变体(该通路的示意图见图1B)。冬眠期是秀丽隐杆线虫交替的第三个幼虫阶段(图2)，在这个阶段，蠕虫为了应对不利于生长和繁殖的环境条件而“冬眠”(Albert and Riddle 1997)。在daer途径中，配体、受体或假定的受体激活的Smads (R-Smads)的突变导致daer -constitutive表型，在这种表型中，蠕虫进入并维持生长停滞，而在野生型蠕虫中，这种条件导致持续生长。在dauer通路中发现的第一个基因是daf-1，它编码一种I型TGF-β家族受体(Georgi et al. 1990)。它作为TGF-β家族受体的身份在…
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.549
O. Lindvall, Z. Kokaia
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...
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.363
P. Lucassen, C. Oomen, A. Dam, B. Czéh
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...
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.299
J. Bischofberger, A. F. Schinder
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...
海马体位于大脑皮层内侧颞叶内，对语义记忆和情景记忆的形成至关重要(Squire et al. 2004)。与其他皮层回路一样，海马体网络(图1)是高度动态的，并且有能力通过以活动依赖的方式改变突触接触的数量和强度来修改其连通性。突触连接可以根据神经元的活动而增加、加强、减弱或消除，这种现象被称为突触可塑性。海马特定突触的可塑性在海马依赖任务的记忆形成和学习中具有重要作用(Nakazawa et al. 2004;Whitlock et al. 2006)。成年海马的齿状回(DG)具有通过增加新的神经元来修改电路的额外能力。因此，网络重塑不仅限于突触，还包括新的功能单位(神经元)的结合，这些功能单位为现有的海马体回路提供了额外的可塑性维度(Schinder and Gage 2004;Song et al. 2005;Lledo等人，2006;Piatti et al. 2006)。成年海马神经发生的生物学意义取决于成年神经元参与海马网络信号处理的程度。新神经元对成年神经元回路的影响将在很大程度上取决于它们如何参与网络活动，以及它们的内在特性和连接如何与发育过程中产生的现有齿状颗粒细胞(GCs)的特性和连接进行比较。列举一些可能性，成人出生的神经元可以连续…
{"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}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.267
Elizabeth T. Buchen, S. Pleasure
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...
在成年哺乳动物大脑的特定区域不断产生神经元是诱人的，并已成为许多研究人员的一个活跃的研究领域。考虑到在成熟回路中添加新神经元的功能重要性，以及调节其产生的复杂生物过程，这是令人兴奋的(Meltzer等人，2005;明宋2005;Lledo et al. 2006)。许多研究人员还对用成体生成的神经元修复受损神经系统的潜力着迷，这些神经元要么产生于专门的成体神经发生龛，要么诱导于通常很少(如果有的话)神经发生的区域，如脊髓或新皮层。无论灵感来自系统神经科学、基础生物学还是生物医学应用，神经发生领域的进步取决于对调节这一过程的潜在分子机制的理解。在考虑到这一核心问题时，大多数研究人员都假设，对发育重要的分子途径在成人中也有类似的作用(deisserth et al. 2004;Meltzer等人，2005;Ming and Song 2005)。然而，重要的是要认识到，证明任何发育调节因子在成人神经发生中所必需和特定作用的研究数量相当少。成人神经发生取决于神经源性生态位的功能，它必须在发育过程中产生，在出生后生活中维持，并在成年期受到调节。这为解释大多数基因操作提出了一个重大障碍，因为在大多数检查这些途径的研究中，几乎不可能区分成人需求和发育损害。建立……
{"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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