Developmental Neuroscience: A Concise Introduction - Hardcover

Fahrbach, Susan E.

Hardcover

ISBN 10: 0691150982 ISBN 13: 9780691150987

Publisher: Princeton University Press, 2013

Synopsis

A concise introductory textbook on the development of the nervous system

This textbook offers a concise introduction to the exciting field of developmental neuroscience, a discipline concerned with the mechanisms by which complex nervous systems emerge during embryonic growth. Bridging the divide between basic and clinical research, it captures the extraordinary progress that has been achieved in the field. It provides an opportunity for students to apply and extend what they have learned in their introductory biology courses while also directing them to the primary literature.

This accessible textbook is unique in that it takes an in-depth look at a small number of key model systems and signaling pathways. The book's chapters logically follow the sequence of human brain development and explain how information obtained from models such as Drosophila and zebrafish addresses topics relevant to this area. Beginning with a brief presentation of methods for studying neural development, the book provides an overview of human development, followed by an introduction to animal models. Subsequent chapters consider the molecular mechanisms of selected earlier and later events, neurogenesis, and formation of synapses. Glial cells and postembryonic maturation of the nervous system round out later chapters. The book concludes by discussing the brain basis of human intellectual disabilities viewed from a developmental perspective.

Focusing on the mechanistic and functional, this textbook will be invaluable to biology majors, neuroscience students, and premedical and pre-health-professions students.

• An accessible introduction to nervous system development
• Suitable for one-semester developmental neuroscience course
• Thorough review of key model systems
• Selective coverage of topics allows professors to personalize courses
• Investigative reading exercises at the end of each chapter
• An online illustration package is available to professors

About this title

About the Author

Susan E. Fahrbach is the Reynolds Professor of Developmental Neuroscience in the Department of Biology at Wake Forest University.

From the Back Cover

"Written with a rare lucidity and grace, Susan Fahrbach's Developmental Neuroscience offers a systematic and logical account of the development of nerve cells and nervous systems, human and otherwise. The book is lecture friendly and the supplementary reading questions are ideal for college courses. It will be of surpassing interest to professors seeking a current treatment of developmental neuroscience."--Donald Pfaff, Rockefeller University and editor ofNeuroscience in the 21st Century

"The words 'delightful textbook' do not often occur together but they describeDevelopmental Neuroscience to a tee. Susan Fahrbach has an exceptional voice and, coupled with a deep scholarly bent, a keen ability for explaining the importance of developmental phenomena and how we come to understand them. There is much that is new here even for longtime instructors of the subject. This is a truly valuable addition to the field."--Darcy Kelley, Columbia University

"Developmental Neuroscience is an elegantly written take on a subject rooted in classical embryology but now yielding to the contemporary tools of molecular genetics and neuroimaging. Fahrbach's approach is patient and steady, surveying the current state of understanding through humans and different model organisms, with a sensitive ear to the cultural issues and contexts that will inform and motivate students."--David Clayton, Queen Mary, University of London

"This is the ideal textbook for students who want to think about particular big-picture topics and engage with the primary literature. With simple language, good points, interesting anecdotes, big ideas, and nice tie-in questions, the book provides broad brushstrokes on important issues, which then allows students, through guided discussion, to delve into specific developmental processes or signaling pathways."--Christopher Korey, College of Charleston

Excerpt. © Reprinted by permission. All rights reserved.

Developmental Neuroscience

A CONCISE INTRODUCTION

By Susan E. Fahrbach

PRINCETON UNIVERSITY PRESS

Copyright © 2013 Princeton University Press
All rights reserved.

ISBN: 978-0-691-15098-7

Contents

List of Illustrations......................................................
xi
Preface....................................................................
xv
Acknowledgments............................................................
xix
What Are Investigative Reading Questions?..................................
xxi
Teaching Using the Primary Literature and Investigative Reading Questions 
to Complement the Text.....................................................
xxiii
Chapter 1 Introduction.....................................................
Chapter 2 Overview of Nervous System Development in Humans.................
Chapter 3 Animal Models....................................................
Chapter 4 Early Events.....................................................
Chapter 5 Neurogenesis.....................................................
Chapter 6 Later Events.....................................................
Chapter 7 Becoming a Neuron................................................
Chapter 8 Glia.............................................................
Chapter 9 Maturation.......................................................
Chapter 10 Thinking about Intellectual Disability in the Context of 
Development................................................................
Abbreviations..............................................................
241
References.................................................................
251
Online Resources...........................................................
271
Full Citations for Investigative Reading Exercises.........................
277
Index......................................................................
281

CHAPTER 1

Introduction

What Do We Mean When We Say "Neural Development"?

Development unfolds smoothly over time but can be divided for experimentalanalysis into successive stages, each with its own defining events. Someof these events have clear beginnings and endings, although others may beprotracted, sometimes unexpectedly so. For example, myelination of axonsin the human brain, a key event that supports behavioral development byincreasing the rate of action potential transmission, begins approximately24 weeks after conception and then continues for decades. In general, theearliest events are most easily categorized as discrete stages shared by almostall members of a species, whereas later events are best described as ongoingprocesses, the exact details of which are unique to each brain. This is particularlytrue in long-lived species such as humans, but the inherent ability ofnervous systems to refine neural circuitry across the life span is evident evenin short-lived invertebrates. The neuroscientist Martin Heisenberg and colleagueswere reflecting on data obtained from neuroanatomical studies offruit fly brains, not human brains, when they were inspired to write, "Anindividual's life experience can ... be encoded in the volume of selectedneuropil regions."

What Is in This Book and How to Use It

After a brief presentation of methods (this chapter), an overview of humandevelopment (Chapter 2), and an introduction to animal models (Chapter3), the subsequent chapters consider the molecular mechanisms of selectedearlier and later events (Chapters 4 and 6), neurogenesis (Chapter 5), andformation of synapses (Chapter 7). Glial cells are the focus of Chapter 8.Chapter 9 describes the postembryonic maturation of the nervous systemvia metamorphosis in some species and adolescence in others. In Chapter 10the focus shifts to human intellectual disabilities. This chapter attempts tobuild a case that at least some forms of human intellectual disability reflectreversible differences in developmental processes rather than permanentdeficits. This chapter was inspired by my personal connections with twooutstanding neuroscientists—William T. Greenough at the University of Illinoisat Urbana-Champaign and Linda L. Restifo of the University of Arizona,a researcher who is also a physician. Many other outstanding investigatorswork in this field, but it was Greenough's studies of the fragile X protein inthe context of his life's work on experience-driven brain plasticity and Restifo'sstudies of mental retardation genes in Drosophila that forced me torethink my views on human intellectual disability.

Each chapter has notes. Some provide additional background informationon the topic being discussed. This information may be useful and/orinteresting, but it has been placed in the notes because I believe it is notessential for an understanding of neural development. The notes are probablymost helpful if they are consulted the first time you read the chapter.Some notes link specific results recounted in the text to specific references.The full references can be found in the chapter-by-chapter reference liststhat appear at the end of the book. These reference lists also include pertinentreviews and commentaries that provide additional context if you areinterested in the history of developmental neuroscience. Short chapter-by-chapterlists of trustworthy online resources can also be found at the end ofthe book. These are intended to provide additional graphic material andtechnical details as well as links to selected patient information web sites.This material is also nonessential. It is included to allow you to follow up aspecific interest, either as you read or in the future.

Students who want to go further will find that there are numerous pointsof entry into the research literature. The student can begin with the end-of-chaptersuggestions for Investigative Reading. Each of these readings is introducedby a short question based on the chapter. The answer to the question(one answer; the student may well come up with a superior alternative) iscontained in the recommended reading. Students are encouraged to try toanswer the questions on their own before going online to retrieve the article.Note that only partial citations are provided at the end of each chapter.This is because the titles of the articles often give the answers away! Thejournal articles listed in the Investigative Reading sections are freely accessibleonline, and full citations are provided at the end of the book.

This text is designed to provide a concise introduction to nervous systemdevelopment. This goal will be achieved, in part, by a nearly exclusive focuson the central nervous system (the brain and spinal cord in vertebrates, thebrain and nerve cord in invertebrates). We'll venture into the peripheralnervous system primarily in Chapter 7, where I use the neuromuscular junctionto describe how synapses form. Topics intentionally shortchanged forthe sake of brevity include the history of embryology, the neural crest, developmentof vertebrate sense organs, and the emerging story of microRNAs(miRNAs) as posttranscriptional regulators of development. In addition,many of the signal transduction pathways described in this book have beenpruned for clarity. Even in the garden, pruning is a tricky business. I apologizein advance if I inadvertently clipped your favorite branches.

Methods for Studying Development of the Nervous System

The modern neuroscientist's tool kit is stocked with powerful tools for studyingthe structure and function of the nervous system. While the tools of theelectrophysiologist (intra- and extracellular recordings of neuronal electricalactivity) and the neuroanatomist (many variants of microscopy) are still inheavy use, many developmental neuroscientists routinely incorporate measuresof gene expression and functional brain imaging into their studies.Others just as routinely use genetically engineered (transgenic) animals.

The following sections introduce key techniques used to study nervoussystem development. Some researchers specialize in a particular technique,but many investigators work in teams and combine multiple approaches toanswer research questions. Students who delve into the primary research literatureare often amazed at the number of techniques required to generatethe data contained in a single paper. This is one of the reasons that manymodern research papers feature lengthy author lists.

Birthdating

All cells, including neurons, are produced by division of other cells. Thetime at which the cell division occurs that produces a particular neuron isreferred to as that neuron's birthdate. Knowing neuronal birthdates is importantfor understanding the sequence of events that builds a neural circuit ora brain. Birthdating is also important for exploring the capacity of maturebrains to add new neurons. Neurons themselves do not divide—part ofbecoming a neuron involves saying farewell to the cell cycle—so the challengeto the developmental neuroscientist wishing to determine a birthdateis to catch the neuron in the act of being produced by a progenitor cell thatby definition is not itself a neuron.

If an animal is small and transparent, the process of cell division can beobserved directly using a microscope. Otherwise, developing tissues may befixed (preserved by chemical treatment), sectioned into thin slices (sectionthickness is typically measured in micrometers, µm), and attached to glassslides for viewing with a microscope. Stains may be applied to the sectionsto enhance detection of dividing cells. A combination of hematoxylin andeosin reveals key features of many tissues, including nervous tissue, becausehematoxylin stains nuclei blue and eosin stains most other structures red orpink. DNA stains aid the identification of mitotic profiles by making condensedmetaphase chromosomes readily visible. The Feulgen stain is traditionallyused to mark DNA for viewing with a standard bright-field microscope.Modern biologists with access to a fluorescence microscope can choosefrom an array of colorful dyes that bind to DNA.

A drawback to searching for mitotic profiles in tissue is that the windowfor detecting these profiles is often so brief that the likelihood of catching aneuron in the act of being born is small. An alternative approach also relieson detection of DNA, but instead of staining all of the nuclear DNA presentin a tissue, the investigator labels only new DNA. This is accomplished byproviding special DNA precursors to cells as they copy their nuclear DNAprior to cell division. These precursors do not occur naturally in cells. Becausethe precursor provided is incorporated into new DNA, any neuronsborn during the time the precursor was present contain labeled DNA andcan therefore be distinguished from cells born when the precursor was notpresent.

In classic studies, living animals were injected with the nucleoside thymidinelinked to a radioactive atom (a nucleoside is a purine or pyrimidinebase attached to a ribose sugar molecule; a radioisotope commonly used tolabel nucleosides is tritium, a radioactive isotope of hydrogen). The distributionof radioactivity in a tissue section prepared from the treated animalwas subsequently detected by applying the section to a photographic emulsion.The radioactive decay particles emitted from the radioisotope exposedthe film. At the end of an exposure period typically measured in months, thelocation of nuclei with radiolabeled DNA was revealed by developing theemulsion using darkroom chemicals. This method of detecting the distributionof a radioisotope in tissue is known as autoradiography.

Tritiated thymidine (³H-thymidine) was used in neuronal birthdating studiesthrough the 1970s. Its use has been superseded by a method based ondetection of bromodeoxyuridine, a synthetic nucleoside that is an analog ofthymidine. Antibodies can be purchased that bind specifically to bromodeoxyuridine.Labels attached to these antibodies make the position of bromodeoxyuridinewithin a tissue section readily evident using standard techniquesof light microscopy (fig. 1.1). Bromodeoxyuridine is commonly referred to byits nickname, BrdU, pronounced bee-are-dee-you. Oval spots representingBrdU-labeled nuclei flash before the mind's eye of a neuroscientist who hearsthe term neuronal birthdating.

Birthdating methods that rely on incorporated nucleosides work onlywhen the investigator can introduce the marker at the appropriate stagewithout perturbing normal development. Depending on the species, thismay be accomplished by injecting or feeding or by immersing the entire animalin a solution containing BrdU. An alternative approach relies on immunodetectionof endogenous molecules expressed by dividing cells. This circumventsthe need to introduce a marker. Antibodies are available thatrecognize proteins expressed during the cell cycle. These include antibodiesthat bind to proliferating cell nuclear antigen (PCNA) and a nuclear proteincalled Ki-67. These proteins are not expressed by mature, postmitotic neurons,but they are good markers for progenitor cells and for newborn neurons,as they persist for several hours after mitosis before being metabolized.

One disadvantage of relying on the immunolabeling of endogenous proteinsas markers for mitosis is that the antibodies used in these studies maynot recognize proteins from a broad range of species. For example, antibodiesraised against a fragment of human Ki-67 nuclear protein will likely crossreactwith similar proteins expressed during the cell cycle in other mammalsbut are unlikely to bind even to related proteins in fish, birds, or insects. Thechallenges imposed by the need to introduce BrdU into developing tissuesare often outweighed by the fact that this marker can be used to birthdateneurons (and other cells) in absolutely all animals, from hydras to humans.

Tissues exposed to BrdU can be chemically fixed for analysis shortly afterintroduction of the marker. This provides a snapshot of the cell divisionsoccurring at a specific point in development. Another approach is to allowthe BrdU-treated animal to survive for some length of time after the markeris introduced. Because neurons do not divide, incorporated BrdU will persistin the nuclear DNA. The incorporated BrdU can be detected as long as theanimal (or the neuron) lives.

Lineage Analysis

Lineage analysis refers to tracing the origin of a particular cell or cell typeback through a series of successive cell divisions. This method differs frombirthdating techniques in that the result is a family tree rather than a birthdate.Of course, the lineage of every cell in the body can be traced back tothe fertilized egg (zygote), so it is not necessary to do experiments to provethis. It is the later portions of the lineage that are interesting to developmentalneuroscientists, because these represent points at which developmentalmechanisms act to limit a cell's fate.

The optical microscopes of the nineteenth century permitted biologiststo observe living tissues directly to determine cell lineage. Direct observationremains a powerful tool for lineage analysis in small transparent ortranslucent embryos. In the 1970s and 1980s, direct observation of celldivisions was used to determine the lineage of every cell in Caenorhabditiselegans, a nematode worm. Researchers used the technique of differentialinterference contrast (DIC) microscopy to enhance the contrast of the unstainedliving embryos and larvae they examined. But determination of celllineage by direct observation is impossible in many animals, either becausethe embryo is not transparent or because development occurs inside an eggwith an opaque shell or inside the mother's body. As a consequence, celllineage determinations are often based on introduction of a marker intosuspected progenitor cells. For example, a small amount of dye can be injectedinto a cell. If that cell subsequently divides, the resulting daughtercells will each contain some of the dye. It can be inferred that the injectedcell was the parent of the pair of dyed cells. If one or both of the dyeddaughter cells divides, the dye will also be found in the granddaughters ofthe injected cell.

A disadvantage of the direct injection method is dilution of the marker.Whatever dye was injected will be partitioned between pairs of progeny andhence diluted upon each successive division. Eventually the lineage markerwill be so diluted that it will become undetectable. As a consequence, the simplestversions of this method cannot be used for analysis of long lineages.

But what if we could introduce a marker that replenished itself in thedaughter cells after each division? Avoiding dilution would make it possibleto trace long cell lineages. This approach is exploited by two powerfulmethods for determining cell lineage. The first is based on retroviruses thatcarry marker genes. The second produces marked cells by a process of generecombination.

The genes of retroviruses are encoded in RNA instead of DNA. When aretrovirus infects a cell, the RNA-based genome of the virus is reverse transcribedand then integrated into the DNA of the infected cell. If the infectedcell is a progenitor cell, its daughters inherit the viral genes along with thegenes of the progenitor cell. Progenitor cells are typically infected by injectingthe retrovirus into the extracellular fluid near the target cell or cells.

Natural retroviruses are altered for use in cell lineage tracing in the followingways. First, they are modified so that they cannot replicate. This modificationprevents the virus from infecting neighboring cells, which may alsobe progenitors. Without this modification, it would be difficult to be certainthat an inferred cell lineage was correct. Second, the retrovirus is modified sothat it carries a reporter gene in addition to its own viral genes. A reportergene produces a product that is easy to measure or see under a microscope.Two commonly used reporter genes code for the enzymes horseradish peroxidase(not surprisingly, a peroxidase enzyme produced by horseradishplants) and β-galactosidase (an enzyme encoded by the lacZ gene of E. coli).The presence of the retrovirus in a particular cell is revealed by supplying thetissue with the appropriate enzyme substrate; for example, the organic compoundX-gal forms a blue product in the presence of β-galactosidase.

(Continues...)

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Edition details

• Publisher: Princeton University Press
• Publication date: 2013
• ISBN 10: 0691150982
• ISBN 13: 9780691150987
• Binding: Hardcover
• Language: English
• Number of pages: 320