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This page intentionally left blank
The Newborn Brain
 Laminar patterns in microcephaly vera.
Architectonic patterns of normal cortex (left
panel) and cortex from microcephalic
subjects (right panel). The Betz cells in
column 3 and 4 of the left and right panels
identify the pre-Rolandic gyrus in normal
and microcephalic brains. The other
columns in each panel illustrate
corresponding regions of frontal, parietal,
and occipital association cortical regions.
The microcephalic cortex is laminated with
attenuation of superficial layers. (From
Hammarberg, 1895; Caviness et al., 2008,
with permission from S. Karger AG, Basel.)

Milestones of brain development. Based on Dobbing, J. and Sands, J. Timing of neuroblast multiplication in developing human brain. Nature
1970; 226: 639–40 and Rakic, P. Specification of cerebral cortical areas. Science 1988; 241: 170–6.
The
Newborn Brain
Neuroscience and Clinical
Applications
Second Edition
Hugo Lagercrantz
Department of Women and Child Health, Astrid Lindgren Children’s Hospital, Karolinska Institutet, Stockholm, Sweden

Co-editors
M. A. Hanson
Institute of Developmental Sciences, University of Southampton, Southampton, UK

Laura R. Ment
Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA

Donald M. Peebles
Department of Obstetrics and Gynaecology, University College London School of Medicine, London, UK
CAMBRIDGE UNIVERSITY PRESS
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Cambridge University Press

The Edinburgh Building, Cambridge CB2 8RU, UK

Published in the United States of America by Cambridge University Press, New York

www.cambridge.org
Information on this title: www.cambridge.org/9780521889759
© Cambridge University Press 2010

This publication is in copyright. Subject to statutory exception and to the

provision of relevant collective licensing agreements, no reproduction of any part
may take place without the written permission of Cambridge University Press.
First published in print format 2010

ISBN-13 978-0-511-71239-5 eBook (NetLibrary)

ISBN-13 978-0-521-88975-9 Hardback

Cambridge University Press has no responsibility for the persistence or accuracy

of urls for external or third-party internet websites referred to in this publication,
and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.
Every effort has been made in preparing this publication to provide accurate
and up-to-date information which is in accord with accepted standards and
practice at the time of publication. Although case histories are drawn
from actual cases, every effort has been made to disguise the identities of
the individuals involved. Nevertheless, the authors, editors and publishers
can make no warranties that the information contained herein is totally
free from error, not least because clinical standards are constantly
changing through research and regulation. The authors, editors and
publishers therefore disclaim all liability for direct or consequential
damages resulting from the use of material contained in this publication.
Readers are strongly advised to pay careful attention to information provided
by the manufacturer of any drugs or equipment that they plan to use.
Contents
List of contributors page vii
Preface to the First Edition xi
Preface to the Second Edition xiii

1 Reflections on the origins of the human 8 Glial cell biology 121

brain 1 Arne Schousboe and Helle S. Waagepetersen
Jean-Pierre Changeux

Section 2: Sensory systems

Section 1: Making of the brain and behavior
2 The molecular basis of central nervous system
9 Development of the somatosensory
development 23
system 129
Ola Hermanson and Urban Lendahl
Sandra Rees, David Walker,
Historic box 1 35
and Ernest Jennings
Hugo Lagercrantz
10 Principles of endogenous and sensory
3 Holoprosencephaly and microcephaly vera:
activity-dependent brain development:
perturbations of proliferation 37
the visual system 147
Verne S. Caviness Jr., Pradeep G. Bhide, and
Anna A. Penn and Carla J. Shatz
Richard S. Nowakowski
Historic box 5 161
Historic box 2 53
Hugo Lagercrantz
Hugo Lagercrantz
11 Fetal and neonatal development of the
4 Neuronal migration 55
auditory system 163
Sandrine Passemard, Angela M. Kaindl,
S. Allen Counter
Virginia Leverche, Pascal Dournaud,
and Pierre Gressens 12 Newborn behavior and perception 185
Elena V. Kushnerenko and
5 The neonatal synaptic big bang 71
Mark H. Johnson
Jean-Pierre Bourgeois
6 Neurotrophic factors in brain development 85
Thomas Ringstedt Section 3: Radiological and
Historic box 3 96 neurophysiological investigations
Hugo Lagercrantz
13 Imaging the neonatal brain 199
7 Neurotransmitters and neuromodulators 99 Mary A. Rutherford
Eric Herlenius and Hugo Lagercrantz
Historic box 4 119 14 Electroencephalography and amplitude-
Hugo Lagercrantz integrated EEG 211
Lena Hellström-Westas and Ingmar Rosén

v
 Contents

15 Emergence of spontaneous and evoked Section 5: Follow-up

electroencephalographic activity
in the human brain 229 20 Injury and recovery in the developing brain 329
Sampsa Vanhatalo and Kai Kaila Koray Özduman and Laura R. Ment
21 Development of motor functions in health
and disease 345
Section 4: Clinical aspects Mijna Hadders-Algra and Hans Forssberg
16 Infection, inflammation, and damage
22 Antenatal glucocorticoids and programming
to fetal and perinatal brain 245
of neuroendocrine function and behavior 361
Gennadij Raivich and Donald M. Peebles
Stephen G. Matthews and Amita Kapoor
17 Hypoxic–ischemic encephalopathy 261
Deanna L. Taylor, Grisha Pirianov, A. David
Edwards, and Henrik Hagberg Section 6: Consciousness
18 Clinical assessment and therapeutic 23 On the emergence of consciousness 377
interventions for hypoxic–ischemic Hugo Lagercrantz and Jean-Pierre
encephalopathy in the full-term Changeux
infant 281
Andrew Whitelaw and Marianne Thoresen
19 Clinical aspects of brain injury in the
Index 395
preterm infant 301
Michael Weindling The color plates appear between pages 146 and 147

vi
Contributors

Pradeep G. Bhide PhD Mijna Hadders-Algra MD, PhD

Department of Neurology, Massachusetts General Department of Paediatrics – Developmental
Hospital, Harvard Medical School, Boston, MA, USA Neurology, University Medical Center Groningen,
Groningen, The Netherlands
Jean-Pierre Bourgeois PhD
Génétique Humaine et Fonctions Cognitives, Henrik Hagberg MD, PhD
Département de Neuroscience, Institut Pasteur, Paris, Institute of Reproductive and Developmental Biology,
France Imperial College, London, UK
Verne S. Caviness Jr. MD, DPhil Lena Hellström-Westas MD, PhD
Department of Neurology, Massachusetts General Department of Women’s and Children’s Health,
Hospital, Harvard Medical School, Boston, MA, USA Uppsala University, Uppsala, Sweden
Jean-Pierre Changeux PhD Eric Herlenius MD, PhD
Département de Neuroscience, Institut Pasteur, Paris, Department of Women and Child Health, Astrid
France Lindgren Children’s Hospital, Karolinska Institutet,
Stockholm, Sweden
S. Allen Counter PhD DMSc
Neurology Department, Harvard Medical School, Ola Hermanson PhD
The Biological Laboratories, Cambridge, MA, USA Department of Neuroscience, Karolinska Institutet,
Stockholm, Sweden
Pascal Dournaud PhD
Inserm, U676, Paris, France; Université Paris 7, Ernest Jennings PhD
Faculté de Médecine Denis Diderot, Paris, France; Department of Anatomy and Cell Biology, University
AP HP, Hôpital Robert Debré, Service de Neurologie of Melbourne, Parkville, Victoria, Australia
Pédiatrique, Paris, France
Mark H. Johnson PhD
A. David Edwards FMedSci Centre for Brain and Cognitive Development, School
Division of Clinical Sciences, Imperial College, of Psychology, Birkbeck College, University of
London, UK London, London, UK
Hans Forssberg MD, PhD Kai Kaila PhD
Division of Neuropediatrics, Department of Woman Department of Neurosciences and Neuroscience
and Child Health, Karolinska Institute, Stockholm, Center, University of Helsinki, Helsinki,
Sweden Finland
Pierre Gressens MD, PhD Angela M. Kaindl PhD, MD
Inserm, U676, Paris, France; Université Paris 7, Inserm, U676, Paris, France; Université Paris 7,
Faculté de Médecine Denis Diderot, Paris, France; Faculté de Médecine Denis Diderot, Paris, France;
AP HP, Hôpital Robert Debré, Service de Neurologie AP HP, Hôpital Robert Debré, Service de Neurologie
Pédiatrique, Paris, France Pédiatrique, Paris, France

vii
 List of contributors

Amita Kapoor PhD Anna A. Penn MD, PhD

Departments of Physiology and Obstetrics and Department of Pediatrics/Neonatal and
Gynecology, Faculty of Medicine, University of Developmental Medicine, Stanford University School
Toronto, Toronto, Ontario, Canada of Medicine, Stanford, CA, USA
Elena V. Kushnerenko PhD Grisha Pirianov PhD
Institute for Research in Child Development, School of Division of Cardiovascular Sciences, St George’s
Psychology, University of East London, London, UK University of London, London, UK
Hugo Lagercrantz MD, PhD Gennadij Raivich MD, DSc
Department of Women and Child Health, Astrid Perinatal Brain Repair Group, Department of
Lindgren Children’s Hospital, Karolinska Institutet, Obstetrics and Gynaecology, University College
Stockholm, Sweden London School of Medicine, London, UK
Urban Lendahl PhD Sandra Rees MSc, MPhil, PhD
Department of Cell and Molecular Biology, Medical Department of Anatomy and Cell Biology, University
Nobel Institute, Karolinska Institutet, Stockholm, of Melbourne, Parkville, Victoria, Australia
Sweden
Thomas Ringstedt PhD
Virginia Leverche PhD Neonatal Unit, Department of Women and Child
Inserm, U676, Paris, France; Université Paris 7, Health, Astrid Lindgren Children’s Hospital,
Faculté de Médecine Denis Diderot, Paris, France; Karolinska Institutet, Stockholm, Sweden
AP HP, Hôpital Robert Debré, Service de Neurologie
Pédiatrique, Paris, France Ingmar Rosén MD, PhD
Department of Clinical Neurophysiology, University
Stephen G. Matthews PhD Hospital, Lund, Sweden
Departments of Physiology and Obstetrics and
Gynecology, Faculty of Medicine, University of Mary A. Rutherford FRCR, FRCPCH
Toronto, Toronto, Ontario, Canada Imaging Sciences Department, MRC Clinical Sciences
Centre, Imperial College, London, UK
Laura R. Ment MD
Department of Pediatrics, Yale University School of Arne Schousboe DSc
Medicine, New Haven, CT, USA Department of Pharmacology and
Pharmacotherapy, Faculty of Pharmaceutical
Richard S. Nowakowski PhD Sciences, University of Copenhagen, Copenhagen,
Department of Neuroscience and Cell Biology, Denmark
University of Medicine and Dentistry, New Jersey –
Robert Wood Johnson (UMDNJ-RWJ) Medical Carla J. Shatz PhD
School, Piscataway, NJ, USA Department of Biology/Director of Bio-X,
Stanford University School of Medicine,
Koray Özduman MD Stanford, CA, USA
Department of Neurosurgery, Yale University School
of Medicine, New Haven, CT, USA Deanna L. Taylor PhD
Division of Neuroscience and Mental Health, Imperial
Sandrine Passemard MD College, London, UK
Inserm, U676, Paris, France; Université Paris 7,
Faculté de Médecine Denis Diderot, Paris, France; Marianne Thoresen MD, PhD, FRCPCH
AP HP, Hôpital Robert Debré, Service de Neurologie Department of Clinical Science at South Bristol,
Pédiatrique, Paris France University of Bristol, Bristol, UK

Donald M. Peebles MA, MD, MRCOG Sampsa Vanhatalo MD, PhD

Perinatal Brain Repair Group, Department of Department of Children’s Clinical Neurophysiology,
Obstetrics and Gynaecology, University College Helsinki University Central Hospital, Helsinki,
viii London School of Medicine, London, UK Finland
 List of contributors

Helle S. Waagepetersen Cand Pharm, PhD Michael Weindling BSc, MA, MD, FRCP, FRCPCH
Department of Pharmacology and Pharmacotherapy, School of Reproductive and Developmental Medicine,
Faculty of Pharmaceutical Sciences, University of University of Liverpool at Liverpool Women’s
Copenhagen, Copenhagen, Denmark Hospital, Liverpool, UK

David Walker PhD, DSc Andrew Whitelaw MD, FRCPCH

Department of Physiology, Monash University, Department of Clinical Science at North Bristol,
Clayton, Victoria, Australia University of Bristol, Bristol, UK

ix
Preface to the First Edition

For ages philosophers have discussed how the brain other hand, the basic scientist may have only a vague
and the mind are created. Descartes and Kant thought idea of the clinical expression of mutations or disor-
that true ideas are innate, while Locke and Hume ders of neuronal migration and synaptogenesis, pre-
claimed that the brain is a blank slate at birth. term birth or perinatal asphyxia.
William Harvey opposed the idea that the organs, Jean-Pierre Changeux commences the book with
e.g., the brain, are preformed and maintained that the some reflections on the origin of the human brain. The
organs develop successively – epigenesis. Sigmund chapters then follow the major milestones of brain
Freud who can be regarded as determinist wrote that development: formation of the neural tube, neurogen-
our ideas and psychology are based on small substruc- esis, migration of neurons, synaptogenesis and organiza-
tures (genes). The mapping of the human genome has tion of the brain wiring. Special chapters are devoted
reinitiated a debate on the concept of preformation – to neurotrophic factors, neurotransmitters, glial cell
today genetic determinism vs. environmental instruc- biology and cerebral circulation. Then the develop-
tionism. A third alternative is the idea of selectionism ment of sensory functions is described.
or neuronal darwinism. The premature brain is a The second part of the book deals with more clin-
jungle according to Gerald Edelman with redundant ical aspects, particularly methods to investigate the
neurons and pathways and due to environmental infant brain by imaging and electrophysiological tech-
influences only the most suitable neuronal circuits niques. Two chapters deal with clinical aspects of the
survive (see chapter by Changeux). “Cells that fire brain of the full-term infant and one with the preterm
together wire together – those that don’t won’t.” infant. The authors have specially emphasized how the
(see chapter by Penn & Shatz). knowledge from basic science can be applied in clinical
The busy obstetrician scanning the fetal brain by practice.
ultrasound or the neonatologist monitoring the new- We hope that this book is of interest for a broad
born brain may have limited time to ponder these readership from the more theoretical biologist, molec-
eternal questions. The main reason for publishing ular geneticist and the biophysicist to the clinical fel-
this book is to present the state of the art on how the low in obstetrics, neonatology or neuropediatrics as
brain is formed. The recent breakthroughs in our well as the neuropsychologist. The book can also be
understanding of the development of the brain origi- recommended as a textbook for graduate courses.
nate from studies of invertebrates like fruit-flies or
nematodes, mice or ferrets. It is difficult for the hard- Stockholm, Paris, and London
working clinician attending the delivery, neonatal or December 30, 2000
neuropediatric ward to grasp this literature. On the The Editors

xi
Preface to the Second Edition

Understanding the development of the human brain necessary to understand these problems. These chapters
and the emergence of consciousness is a fundamental encompass imaging the brain, biophysical assessment
quest, of similar magnitude to the study of the origin of the brain, hypoxic–ischemic encephalopathy, the
of life from inorganic matter. We can talk about a “big vulnerable preterm brain, and infections of the brain.
bang” of brain development, when hundreds of thou- The mechanisms leading to abnormal neuropsycholog-
sands of new neurons are formed every minute in the ical outcome are also discussed in detail.
fetal brain and up to one million synapses are gener- In this second edition most of the chapters from
ated every second in the child’s brain. Jean-Pierre the first edition have been completely rewritten in line
Changeux opens this book with a reflection on the with modern science and clinical practice. Some new
origin of the human brain. The main milestones – chapters have been added, for example on behavior
such as the proliferation and migration of neurons, and the emergence of consciousness.
synaptogenesis, formation of glial cells – are presented We hope that this book will be of interest for a
in separate chapters by leading authorities in the field. broad readership from theoretical biologists, mole-
The selection of neuronal pathways and the organiza- cular geneticists, and biophysicists to clinicians in
tion of the neuronal circuits are discussed by Carla obstetrics, neonatology, and neuropediatrics, as well
Shatz and others. The development of somatosensory, as neuropsychologists. The book can also be recom-
visionary, and auditory modalities are described in mended as a textbook for graduate courses.
detail. There are also separate chapters on neurotro-
phic agents and neurotransmitters/neuromodulators. Stockholm, New Haven, Southampton, and London
The remainder of the book deals more with clin- October 13, 2009
ical matters, while also presenting the basic science The Editors

xiii
 1
Chapter

Reflections on the origins

of the human brain
Jean-Pierre Changeux

Introduction Universality, diversity, complexity

Human beings belong to the biological species Homo A primary difficulty, raised by the philosopher John
sapiens. The definition of the species includes the Searle (1995), concerns the notion of function, specially
description of the characteristic anatomy and physio- psychological function in the case of humans. One
logy of the body, as well as of the functional organiza- should never underestimate the conceptual and exper-
tion of the brain together with the multiple facets imental predicaments posed by any attempt to singu-
of behaviors unique to human beings. The human larize a behavioral or mental trait. Searle even suggests
brain is obviously a fascinating object of scientific that functions are not intrinsic, but might be assigned
investigation. to, or imposed on, living objects or organisms, and
The aim of this chapter is to debate the origins of the in particular the human brain, by the observer. This
human brain. This raises an overwhelming challenge. problem must be taken seriously. Even though, since
First of all, one should attempt to delineate what makes Darwin, attempts have been made to eliminate
the human brain “human,” even in the newborn, and to teleology from the life sciences, one has to be aware
identify the features that distinguish it from the current of a possible observer bias in the definition of a func-
living primates and from its fossil antecedents. It is tion. The difficulty is real for the pediatrician who has
intriguing, on the one hand, to find ways of specifying to objectively evaluate newborn perceptive abilities and
the universal traits of “human nature” in objective behavior. In my opinion, Searle’s criticism could go
terms. On the other hand, the broad diversity between beyond the definition of function and equally applies
individuals, in particular as a consequence of their past to the description of the anatomy or to the dynamics
and recent personal and/or cultural history, raises a of the electrical and chemical activities that take place
second challenge. Does such diversity break the unity within the brain. To overcome these difficulties, a rec-
of the human brain within the human species? ommended strategy is to elaborate theoretical models,
A tension thus exists in neuroscience, as well as in even within the clinical framework of pediatrics.
the humanities, between two main lines of research: Furthermore, the theoretical models that will primarily
one that aims at defining the universal characteristics aim at resolving brain complexity, to my view, should
of the human species, for instance at the level of the not to be confined to a given discipline or technique.
infant brain, and the other that stresses the variability On the contrary, they have to systematically bring
of cognitive abilities in adults, such as the language together well-defined molecular, anatomical, physio-
they speak and the social conventions they adopt. It logical, behavioral, and psychological data (see
is a formidable task to deal with these contrasting Changeux et al., 1973; Changeux, 2004). In any case,
approaches with the aim of achieving a meaningful the aim of the modeling enterprise will not be to give
scientific understanding of the human brain, its learn- an exhaustive description of brain reality: one has to
ing capacities, and its higher functions, and it remain humble! It will, furthermore, in any case be
seems plausible that a realistic picture of the human limited by its scope and by its formulation. Moreover,
brain will require the synthesis of these divergent one should never forget that the modeling process
approaches. I shall therefore consider successively involves the selection of theoretical representations…
these two aspects of research on the human brain. by the brain of the model builder!

The Newborn Brain: Neuroscience and Clinical Applications, 2nd edn., eds. Hugo Lagercrantz, M. A. Hanson, Laura R. Ment, and
Donald M. Peebles. Published by Cambridge University Press. © Cambridge University Press 2010.
 Chapter 1: Reflections on the origins of the human brain

(a) (b)

(c) (d)

Fig. 1.1 Comparison of the impression of the meningeal vessels on endocranial casts of 40-day-old infant (a) and 1-year-old infant (b) with
the endocranial casts of Australopithecus gracilis (c) and Homo habilis (d). (From Saban, 1995.)

Another difficulty resides in the very attempt to hierarchical level (or, more probably, levels) of organiza-
establish an appropriate causal link, or “bridge,” tion at which a relevant causal link will be estab-
between the structural elements of the system and the lished between anatomy, physiology, and behavior,
function considered. The reductionist approach, as together with the massive parallelism and strong lat-
mentioned, has to be “fair.” One should deliberately eral interactions that potentially contribute to coher-
avoid frequently encountered statements such as ent unitary brain processes.
“the gene(s) of intelligence” or the “neurotransmitters I will make one last remark about brain complex-
of schizophrenia!” Such simplistic and incorrect pro- ity, which may seem far-fetched to the pediatrician:
posals bypass one essential feature of brain organiza- my conviction is that investigations on the human
tion; that is, there is no direct and unequivocal link brain, in particular that of the newborn, should deal
between the molecular and the cognitive levels. In with our current understanding of biological evolution
between these, there exist parallel and hierarchical (Fig. 1.1). This requirement is obviously of practical
levels of organization nested within each other and interest, since it may lead to a fair evaluation of the
with abundant cross-connections. These levels develop commonly adopted (sometimes erroneous) use of
step by step from the molecule to the cell, from ele- lower animal species as models for human diseases,
mentary circuits to populations (or assemblies) of in particular for neuropsychiatric deficits. But the evo-
neurons, up to complex global neuronal patterns lutionary perspective also points to interesting empi-
engaged in higher cognitive functions. The definition rical questions. Take, for instance, the case of brain
of these relevant parallel and hierarchical levels is anatomy. No simple apparent logic accounts for the
in itself a difficult theoretical problem that should be actual morphology, distribution, and interrelation of
made explicit (Changeux & Connes, 1989). A critical the multiple areas (or nuclei) that compose the brain
conceptual and practical issue in any investigation of (see Changeux, 1985). For instance, the actual nesting
2 the newborn brain will thus be to specify the selected of the archeo-, paleo-, and neocortices within human
 Chapter 1: Reflections on the origins of the human brain

brain anatomy cannot be understood without consid- (Watson et al., 2007). But these genes are not expressed
ering that they have been derived by some kind of all at once in the egg or the embryo or the newborn, as
evolutionary “tinkering” (Jacob, 1981) from prior postulated by the extreme views of the eighteenth-
ancestral brains. The older structures have not been century preformationists, views that assumed that the
eliminated, but rather incorporated and nested within adult organism was already present in a miniaturized
the newer ones. Millions of years of evolutionary his- form in the sperm and in the egg. On the contrary, they
tory under extremely variable environmental condi- are activated (or suppressed) throughout embryogen-
tions thus introduce, indirectly, contingencies in the esis and postnatal development in a sequential and
anatomy such that the intrinsic logic of the functional combinatorial manner.
organization of the brain may no longer be apparent The straightforward inspection of the genetic
by simple inspection. This situation frequently inva- endowment of the species compared with the organiza-
lidates attempts to infer function from anatomy or to tion of the brain raises, however, two apparent
relate a given behavior to a single brain structure, such paradoxes (Changeux, 1983a,b, 2004; Edelman, 1987;
as, for instance, the current debates about the role of Miklos & Rubin, 1996). The total amount of DNA
the hippocampus, amygdala, or prefrontal cortex in present in the haploid genome comprises approxi-
behavior. It also illustrates why the best models may mately 3.1 billion base pairs, but no more than
not be the simplest or the most minimalistic ones. 20 000–25 000 genes sequences (Lander et al., 2001;
Model building thus has to rely on concrete observa- Venter et al., 2001). The coding exons represent only
tional approaches, to be “neurorealist,” and it becomes 1.2% of our genome, yet alternative splicing may
a particularly difficult, though necessary, process to increase the number of mRNA protein-coding sequen-
progress in the understanding of the human brain. ces up to 100 000. On the other hand, the total number
Finally, one should not limit the evolutionary per- of cells in the brain is in the order of 170 billion,
spective to the context of the biological – or genetic – including 86 billion neurons (Herculano-Houzel et al.,
origins of the human brain. Rather, as discussed in 2007, Azevedo et al., 2009), each neuron possessing its
the following sections, the brain of a human subject particular connectivity – or “singularity” (Changeux,
may be more appropriately viewed as the synthesis 1983a). There is thus a striking parsimony of genetic
of multiple nested evolutions by variation selection information to code for brain complexity.
(Changeux, 1983a,b, 2004). These developments Another paradox is raised by the relation between
include not only the past genetic evolution of the the total number of genes and the evolution of brain
species, but also the epigenetic development of the organization. The 97 million bases that constitute
brain of each individual, within the framework of the total sequence of the genome of a small inverte-
his or her personal history, as well as the more brate, the nematode Caenorhabditis elegans (Miklos &
recent social and cultural evolution of the social envi- Rubin, 1996; Chervitz et al., 1998; Hodgkin et al.,
ronment with which the newborn interacts. The data 1998; Thompson et al., 2001) with its humble 302-
are scarce, but the potential outcomes of future neuron nervous system, contains a predicted 18 266
research could be richly rewarding. protein-coding genes. Drosophila possesses a much
larger nervous system, with about 250 000 neurons,
but with a similar number of genes (13 338; Rubin
Genes and the newborn brain et al., 2000). Even more striking, the gene number
The brain of the newborn is often taken as holding from bony fish, through the laboratory mouse, to the
the innate features that characterize “human nature.” human is roughly constant. Yet, notwithstanding
In reality, many more characteristics proper to the the increase of cell numbers (from about 70 million
human brain develop after birth, in particular in the mouse to 86 billion in humans [Azevedo et al.,
through learning during postnatal development, 2009]), mammalian brain anatomy has evolved dra-
which is one of the longest known among living spe- matically from a poorly corticalized lissencephalic
cies. Even though, as we shall see, epigenetic regula- brain with about 10–20 identified cortical areas to
tions may take place which involve specific interactions a brain with a very high relative cortical surface,
with the environment, strictly innate, DNA-encoded multiple gyri, and sulci and possibly as many as 100
mechanisms contribute, in a definite manner, to the identified cortical areas (Mountcastle, 1998). Thus,
prenatal and postnatal development of the adult brain there exists a remarkable nonlinearity between the 3
 Chapter 1: Reflections on the origins of the human brain

evolution of brain anatomy and that of the total num- (see Mannervik et al., 1999). These protein molecules
ber of genes (Changeux, 1983a,b, 2004; Edelman, may have played a critical role in the phylogenetic
1987; Miklos & Rubin, 1996). evolution of the body form (Koentges, 2008). They
The molecular genetics of the early stages of bind to DNA elements (enhancers or silencers) that
embryonic development in Drosophila, Xenopus, lock or unlock the transcription of adjacent structural
chick, and mouse offers at least one major perspective genes and are themselves often conserved across
on resolving these paradoxes. For example, in species. Interplay between morphogens and transcrip-
Drosophila a variety of genes have been identified tion factors (coactivators and/or corepressors)
that control the cartesian coordinates of the embryo, builds up an intracellular network of protein–protein
the segmentation of the body, and the identity of its interaction (Rual et al., 2005; Stelzl et al., 2005) and
segments (Nüsslein Volhard, 1990; Lawrence, 1992). thus of gene regulation, together with membrane
A significant fraction of these “homeotic genes,” which receptors and the relevant second messengers.
are also found in C. elegans (Ruvkun & Hobert, 1998), Models have been proposed according to which par-
are absent in bacteria and yeast but conserved ticular sets of such molecules may contribute to the
throughout the evolution of higher animal species “reading” of a gradient of morphogen by some
and possibly act in equivalent regulatory cascades in kind of all-or-none switch in both a noncellularized
mammals. In the course of embryonic and postnatal (Kerszberg & Changeux, 1994) and a cellularized
development, these developmental genes become embryo (Kerszberg, 1996) (Fig. 1.2). It has been fur-
expressed according to well-defined spatiotemporal ther suggested that such reading may require parti-
patterns, in a hierarchical and parallel manner with cular kinds of molecular interconnections at the
cross-regulatory interactions and reutilizations. Such level of the transcription factors: the assembly of
a view of morphogenesis, as a developing network molecular partners into hetero-oligomers between,
of gene interactions (Koentges, 2008), may account, for instance, one morphogen molecule from the gra-
at least in part, for the parsimony paradox. An enor- dient and a transcriptional coregulator now coded by
mous diversity, indeed, may arise from such combi- a gene expressed in the embryonic nuclei. Nonlinear
natorial expression of a limited number of genes. relationships between transcription factor concentra-
tion and morphogenesis may thus emerge from these
combinations. Such a concept of nonlinear networks
Development of the body plan of transcription factors (Kerszberg & Changeux,
As a consequence of the combinatorial gene expres- 1994) has been recently documented with particular
sion described in the previous section, the plan of the reference to Drosophila (Mannervik et al., 1999) and
body’s embryo develops. At defined critical stages, may plausibly contribute to morphogenesis, together
anteroposterior and dorsoventral polarities, and with receptors, kinases, phosphatases, G-proteins,
sharp boundaries between territories and/or of pat- and second messengers (Lisman & Fallon, 1999)
terns of stripes become established. The symmetry of within and between the developing embryonic cells
the embryo evolves in the course of development. (Koentges, 2008).
“Symmetry breakings” (Turing, 1952; Meinhardt & Many developmental genes are expressed in the
Gierer, 1974) take place. On theoretical grounds, nervous system. They are part of a still largely unchar-
such defined and reproducible patterns can be gener- acterized population of genes concerned with brain
ated from a set of chemical substances, or morpho- morphogenesis: its segregation into definite patterns
gens, which cross-react and diffuse throughout the of areas and nuclei and even the differentiation of
organism (Turing, 1952). For instance, gradients of asymmetrical hemispheres. The concepts mentioned
diffusible morphogens are thought to contribute to for embryonic development may also apply to brain
the unfolding of developmental gene expression morphogenesis, in particular to the very early stage
resulting in anteroposterior polarity (Meinhardt & referred to as neurulation (see Kerszberg & Changeux,
Gierer, 1974). The main factors (but not the only 1998). The process of neurulation differs strikingly
ones) are the products of the developmental genes: in invertebrates and vertebrates. In the former case,
regulatory proteins referred to as transcription the neuroblasts delaminate from the neural ectoderm
factors that control gene transcription at the level of to form progressively the ventral solid ganglion
4 the core RNA polymerase II transcription complex chain of the adult (which may reach up to 520 million
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