The Basics of Brain Development PDF

Neuropsychol Rev (2010) 20:327–348 DOI 10.1007/s11065-010-9148-4 REVIEW The Basics of Brain Development Joan Stiles & Terry L. Jernigan Received: 7 August 2010 / Accepted: 11 October 2010 / Published online: 3 November 2010 # The Author(s) 2010. This article is published with open access at Spri...

Neuropsychol Rev (2010) DOI 10.1007/s11065-010-9148-4 REVIEW The Basics of Brain Development Joan Stiles & Terry L. Jernigan Received: 7 August 2010 / Accepted: 11 October 2010 # The Author(s) 2010. This article is published with Abstract Over the past several decades, significant advances have been made in our understanding of the basic stages and mechanisms of mammalian brain development. Studies elucidating the neurobiology of brain development span the levels of neural organization from the macroanatomic, to the cellular, to the molecular. Together this large body of work provides a picture of brain development as the product of a complex series of dynamic and adaptive processes operating within a highly constrained, genetically organized but constantly chang- ing context. The view of brain development that has emerged from the developmental neurobiology literature presents both challenges and opportunities to psychologists seeking to understand the fundamental processes that underlie social and cognitive development, and the neural systems that This work was supported by grants to Joan Stiles Institute of Child Health and Human Development: R01-HD25077, R01 HD060595, and to Terry Jernigan from the National Institute of Drug Abuse: RC2DA029475 and the Lundbeck Foundation: R32- A3161. The authors would also like to acknowledge the support of the UCSD Kavli Institute for Brain and Mind. J. Stiles : T. L. Jernigan Department of Cognitive Science, Center for Human Development, University of California, San Diego, CA, USA T. L. Jernigan Departments of Psychiatry and Radiology, School of University of California, San Diego, CA, USA T. L. Jernigan (*) UCSD Center Human Development 0115, 9500 Gilman Drive, La Jolla, CA 92093, USA e-mail: [email protected] VZ ventricular zone Neuropsychol Rev (2010) 20:327–348 ogy of the prenatal neural system are underpinned by changes occurring at the cellular level. Neuron production in humans begins on embryonic day 42. E42, i.e. 42 days post conception (Bystron et al. 2008; Stiles 2008) and is largely complete by midgestation. As they are produced neurons migrate to different brain areas where they begin to make connections with other neurons establishing rudimentary neural networks. By the end of the prenatal period major fiber pathways, including the thalamocortical pathway, are complete. Brain development continues for an extended period postnatally. The brain increases in size by four-fold during the preschool period, reaching approximately 90% of adult volume by age 6 (Reiss et al. 1996; Iwasaki et al. 1997; Courchesne et al. 2000; Kennedy and Dehay 2001; Paus et al. 2001; Kennedy et al. 2002; Lenroot and Giedd 2006). But structural changes in both the major gray and white matter compartments continue through childhood and adolescence, and these changes in structure parallel changes in functional organization that are also reflected in behavior. During the early postnatal period, level of connectivity throughout the developing brain far exceeds that of adults (Innocenti and Price 2005). This exuberant connectivity is gradually pruned back via competitive processes that are influenced by the experience of the organism. These early experience dependent processes underlie the well-documented plasticity and capacity for adaptation that is the hallmark of early brain development. By way of background, this chapter begins with a consideration of two important concepts that are essential for understanding how brains develop. The first involves gene expression: what genes are and how they play an important role in brain development. The second is the outcome of brain development, the mature brain: what are the major structures and what are the basic principles of brain organization. The chapter then considers some of the major milestones of brain development with the aim of illustrating the dynamic, interactive nature of brain development. Genes and Gene Products Genes are the material substance that is passed intergenerationally from parent to offspring. Genes are contained in the nucleotide sequences of DNA that are found in the nucleus of every cell in the body. The expression of a gene has one result: the production of a protein molecule. These molecular products of gene expression are essential for all aspects of development. Genes provide a template for making proteins and it is the proteins that are the active agents in biological development. Thus, while genes contain information that is essential for the Graduate School of of Dr. development and functioning of the biological organism, genes are basically inert molecules. Genes cannot participate directly in biological processes. They do not directly create 329 thoughts, sensations, feelings and actions. Since each neuron can make connections with more than 1,000 other neurons, the adult brain is estimated to have more than 60 trillion neuronal connections. The point of connection between two neurons is called a synapse. The mature human brain has a characteristic pattern of folds (the sulci) and ridges (the gyri). The enfolding of the mature brain is thought to be an adaptation to the dramatic growth in the size of the brain during the course of evolution. The folding of brain tissue allowed large brains to fit in comparatively small cranial vaults that had to remain small to accommodate the birth process (see Fig. 3a). The largest and most important brain information processing networks involve the neocortex and the subcortical nuclei that relay information to and from the neocortex. The neocortex is a 2–5 mm thick layer of cells that lies on the surface of the brain (the word cortex comes from the Latin term meaning bark, as in the bark of a tree). In the cross- section of the brain shown in Fig. 3b the neocortex is the thin, dark gray strip that follows the brain surface. The subcortical nuclei are clusters of neurons that serve as both signal relay centers communicating between the neocortex and the rest of the body, and as relays among different areas of the cortex. They are located deep in the brain below the cortex and are thus referred to as “subcortical” nuclei. Because both the neocortex and the subcortical nuclei contain the cell bodies of neurons they are gray in appearance, thus giving rise to the term “gray matter”. Populations of neurons are connected to one another by fibers that extend from cell bodies of the individual neurons. There are two kinds of connecting fibers, dendrites and axons (see Fig. 2). Dendrites are arrays of short fibers that look like the branches of a tree; collections of dendrites are often referred to as dendritic arbors. They extend only a short distance away from the neuron cell body. Their main Fig. 3 Two views of the human brain. a. Lateral view (rostral end is left, caudal is right) shows an apparently uniform surface marked by that serves to guide gyri and sulcal folds (Right hemisphere of J. Piłsudski’s brain, lateral view, image in the public domain). b. Coronal cross-section (cut at approximately the level of the dotted line in A) stained for cell bodies that mark neurons. The neocortex is the thin mantel layer (dark purple) on the surface of the brain. The white areas are connecting fiber pathways. Image reproduced with permission from http://www.brains. rad.msu.edu which is supported by the U.S. National Science Foundation. Images obtained with permission from Wiki Commons, http://commons.wikimedia.org/wiki Neuropsychol Rev (2010) 20:327–348 The First Step in Brain Development: Differentiation of the Neural Progenitor Cells At the end of the second week after conception, the embryo is a simple, oval-shaped, two-layered structure. Figure 4a provides an overview of the major spatial dimensions of the embryo on embryonic day 13 (E13; note during the embryonic period age is often denoted by the number of days after conception, which is referred to as the embryonic day, thus gastrulation begins on embryonic day 13, or E13). Figure 4b orients the embryo within the context of the embryonic placenta, and Fig. 4c shows how the embryonic spatial axes relate to the major spatial dimensions of the infant (see figure caption for details). Each of the two layers contains a different, very primitive cell type (Fig. 5b). The upper layer contains epiblast cells and the lower layer contains hypoblast cells. By the end of the third week, the embryo is transformed through a set of processes that are referred to collectively as gastrulation into a three-layered structure. While this may seem to be a simple change, the transformations of cell lines that occur during gastrulation set the stage for all subsequent developments in the embryo. The epiblast cells of the upper cell layer will differentiate into the three primary stem cell lines that will eventually give rise to all of the structures in the developing embryo, while the hypoblast cells of the lower layer will form extraembryonic tissues such as the fetal component of the placenta and the connecting stalk. Among the stem cell lines that emerge during gastrulation are the neural stem cells. The neural stem cells are capable of producing all of the different cells that make up the brain and central nervous system, and for this reason the neural stem cells are usually called the neural progenitor cells. The first step in the process of gastrulation is signaled by the appearance of a slit-like opening in the upper layer of the embryo called the primitive streak (Fig. 5a). This opening provides access to the lower regions of the embryo. Next, a subset of the epiblast cells detach from the upper layer of the embryo and begin to migrate toward the primitive streak. When they reach the opening they change direction and pass through the primitive streak and under the upper layer (see Fig. 5b). They then change direction again and begin moving toward the rostral end of the embryo (see Fig. 5c). The rostral end of the embryo will develop into the head of the baby. The earliest migrating cells will move to the most rostral positions in the embryo, later migrating cells will move to successively more caudal regions that will develop into the neck and trunk of the body. The migrating cells will form two new embryonic layers. The cells that form the deepest layer will displace the hypoblast cells and form the endodermal stem cell layer which will give rise to structures of the gut and respiratory 331 an E13 Embryo Rotated to Position in Placenta (in B): o o Rotate 90 right Rotate 90 in depth C. Comparable Spatial Axes for an Infant Dorsal Surface of Embryo Rostral End of Embryo context of the lateral view of the embryo and placenta shown in B, it is necessary to first rotate the embryo so that the rostral end faces right the dorsal surface (second panel of A), and then rotate the embryo in depth so that the end of the embryo dorsal surface faces up (last panel of A). C. The comparable rostral- end is at the bottom. caudal and dorsal-ventral spatial axes of an infant. The spatial axes of a crawling infant are comparable to the position of the embryo in B. Illustrations by Matthew Stiles Davis reprinted by permission of the publisher from THE FUNDAMENTALS OF BRAIN DEVELOP- MENT: INTEGRATING NATURE AND NURTURE by Joan Stiles, Cambridge, Mass.: Harvard University Press, Copyright © 2008 by the President and Fellows of Harvard College C D (blue arrows). The first cells to migrate form the most rostral regions of the newly forming endodermal and mesodermal layers. Later migrating cells form progressively more caudal regions of the layers. node is a critical d. Cells that migrate along the axial midline send molecular signals epiblast layer begin that induce cells in the overlying epiblast layer to differentiate into neuroectodermal cells (red band) which are the neural progenitor cells. in panel B. b. The Migrating cells also receive a second set of signals from the node that induce anterior or posterior fate in different subpopulations of the neurectodermal cells. Early migrating cells signal anterior fate in the that induce gene progenitor cells, while late migrating cells signal posterior fate. Illustrations by Matthew Stiles Davis reprinted by permission of the publisher from THE FUNDAMENTALS OF BRAIN DEVELOP- MENT: INTEGRATING NATURE AND NURTURE by Joan Stiles, Cambridge, Mass.: Harvard University Press, Copyright © 2008 by the President and Fellows of Harvard College Neuropsychol Rev (2010) 20:327–348 ing epidermal cells move to the most rostral end of the embryo and later migrating cells move to successively more caudal locations. The primitive node signals all migrating cells to produce the proteins that signal neural progenitor fate, but each successive wave of migrating cells also receives a second signal that specifies a regional identity for the neural progenitors. Thus, primitive node signals early migrating epidermal cells to produce molecular signals for the cells in the overlying layer to differentiate into neural progenitors capable of producing cells appropriate for forebrain structures, while later migrating cells signal differentiation of neural progenitors capable of producing cells appropriate for hindbrain or spinal cord structures. the The Formation of the Neural Tube: The First Brain Structure 5d). The The next major step in brain development involves the formation of the first well-defined neural structure, the neural tube. The neural tube forms during the third week of gestation, between E20-27. As discussed in the last section, by the end of gastrulation the neural progenitor cells have differentiated and are positioned along the rostral-caudal midline of the upper layer of the three-layered embryo. The region of the embryo containing the neural progenitor cells is referred to as the neural plate. The first sign of neural tube development is the appearance of two ridges that form along the two sides of the neural plate on approximately E21 (Fig. 6a). The neural progenitor cells lie between the two ridges. Over the course of several days, the ridges rise, fold inward and fuse to form a hollow tube (Copp et al. 2003). Fusion begins in the center of the developing neural tube and then proceeds in both the rostral and caudal directions (Fig. 6b and c). The anterior neuropore at the most rostral end of the neural tube and the posterior neuropore at the caudal end, are the last segments to close, on E25 and E27, respectively (Fig. 6d). When the neural tube is complete, the neural progenitors form a single layer of cells that lines the center of the neural tube immediately adjacent to its hollow center. In the embryo, the hollow center of the neural tube is cylindrical, like the center of a straw. But as the brain becomes larger and more complex, the shape of the hollow cavity also changes, eventually forming the ventricular system of the brain. Because the neural progenitors are located in the region that will become the ventricles, the region is called the “ventricular zone” (VZ). The neural progenitor cells in the most rostral region of the neural tube will give rise to the brain, while more caudally positioned cells will give rise to the hindbrain and spinal column. Although the basic three-dimensional organization of the embryo is evident with the formation of the neural tube, over the next month, the embryo undergoes rapid growth. 333 C D F E49 evident by E28. These include the Prosencephalon, Mesencephalon, and Rhombencephalon. f. By E49 the secondary vesicles emerge. The Prosencephalon differentiates into the Telencephalon and Diencephalon, and the Rhombencephalon into the Metencephalon and Myelencephalon. Illustrations by Matthew Stiles Davis reprinted by permission of the publisher from THE FUNDAMENTALS OF BRAIN DEVELOPMENT: INTEGRATING NATURE AND NURTURE by Joan Stiles, Cambridge, Mass.: Harvard University Press, Copyright © 2008 by the President and Fellows of Harvard College “metencephalon” and “myelencephalon”. The mesenceph- alon does not further divide. These five subdivisions are aligned along the rostral-caudal axis of the embryo and establish the primary organization of the central nervous system (Stiles 2008). Neural Patterning in the Embryonic Period which is the The transformations in the overall shape of the embryo reflect more specific change in neural patterning within all regions of the embryonic nervous system. These changes mark the beginning of a protracted process of neural patterning within the central nervous system that begins in the embryonic period and extends for many years. The changes are gradual and follow an ongoing course of continuous specification and refinement (Sur and Rubenstein Neuropsychol Rev (2010) 20:327–348 areas shrink (Fig. 7c). Thus it is the effect of the particular level of one molecular signal in combination with the particular level of another signal that produces the classical pattern of sensorimotor organization in the developing cortex. Since these original reports of the role of Pax6 and Emx2 signaling in neocortical patterning, it has become clear that the interactions are more complex. At least two additional molecules have been identified, Coup-TF1 and SP8. Both are produced in gradients. Coup-TF1 is expressed in greatest concentration in caudal-lateral regions, while SP8 is expressed in rostral-medial regions. As was the case with Pax6 and Emx2, blocking the expression of these genes results in dramatic alteration in the sensorimotor organization of the neocortex (O’Leary et al. 2007; Zembrzycki et al. 2007; O’Leary and Sahara 2008; Sansom and Livesey 2009). These graded patterns of molecular signaling occur in regions of the neocortical proliferative zone that during gastrulation had been specified as “anterior”. Thus this later patterning constitutes a regional elaboration or refinement of an earlier phase of neural patterning. As will be discussed later, patterning within these regions is far from complete at the end of the embryonic period. Fundamental organizational features of the sensory and motor cortices will not arise until the late fetal period. In addition, across the period of fetal and early postnatal development the structural and functional identity of these basic brain areas remains malleable and subject to the effects of input and experience. of the Brain Development in the Fetal Period and The fetal period of human development extends from the ninth gestational week through the end of gestation. The gross morphology of the developing brain undergoes striking change during this time. The human brain begins as a smooth, “lissencephalic” structure and gradually develops the characteristic mature pattern of gyral and sulcal folding. The formation of gyri and sulci follows an orderly sequence. Primary sulci are first seen as grooves positioned in specifically targeted brain regions, second- ary branches then begin to form off the primary sulci, followed later by the tertiary branches. The first fissure to form is the longitudinal fissure that separates two cerebral hemispheres. Its development begins in rostral regions as early as GW8 (Chi et al. 1977) and proceeds caudally until it is complete at GW22. Other primary sulci form between GW14-26. These include: Sylvian, Cingulate, Parieto- Occipital and Calcarine (GW14-16); Central and Superior Temporal (GW20-24); and Superior Frontal, Precentral, Inferior Frontal, Postcentral, and Intraparietal (GW25-26). Secondary sulci emerge between GW30-35; formation of tertiary sulci begins during GW36 and extends well into the postnatal period. 335 step in neuron production involves increasing the size of the neural progenitor cell population. Neural progenitors are a mitotic population of cells, that is, they can divide to form new cells. Neurons are post-mitotic cells; once formed they are no longer capable of dividing and producing new cells. From the end of gastrulation through approximately E42 in humans, the population of neural progenitor cells divides by what is described as a “symmetrical” mode of cell division. Symmetrical cell division produces two identical neural progenitor cells. Over multiple rounds of cell division between E25 and E42, symmetrical cell division provides the means for augmenting the size of the neural progenitor pool. Beginning on E42, the mode of cell division begins to shift from symmetrical to asymmetrical. During asymmet- rical cell division, two different types of cells are produced. In neural progenitors, asymmetrical cell division produces one neural progenitor and one neuron (Wodarz and Huttner 2003). The new progenitor cell remains in the proliferative zone and continues to divide, while the postmitotic neuron leaves the proliferative zone to take its place in the developing neocortex. The shift to asymmetrical cell division among the progenitor population is gradual and initially includes only a small proportion of progenitors, but those numbers increase dramatically by the end of cortical neurogenesis. In humans cortical neurogenesis is complete by approximately E108 (Clancy et al. 2001). Neuron Migration Most neurons are produced in the VZ and migrate radially from the VZ in the center of the brain out to the developing neocortex (see Fig. 8a and b). Very early in neocortical Neuropsychol Rev (2010) 20:327–348 Pial Surface C Ventricular Zone (2003). Neuronal Migration in the Developing Cerebral Cortex: Observations Based on Real- time Imaging. Cerebral Cortex, 13, 607–611. Figure 5. Figure C adapted from illustrations by Matthew Stiles Davis reprinted by permission of the publisher from THE Radial glial provides FUNDAMENTALS OF BRAIN DEVELOPMENT: INTEGRATING NATURE AND NURTURE by Joan Stiles, Cambridge, Mass.: Harvard University Press, Copyright © 2008 by the President and Fellows of Harvard College Nadarajah et al. are actually the neural progenitor cells (Noctor et al. 2001; Noctor et al. 2002; Parnavelas et al. 2002; Weissman et al. 2003). Very recent studies have identified a second proliferative zone located in the region of the ventral telencephalon that will later develop into the basal ganglia (see Fig. 8c). During embryonic and fetal development three compart- ments in this region, the medial, lateral and caudal ganglionic eminences, are the source of an important class of inhibitory cortical interneurons (Anderson et al. 2001; Corbin et al. 2001; Nery et al. 2002). Unlike neurons migrating from the VZ, these neurons traverse long distances using a mode of migration that has been termed “tangential migration”, because the route of migration traverses the contour of developing cortical mantle tangen- tially. Tangential migration involves a variety of signaling pathways not seen in radial migration. Neurons use a number of guidance molecules produced in local regions along their migratory route to direct their movement into the cortex (Marin and Rubenstein 2001; Huang 2009; Valiente and Marin 2010). The migration of neurons into the developing neocortex results in the formation of an orderly 6-layered structure (Cooper 2008). With one exception, earlier migrating neurons form deepest layers of cortex and later migrating neurons form successively more superficial layers (see Fig. 9a) such that the order of migration has been described as inside-out. The exception to the inside-out rule is the very earliest set of migrating neurons. These first neurons to leave the proliferative zone initially form a primitive structure called the preplate (PP; see Fig. 9b, first panel). Once the preplate is complete, the next wave of migrating neurons splits the preplate into two separate regions, the 337 Fig. 9b, third panel). The MZ contains an important class of cells, the Cajal-Retzius cells (CR), that control the positioning of neurons into the correct layers of cortex. The CR cells produce a molecular signal, called Reelin, that is part of the pathway that signals neurons when to stop migrating and take up their positions in cortex (Bielle et al. 2005; Huang 2009; Valiente and Marin 2010). Each new wave of migrating neurons bypasses the previous wave of neurons such that each new wave of migrating cells assumes the most superficial position within the developing cortex. As each new wave of neurons reaches the top of the cortical plate, it moves into the zone of Reelin signaling and receives the cue to stop. The cortex of animals with defects in Reelin signaling lack laminar structure; the preplate fails to split, and the neurons simply conglomerate under the abnormal preplate (Rice and Curran 2001). Finally, neurons in the subplate layer do not participate in the formation of cortical layers, but as will be discussed later, they are essential for establishing the primary sensory inputs to the developing neocortex. Neuron Differentiation The different layers of cortex contain different types of neurons. One question is how these different classes of neurons are derived. This question was addressed by McConnell and colleagues (McConnell and Kaznowski 1991; Frantz and McConnell 1996; Desai and McConnell the deepest cortical 2000) in a series of studies that asked whether different subsets of progenitor cells produce specific kinds of an inside out order neurons, or if the same progenitor is capable of producing (2008). Trends in multiple neuron types? They found that early in cortico- genesis neural progenitor cells are capable of producing any neuron type, but that with development they became more transient brain and more restricted in the types of neurons they can panel, has six well produce. McConnell and colleagues used progenitor cell transplant studies to examine this question. They took dividing progenitor cells from a host fetus of a particular age, and transplanted the cells into a donor animal of a different age. The key question was, what kinds of neurons do the transplanted progenitors produce in the host environment? In the first experiment, progenitor cells were taken from young donor animals (if left in the donor these progenitors would produce neurons for layer 6 of cortex), and transplanted them into an older host (whose progenitors were producing layer 2–3 neurons). The transplanted progenitors produced layer 2–3 neurons suggesting that some kind of signaling from the host induced a change in the type of neurons being produced by the transplanted progenitors. However, when the timing was reversed and progenitors from an older host were transplanted to a younger animal, the progenitors continued to produce cells appropriate for the donor animal. It appears that early in Neuropsychol Rev (2010) 20:327–348 instructive input to the TC neurons during this period. In the absence of subplate neuron signaling, normal patterns of connectivity between TC axons and layer 4 cortical neurons do not develop. A similar pattern of instructive connectivity is seen in the development of the CT pathway. Prior to the establishment of connections between neurons from the deep layers of cortex (layers 5 and 6) and the thalamus, subplate neurons extend and establish connec- tions with thalamic neurons. It is thought that the subplate connections may serve to guide the CT axons to their positions in the thalamus. Once the TC and CT pathways are complete, the subplate neurons retract their connections and the cells themselves gradually die off. Regressive Events in Prenatal Brain Development While most neurodevelopmental events involve the prolif- eration of neural elements, two important processes involve substantial loss of neural elements. These two processes include naturally occurring cell death, which involves the normal loss of 50% or more of the neurons within a brain region; and synaptic exuberance and pruning in which there is massive excess production of connections followed by the systematic elimination of up to 50% of those con- nections. Both of these processes reflect nonpathological events that play an essential role in establishing the complex networks of the developing brain. The timescales of these two sets of events are different. Most naturally occurring cell death in neuronal populations occurs prenatally, while both cell death in glia populations and the events involving exuberant production and pruning of connections are largely postnatal events. This section will consider cell death in neural populations during the prenatal period. The major postnatal regressive events will be discussed in the next section. There are two broad categories of cell death. Necrotic cell death is a pathological process that follows insult or injury to a population of cells and is a mechanism for eliminating damaged tissue from the biological system. Apoptosis is a distinct form of cell death that reflects a highly regulated sequence of physiological events. Apoptosis is a well-understood cell-intrinsic process. It involves a cascade of gene expression that ultimately results in the breakdown of nuclear chromatin (DNA and support proteins) and the fragmenting of the cell. All neurons and neural progenitor cells (as well as many other types of cells) have this intrinsic “suicide” program. The set of genes involved in the apoptotic cascade is large, but very specific, with each molecular signal triggering the next step in the cascade. A wide variety of cell intrinsic and environmental factors can influence the apoptotic process. Some trigger cell death, while others protect the cell by preventing the cascade. Apoptosis has been documented within all of the neuronal and neural 339 proliferation, migration, differentiation, and regression during the postnatal period in humans, and about the timing of these processes relative to each other. In vivo brain imaging of children is providing important clues about the time course of age-related biological alterations in the brain, and provides an opportunity to link these changes to evolving behavior. Postnatal Proliferation and Migration In the postnatal period, neurogenesis continues to only a very limited degree; however, in the subventricular zone, new neurons continue to emerge and migrate to the olfactory bulb, and neurons are also produced in the dentate gyrus of the hippocampus, where they migrate from the subgranular layer only as far as the nearby granular layer. These exceptional forms of neurogenesis appear to continue throughout adult life but produce only a small percentage of the neuronal population. In contrast, proliferation and migration of glial progenitors, while beginning prenatally, continue for a protracted period as oligodendrocytes and astrocytes differentiate; in fact, glial progenitors (particularly oligodendrocyte progenitor cells, or OPCs) appear to persist indefinitely in the adult brain in a wide anatomical distribu- tion, and can differentiate in response to injury. Glial progenitors proliferate in the forebrain subventricular zone and migrate outward into the overlying white matter and cortex, striatum, and hippocampus, where they differentiate into oligodendrocytes and astrocytes. Unlike neural progen- itors, glial progenitors continue to proliferate as they migrate (Cayre et al. 2009). Myelination that enter Upon reaching its destination, an OPC begins to differen- tiate by extending processes and increasing myelin protein expression. The processes then begin to form membrane wraps around nearby axons. Eventually the oligodendrocyte forms tightly wrapped multi-layered sheaths from which most of the cytoplasm has been extruded. The dramatic increase in axonal conduction velocity associated with myelination is well known. However, recent research suggests that functional interactions between oligodendro- cytes and neurons extend far beyond the effects of the electrically insulating sheath. Oligodendrocytes synthesize a number of trophic factors that appear to contribute to the maintenance of axonal integrity and neuronal survival, and neuron-oligodendrocyte interactions have been shown to influence neuronal size and axon diameter (McTigue and Tripathi 2008). An intriguing new line of evidence also suggests that a subset of the OPCs dispersed throughout the brain form excitatory and inhibitory connections with neurons, and thus may contribute actively and directly to neural signaling (Lin and Bergles 2004). Neuropsychol Rev (2010) 20:327–348 exuberance of connectivity extends beyond the sheer numbers of connections within a brain region. Early in development transient connections form throughout the brain, which are not observed in adults. Exuberant connectivity has been documented in pathways as diverse as the corpus callosum, thalamocortical pathways, cortico- spinal tract and pathways linking the temporal lobe and the limbic system (Stanfield et al. 1982; Stanfield and O’Leary 1985; Innocenti and Price 2005). Many factors affect the retention or elimination of pathways. Competition for resources such as neurotrophic factors plays a significant to the from glial in the process Fig. 10 Synaptic connectivity in the primate brain exhibits initial exuberant production followed by gradual pruning. a. In primate brain, the number of synaptic contacts per probe was plotted along a logarithmic scale as a function of days after conception (DAC). Months after birth (MAB) are indicated along the top of the graph, birth (B) at 166 days post conception is indicated by the thin vertical line and puberty (P) at 3–4 years by the thick vertical line.Reprinted with permission from Bourgeois and Rakic (1993). “Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage.” Journal of Neuroscience 13(7): 2801–2820, Fig. 3. b. In human brains, counts of the number of synapses per constant volume of tissue were measured as a function of pre- and postnatal age. Adapted with permission from Huttenlocher and Dabholkar (1997). Regional differences in synaptogenesis in human cerebral cortex. Journal of Comparative Neurology, 387, 167–178, Fig. 2 341 synaptic density in cortex during childhood (Huttenlocher and Dabholkar 1997), but it remains unclear to what extent these factors, and perhaps others, contribute to the changing morphology observed with MRI. Data shown in Fig. 11, plotting estimated volumes of brain structures across the lifespan, illustrate that during childhood and adolescence changes in brain structure are at least as dramatic as those at the end of life. The plots illustrate results from an extended age-range for volumes of particular brain structures (modified from Jernigan and Gamst 2005). Shown are continuous age- related decreases in volume of frontal cortex, thalamus, and nucleus accumbens across the lifespan, and increases in cerebral white matter volume during childhood and early adulthood that give way to decreases later in life. All volumes are normalized for cranial volume—which does not change appreciably over this age range. More recent MR morphometry studies have provided more anatomical detail by employing mapping methods for visualizing the pattern of age-related change (Giedd, Snell and et al. 1996; Giedd, Vaituzis and et al. 1996; Sowell et al. 1999a; Sowell et al. 1999b; Sowell et al. 2002). Studies of developing children describe the protracted course of postnatal white matter growth and establish that before adolescence the volume of tissue with the MR signal characteristics of “gray matter” begins to decline concur- rently in locations throughout the brain, e.g., in cerebral cortex and deep nuclei. The most detailed studies, employing both high-resolution mapping techniques and longitudinal assessments (Gogtay et al. 2004; Sowell et al. 2004) have revealed a modal pattern of childhood and adolescent change in the cerebral cortex that includes not only widespread, regionally specific, apparent cortical thinning, but more limited areas of cortical thickening as well. On average, cortical thinning appears to occur first in primary sensory- motor cortex and then to progress into secondary, then multimodal, and then supramodal cortical areas throughout childhood and adolescence. A recent study [Ostby et al. 2009] confirmed these observations in a large cross-sectional sample and provided concurrent estimates of cortical surface area and cortical thickness. This is an important contribution since studies of cortical volume conflate these factors, and no previous studies had addressed whether the changes in cortical thickness are accompanied by alterations of surface area as well. Ostby et al. (2009) report that between the ages of 8 and 30 years more modest decreases in cortical surface area accompany robust decreases in cortical thickness. An important issue germane to the interpretation of these effects is their relationship to myelination. At the most basic level, cortical “thinning” could simply reflect increased myelination in the white matter tracts coursing within and near the deepest layer of cortex. In other words the “gray” signal of the unmyelinated fibers could simply be becoming more “white” as myelin is deposited. This is clearly a part of Neuropsychol Rev (2010) 20:327–348 matter. Note the rapid age-related change (and striking individual differences) in the childhood and adolescent age-range. (Figures modified from Jernigan & Gamst, Neurobiology of Aging, 26 (9), 1271–1274, 2005) cerebral white Diffusion Imaging of Fiber Tract Development Diffusion imaging measures the diffusion of water mole- cules through the tissue. A common use of diffusion imaging involves fitting, for each voxel, a mathematical function called a tensor, that estimates proton diffusion (motion) along each of 3 orthogonal spatial axes. Tensors from voxels in the brain with high water content, such as in ventricles, exhibit high levels of proton diffusion that has no preferred direction; i.e., the diffusion is random, or isotropic. Diffusion in gray matter voxels is lower but also relatively isotropic. However, in voxels that contain fiber bundles, the diffusion is higher along the long axis of the fibers. This directionality of the diffusion is usually measured as an index of anisotropy, usually as fractional anisotropy (FA). It has been shown that proton diffusion in the cerebral white matter of human newborns is high, and exhibits low anisotropy (Hermoye et al. 2006). As the fiber tracts mature, and myelination proceeds, diffusion declines, and anisotropy (or FA) increases. By examining the change in detail, i.e., by measuring the three tensor eigenvalues (each a measure of the amount of diffusion along one of the spatial axes), it has been shown that developmental increase in FA often reflects a decrease in all three diffusivities, which is, however, smaller in the principal eigenvalue (i.e., in diffusion along the long axis of the tracts). The interpretation (Suzuki et al. 2003) is that unrestricted water in extra-axonal space declines, decreasing tissue diffusivity overall, while diffusion within and/or along the membranes of the axons remains relatively constant or increases. The denser packing of axons that results from myelination and increases in axonal diameter are likely to reduce diffusion by decreasing extra-axonal water. How alterations of fiber morphology or intra-axonal diffusion contribute to changing tensor values is less well understood. Nevertheless, there is growing evidence that alterations reflected in and measurable with diffusion imaging continue throughout childhood and adolescence (Schneider et al. 2004; Barnea-Goraly et al. 2005; Snook et al. 2005). The pattern of FA increases, for 343 In summary, in vivo brain imaging is opening a window on continuing brain development during infancy and childhood. As the imaging techniques mature, and the biological significance of the signals they record are more firmly established, these techniques promise to reveal much more about the dynamic interactions within human brain tissues that attend the molecular and microstructural events described in this review. The Role of Experience in Brain Development The events of the prenatal period serve to establish the core compartments of the developing nervous system from the spinal cord and hindbrain to the cortical structures of the telencephalon. These early events also provide initial patterning within each of the major subdivisions of the brain, but this early patterning, particularly in the neocortex, is both underspecified and malleable. The mature organization of the neocortex emerges over a protracted time during the postnatal period, and it requires diverse forms of input. Some of this input arises from within the organism in the form of molecular signaling and cross-regional activity. But the specific experience of the individual organism also plays an Neuropsychol Rev (2010) 20:327–348 and functional organization of the developing brain. Greenough has shown that simply rearing animals in either impoverished (standard laboratory cage) or enriched environ- ments (large enclosures with interesting and changing landmarks and multiple littermates) affects the development of a wide range of brain structures and functions (Black et al. 1987; Greenough and Chang 1988; Jones and Greenough 1996; Markham and Greenough 2004). Animals reared in complex environments show enhancement in density of cortical synapses, increases in the number of brain support cells, and even augmentation of the complexity of the brain vascular system. Further, many of the effects of rearing in the complex environment persist even when the animal is returned to more impoverished conditions. Sensory deprivation has more selective effects that target particular cortical sensory systems. The seminal

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