Biopsychology Development of the Nervous System PDF

Chapter 9 Development of the Nervous System From Fertilized Egg to You Robbi Akbari Kamaruddin/Alamy Stock Photo Chapter Overview and Learning Objectives Five Phases of Early LO 9.1 Define the terms totipotent, plurip...

Chapter 9 Development of the Nervous System From Fertilized Egg to You Robbi Akbari Kamaruddin/Alamy Stock Photo Chapter Overview and Learning Objectives Five Phases of Early LO 9.1 Define the terms totipotent, pluripotent, multipotent, unipotent Neurodevelopment and stem cell, and identify the major sources of new cells in the developing nervous system. LO 9.2 Describe the development of the neural plate into the neural tube. LO 9.3 Describe the process of neural proliferation and identify the two organizer areas. LO 9.4 Describe the processes of migration and aggregation. 236 M09_PINE1933_11_GE_C09.indd 236 22/01/2021 11:12  Development of the Nervous System 237 LO 9.5 Describe the processes of axon growth and synapse formation. Also, explain the chemoaffinity hypothesis and the topographic gradient hypothesis. LO 9.6 Describe the processes of neuron death and synapse ­rearrangement. Why is apoptosis safer than necrosis? Early Cerebral LO 9.7 Describe what has been discovered about human prenatal Development in Humans growth of the brain. LO 9.8 Describe the various qualities of postnatal growth of the human brain. LO 9.9 Describe the functions of the prefrontal cortex and what sorts of behaviors infants display prior to its development. Effects of Experience on LO 9.10 Explain the difference between a “critical period” and a Postnatal Development of “­sensitive period” of development. Neural Circuits LO 9.11 Explain the different effects of deprivation and enrichment on neurodevelopment. LO 9.12 Give two examples of the effects of experience on neurodevelopment. Neuroplasticity in Adults LO 9.13 Describe the evolution in our thinking about the birth of new neurons in the adult mammalian brain. Also, explain the ­possible function(s) of adult-born hippocampal neurons. LO 9.14 Describe four examples of experience affecting the organization of the adult cortex. Atypical Neurodevelopment: LO 9.15 Describe autism spectrum disorder and attempts to identify its Autism Spectrum Disorder neural mechanisms. and Williams Syndrome LO 9.16 Describe Williams syndrome and attempts to identify its neural mechanisms. Most of us tend to think of the brain as a three-dimensional in neurodevelopment, such as occur in autism spectrum array of neural elements “wired” together in a massive net- disorder and Williams disorder. work of circuits. However, the brain is not a static network But first, a case study. Many of us are reared in similar of interconnected elements. It is a plastic (changeable) living circumstances—we live in warm, safe, stimulating envi- organ that continuously changes in response to your ongo- ronments with supportive families and communities and ing experiences. plenty to eat and drink. Because there is so little variation This chapter focuses on the incredible process of neuro- in most people’s early experience, the critical role of experi- development (development of the nervous system), which ence in human cerebral and psychological development is begins with a single fertilized egg cell and continues not always obvious. In order to appreciate the critical role through to adulthood. Four general ideas are emphasized: played by experience in neurodevelopment, it is impor- (1) the amazing nature of neurodevelopment, (2) the impor- tant to consider cases in which children have been reared tant role of experience in neurodevelopment, (3) the plastic- in grossly abnormal environments. Genie is such a case ity of the adult brain; and (4) the consequences of “errors” (­Curtiss, 1977; Rymer, 1993). M09_PINE1933_11_GE_C09.indd 237 22/01/2021 11:12  238 Chapter 9 a mature organism is produced. Of course, there must be The Case of Genie more to development than this; if there were not, each of us would have ended up like a bowl of rice pudding: an When Genie was admitted to the hospital at the age of 13, she amorphous mass of homogeneous cells. was only 1.35 meters (4 feet, 5 inches) tall and weighed only To save us from this fate, three things other than cell 28.1 kilograms (62 pounds). She could not stand erect, chew solid food, or control her bladder or bowels. Since the age of multiplication must occur. First, cells must differentiate; some 20 months, Genie had spent most days tied to a potty in a must become muscle cells, some must become multipolar small, dark, closed room. Her only clothing was a cloth har- neurons, some must become glial cells, and so on. Second, ness, which kept her from moving anything other than her feet cells must make their way to appropriate sites and align and hands. In the evening, Genie was transferred to a covered themselves with the cells around them to form particular crib and a straitjacket. Her father was intolerant of noise, and structures. And third, cells must establish appropriate func- he beat Genie if she made any sound whatsoever. According tional relations with other cells. This module describes how to her mother, who was almost totally blind, Genie’s father and the developing nervous system accomplishes these three brother rarely spoke to Genie, although they sometimes barked things in five phases: (1) induction of the neural plate, at her like dogs. The mother was permitted only a few minutes (2) neural proliferation, (3) migration and aggregation, with Genie each day, during which time she fed Genie cereal or (4) axon growth and synapse formation, and (5) neuron baby food—Genie was allowed no solid food. Genie’s severe death and synapse rearrangement. childhood deprivation left her seriously scarred. When she was admitted to the hospital, she made almost no sounds and was totally incapable of speech. After Genie was rescued from this horrific life at the age Stem Cells and Neurodevelopment of 13, a major effort was made to get her development back LO 9.1 Define the terms totipotent, pluripotent, on track and to document her problems and improvements. multipotent, unipotent and stem cell, and Genie received special care and training after her rescue, but her behavior never became typical. The following were a few of her identify the major sources of new cells in the continuing problems: She did not react to extremes of warmth developing nervous system. and cold; she tended to have silent tantrums during which she A fertilized egg is totipotent, that is, the cell has the ability would flail, spit, scratch, urinate, and rub her own “snot” on to develop into any class of cell in the body (e.g., bone, skin, herself; she was easily terrified (e.g., of dogs and men wearing neuron, or heart cells). However, soon after, generations of khaki); she could not chew; she could speak only short, poorly new cells start to be created by cell division; these newly cre- pronounced phrases. ated cells are not totipotent (see Boroviak & Nichols, 2014; It is believed that Genie is currently living in a home for intellectually disabled adults. Kohwi & Doe, 2013). At this stage, developing cells have the ability to develop into many, but not all, classes of body cells and are said to be pluripotent. As the embryo develops, new cells become more and more specialized, and eventu- Genie’s developmental issues were apparently the result ally the new cells can develop into different cells of only one of the severe abuse she experienced. Accordingly, this case class (e.g., different kinds of blood cells). These new cells are study suggests the important role that experience plays in said to be multipotent. Eventually, most developing cells neurodevelopment. Reports of childhood adversity affect- are unipotent: that is, they can develop into only one type ing neurodevelopment are by no means limited to Genie’s of cell (e.g., bipolar neurons). case (see Teicher et al., 2016). For example, research has The totipotent, pluripotent, and multipotent cells cre- established that malnutrition associated with poverty is suf- ated during early development are all embryonic stem cells ficient to negatively impact neurodevelopment (see Storrs, (see Figure 9.1). To understand nervous system develop- 2017). It is clear that neurodevelopment is an important and ment, it is necessary to understand two important properties vulnerable process. Let’s learn more. of stem cells (see Morey, Santanach, & Di Croce, 2015). First, they have an almost unlimited capacity for self-renewal if maintained in an appropriate cell culture—for example, cultures of embryonic stem cells can be kept alive and mul- Five Phases of Early tiplying for more than a year. This almost unlimited capac- Neurodevelopment ity of stem cells for self-renewal is a product of asymmetric cell division. The second property of stem cells that plays a In the beginning, there is a zygote, a single cell formed by critical role in nervous system development is the ability of the amalgamation of an ovum (an egg) and a sperm. The each stem cell to develop into many different kinds of cells. zygote divides to form two daughter cells. These two divide These two defining properties of embryonic stem to form four, the four divide to form eight, and so on, until cells appear to be related to the mechanism by which M09_PINE1933_11_GE_C09.indd 238 22/01/2021 11:12  Development of the Nervous System 239 Di Lullo & Kriegstein, 2017; Kelava & Lancaster, 2016; Figure 9.1 Totipotent, pluripotent, and multipotent cells are all considered to be stem cells. However, their capacity to develop Pasca, 2018; Shen, 2018). into the different cells of the body differs. Also depicted here is Because of the ability of stem cells to develop ­asymmetric cell division—which is required for a stem cell culture into different types of mature cells, their therapeutic to be self-renewing. potential is under intensive investigation. Do stem cells injected into a damaged part of a mature brain Totipotent cell develop into the appropriate brain structure and improve function? You will learn about the potential of stem-cell therapies in Chapter 10. Induction of the Neural Plate LO 9.2 Describe the development of the neural plate into the neural tube. Pluripotent cells Three weeks after conception, the tissue that is ­destined to develop into the human nervous system becomes recognizable as the neural plate—a small patch of ectodermal tissue on the dorsal surface of the developing embryo. The ectoderm is the outermost of the three layers of embryonic cells: ectoderm, ­mesoderm, Multipotent cells and endoderm. The development of the neural plate is the first major stage of neurodevelopment in all vertebrates (see Figure 9.2). The development of the neural plate is induced by chemical signals from an area of the underlying ­mesoderm layer—an area consequently referred to as an organizer (see Araya et al., 2014; Kiecker & ­Lumsden, 2012). Indeed, tissue taken from the dor- Lung Pancreas Heart Red blood Skin Neuron sal mesoderm of one embryo (i.e., the donor) and muscle cell implanted beneath the ventral ectoderm of another embryo (i.e., the host) induces the development of an extra neural plate on the ventral surface of the host. they multiply: asymmetric cell division (cell division that As Figure 9.3 illustrates, the growing neural plate folds ­produces two daughter cells with different characteristics). to form the neural groove, and then the lips of the neural When a stem cell divides into two daughter cells, one of the groove fuse to form the neural tube—neural tube defects, daughter cells is a stem cell, while the other daughter cell which develop into severe birth defects of the CNS, can develops into a more specific cell type—see Ito and Suda (2014). But how does one embryonic stem cell develop into different cell types when every cell in a person’s body Figure 9.2 A cross section through the ectoderm, ­ esoderm, and endoderm in a developing embryo. The neural m has exactly the same DNA? What makes one cell develop plate develops from some of the tissue in the endoderm. into a skin cell and another into a neuron? The answer lies in the ability of cells to transcribe different sections of DNA depending on their experience. These mechanisms are gener- ally referred to as epigenetic (see Bale, 2015; Yao et al., 2016). Amniotic cavity Epigenetic mechanisms were the focus of Chapter 2 and thinking Ectoderm about epigenetics is one of the emerging themes in this text. Neural plate The ability of scientists to study development has Mesoderm increased greatly by the development of biochemical tools Notochord for controlling the fates of developing cells. For example, with modern biochemical tools, a culture of stem cells can Endoderm be induced to develop into one of many different brain Yolk sac cell types (see Tsunemoto et al., 2018). It is even possible to watch a miniature three-dimensional brain (a so-called brain organoid) develop in culture from stem cells (see M09_PINE1933_11_GE_C09.indd 239 22/01/2021 11:12  240 Chapter 9 result from errors in this folding process Figure 9.3 How the neural plate develops into the neural tube during the (see Greene & Copp, 2014). The inside of the third and fourth weeks of human embryological development. neural tube eventually becomes the cerebral ventricles and spinal canal. By 40 days after conception, three swellings are visible at the Dorsal surface Cross section of dorsal anterior end of the human neural tube. of embryo ectoderm of embryo Neural Proliferation LO 9.3 Describe the process of neural proliferation and identify the two organizer areas. Once the lips of the neural groove have Neural plate 18 days fused to create the neural tube, the cells of the tube begin to proliferate (increase greatly in number). Remarkably, cells are generated at a rate of more than 4 million per hour (see ­ S ilbereis et al., 2016). This neural proliferation does not occur simultaneously or equally in all parts of the tube. Most cell Neural 21 days division in the neural tube occurs in the groove ventricular zone and subventricular zone—the two regions adjacent to the ventricle (the fluid-filled center of the Neural crest tube). In each species, the cells in different Central canal parts of the neural tube proliferate in a particular sequence that is responsible for the pattern of swelling and folding that gives the brain of each member of that species its characteristic shape. For example, in many animals, these Neural tube 24 days swellings ultimately develop into the forebrain, midbrain, and hindbrain (see ­F igure 3.18). The complex pattern of Based on Cowan, W. M. (1979, September). The development of the brain. Scientific American, 241, 113–133. proliferation is in part controlled by chemical signals from two organizer areas in the neural tube: the f loor plate, which runs along the midline of the ventral surface of the tube, and the roof plate, Migration and Aggregation which runs along the midline of the dorsal surface of the LO 9.4 Describe the processes of migration and tube (see Kanold & Luhmann, 2010). aggregation. Remarkably, the stem cells created in the devel- oping neural tube are virtually always radial glial MIGRATION. Once cells have been created through cell cells (see Falk & Götz, 2017)—cells whose cell bod- division in the ventricular zone of the neural tube, they ies lie either in the ventricular zone or subventricular migrate to the appropriate target location. During this zone and have a long process that extends to the out- period of migration, the cells are still in an immature form, ermost part of the developing neural tube. Figure 9.4 lacking the processes (i.e., axons and dendrites) that char- depicts how radial glial cells undergo asymmetric cell acterize mature neurons. Two major factors govern migra- division to achieve the creation of neurons, glia, and tion in the developing neural tube: time and location. In a other cells of the developing nervous system. Interest- given region of the tube, subtypes of neurons arise on a pre- ingly, in addition to being stem cells, radial glial cells cise and predictable schedule and then migrate together to play a key role in cell migration during development particular destinations (see Itoh, Tyssowski, & Gotoh, 2013; (see Figure 9.4). Kohwi & Doe, 2013). M09_PINE1933_11_GE_C09.indd 240 22/01/2021 11:12  Development of the Nervous System 241 Figure 9.4 Radial glial cells are the stem cells in the developing nervous system. Asymmetric cell division of radial glial cells leads to the production of neurons, glia, and other cells of the nervous system. be l Tu Oligodendrocytes ra N eu ing e lop D ev Astrocytes Neurons Neurons Radial Glial Cells Central Canal Ependymal Time cells Based on Kriegstein, A., & Alvarez-Buylla, A. (2009). Cell migration in the developing neural tube is consid- Budday, Steinmann, & Kuhl, 2015; Evsyukova, Plestant, ered to be of two kinds (see Figure 9.5): Radial ­migration & Anton, 2013). proceeds from the ventricular zone in a straight line out- There are two mechanisms by which developing ward toward the outer wall of the tube; tangential migra- cells migrate (see Figure 9.6). One is somal translocation. tion occurs at a right angle to radial migration—that is, The second is radial-glia-mediated migration. In somal parallel to the tube’s walls. Many cells engage in both ­translocation, the developing cell has a process that extends radial and tangential migration to get from their point of from its cell body that seems to explore the immediate envi- origin in the ventricular zone to their target destination (see ronment. Numerous chemicals guide the movement of these processes, by either attracting or repelling them (see Figure 9.5 Two types of neural migration: radial migration Devreotes & Horwitz, 2015; Maeda, 2015). Once the process and tangential migration. finds a suitable environment, the cell body moves into and along the process (see Cooper, 2013). Somal translocation Neural allows a cell to migrate in either a radial or tangential fashion. tube In radial-glia-mediated migration, the developing cell uses the long process that extends from each radial-glia cell as a sort of rope along which it pulls itself up and away from the ventricular zone (see Figure 9.6). Radial-glia-mediated migration allows a cell to migrate in only a radial fashion (see Ohshima, 2015). Early research on migration in the developing neural tube focused on the cortex. Based on the results of that research, it was asserted that cells migrated in an orderly fashion, progressing from deeper to more superficial lay- ers. Because each wave of cortical cells migrates through the already formed lower layers of cortex before reaching Tangential migration Radial migration its destination, this radial pattern of cortical development is referred to as an inside-out pattern (see Greig et al., 2013). M09_PINE1933_11_GE_C09.indd 241 22/01/2021 11:12  242 Chapter 9 (mice that lack a particular Figure 9.6 Two methods by which cells migrate in the developing neural tube: somal translocation and radial-glia-mediated migration. gene under investigation; see Chapter 5) has been shown to Somal Translocation (Radial or Tangential Movement) have a devastating effect on brain development (DiCicco- Bloom, 2006; Lien et al., 2006). Process Second, there is evidence that gap junctions play a role in aggregation and other aspects of Neuronal soma Translocated neurodevelopment (see Belousov soma & Fontes, 2013; Niculescu & Lohmann, 2014). You may recall from Chapter 4 that gap junctions are points of communication Radial-Glia-Mediated Migration (Radial Movement Only) between adjacent cells; the gaps are bridged by narrow Radial tubes called connexins (see glial Figure 4.13). Third, the process cells of aggregation is also achieved Neuron through interactions between glial cells and neurons; for example, through interactions between microglia and neurons (see Thion & Garel, 2017). However, cortical migration patterns have turned out to be Axon Growth and Synapse much more complex than originally thought: Many corti- cal cells engage in long tangential migrations to reach their Formation final destinations, and the patterns of proliferation and LO 9.5 Describe the processes of axon growth migration are different for different areas of the develop- and synapse formation. Also, explain the ing cortex (see Anderson & Vanderhaeghen, 2014; Silbereis chemoaffinity hypothesis and the topographic et al., 2016; Sun & Hevner, 2014). gradient hypothesis. The neural crest is a structure situated just dorsal to the neural tube (see Figure 9.3). It is formed from cells that AXON GROWTH. Once neurons have migrated to their break off from the neural tube as it is being formed. Neural appropriate positions and aggregated into neural struc- crest cells develop into the neurons and glial cells of the tures, axons and dendrites begin to grow from them (see peripheral nervous system as well as many other cell types Yogev & Shen, 2017). For the nervous system to function, in the body (see Buitrago-Delgado et al., 2015; Kuratani, these projections must grow to appropriate targets. At Kusakabe, & Hirasawa, 2018). each growing tip of an axon or dendrite is an amoebalike AGGREGATION. Once developing neurons have structure called a growth cone, which extends and retracts migrated, they must align themselves with other develop- fingerlike cytoplasmic extensions called filopodia (see ing neurons that have migrated to the same area to form ­Figure 9.7). The filopodia behave as though they are search- the structures of the nervous system. This process is called ing for the correct route (see Kerstein, Nichol, & Gomez, aggregation. 2015; Kahn & Baas, 2016). Aggregation is thought to be mediated by at least three Remarkably, most growth cones reach their correct tar- non-exclusive mechanisms. First, cell-adhesion molecules gets. A series of studies of neural regeneration by Roger (CAMs), which are located on the surfaces of neurons and Sperry in the early 1940s first demonstrated that axons are other cells (see Mori et al., 2014; Sytnyk, Leshchyns’ka, & capable of precise growth and suggested how it occurs. Schachner, 2017; Weledji & Assob, 2014), have the ability In one study, Sperry cut the optic nerves of frogs, rotated to recognize molecules on other cells and adhere to them. their eyeballs 180 degrees, and waited for the axons of the Elimination of just one type of CAM in a knockout mouse retinal ganglion cells, which compose the optic nerve, M09_PINE1933_11_GE_C09.indd 242 22/01/2021 11:12  Development of the Nervous System 243 their target in every member of a species rather than grow- Figure 9.7 Growth cones. The cytoplasmic extensions (the ­filopodia) of growth cones seem to search for the correct route. ing directly to it. This discovery led to a revised notion of how growing axons reach their specific targets. According to this revised hypothesis, a growing axon is not attracted to its target by a single specific attractant released by the target, as Sperry thought. Instead, growth cones seem to be influenced by a series of chemical and physical signals along the route (see Goodhill, 2016; Koser et al., 2016; S ­ quarzoni, Thion, & Garel, 2015; Tamariz & ­Varela-Echavarría, 2015); some attract and others repel the growing axons (see Seabrook et al., 2017). Pioneer growth cones—the first growth cones to travel along a particular route in a developing nervous system— are believed to follow the correct trail by interacting with guidance molecules along the route. Then, subsequent Figure 9.8 Sperry’s classic study of eye rotation and regeneration. Courtesy of Naweed I. Syed, Ph.D., Departments of Anatomy and Medical Retina Physiology, the University of Calgary. to regenerate (grow again). (Frogs, unlike mammals, have retinal ganglion cells that regenerate.) Once regeneration Optic was complete, Sperry used a convenient behavioral test to tectum assess the frogs’ visual capacities (see Figure 9.8). When he dangled a lure behind the frogs, they struck forward, thus When an insect is dangled in front of a normal frog, the frog strikes at it accurately with its tongue. indicating that their visual world, like their eyes, had been rotated 180 degrees. Frogs whose eyes had been rotated, but whose optic nerves had not been cut, responded in exactly the same way. This was strong behavioral evidence that each retinal ganglion cell had grown back to the same point of the optic tectum (called the superior colliculus in mammals) to which it had originally been connected. N ­ euroanatomical investigations have confirmed that this is exactly what hap- pens (see Guo & Udin, 2000). On the basis of his studies of regeneration, Sperry When the eye is rotated 1808 without cutting the optic proposed the chemoaffinity hypothesis of axonal nerve, the frog misdirects its strikes by 1808. development (see Sperry, 1963). He hypothesized that each postsynaptic surface in the nervous system releases a specific chemical label and that each growing axon is attracted by the label to its postsynaptic target during both neural development and regeneration. In the time since Sperry proposed the chemoaffinity hypothesis, many guidance molecules for axon growth have been identified (see Dudanova & Klein, 2013; Onishi, Hollis, & Zou, 2014). Indeed, it is difficult to imagine another mechanism by which an axon growing out from a rotated eyeball could When the optic nerve is cut and the eye is rotated by find its precise target on the optic tectum. 1808, at first the frog is blind; but once the optic nerve Although it generated a lot of research, the chemoaffin- has regenerated, the frog misdirects its strikes by 1808. This is because the axons of the optic nerve, although ity hypothesis fails to account for the discovery that some rotated, grow back to their original synaptic sites. growing axons follow the same circuitous route to reach M09_PINE1933_11_GE_C09.indd 243 22/01/2021 11:12  244 Chapter 9 growth cones embarking on the same journey are presumed gradient and a medial–lateral gradient; see Seabrook et al., to follow the routes blazed by the pioneers. The tendency 2017; but see Goodhill, 2016). However, other mechanisms of developing axons to grow along the paths established by have also been shown to contribute to accurate topographic preceding axons is called fasciculation. mapping (e.g., Quast et al., 2017), such as spontaneous neu- Much of the axonal development in complex nervous ral activity (see Seabrook et al., 2017; Zhang et al., 2017) systems involves growth from one topographic array of and neuron-­astrocyte interactions (see López-Hidalgo & neurons to another. The neurons on one array project to Schummers, 2014). another, maintaining the same topographic relation they SYNAPSE FORMATION. Once axons have reached their had on the first array; for example, the topographic map of intended sites, they must establish an appropriate pattern of the retina is maintained on the optic tectum. synapses. During neurodevelopment, synapses are formed At first, it was assumed that the integrity of topograph- at an astonishing rate of about 700,000 synapses per second ical relations in the developing nervous system was main- (see Silbereis et al., 2016). tained by a point-to-point chemoaffinity, with each retinal A single neuron can grow an axon on its own, but it ganglion cell growing toward a specific chemical label. takes coordinated activity in at least two neurons to create a However, evidence indicates that the mechanism must be synapse between them (see Andreae & Burrone, 2014). This more complex. In most species, the synaptic connections is one reason why our understanding of how axons connect between retina and optic tectum are established long before either reaches full size. Then, as the retinas and the optic tectum grow at different rates, the initial synaptic connections shift to other Figure 9.9 The regeneration of the optic nerve of the frog after portions of tectal neurons so that each retina is precisely either the retina or the optic tectum have been destroyed. These phenomena mapped onto the tectum, regardless of their support the topographic gradient hypothesis. relative sizes. Studies of the regeneration (rather than Axons normally grow from the development) of retinal-tectum projec- Retina the frog retina and tions tell a similar story. In one informative terminate on the optic series of studies, the optic nerves of mature tectum in an orderly fashion. The assumption frogs or fish were cut and their pattern of that this orderliness results regeneration was assessed after parts of from point-to-point either the retina or the optic tectum had chemoaffinity is challenged by the following two been destroyed. In both cases, the axons observations. Optic tectum did not grow out to their original points of connection; instead, they grew out to fill the available space in an orderly fashion. These results are illustrated schematically in Figure 9.9. The topographic gradient hypothesis 1 When half the retina was destroyed and the optic nerve cut, the has been proposed to explain accurate axo- retinal ganglion cells from nal growth involving topographic map- the remaining half retina projected systematically ping in the developing brain (see Weth over the entire optic tectum. et al., 2014). According to this hypothesis, Lesioned half of retina axons growing from one topographic sur- face (e.g., the retina) to another (e.g., the Lesioned half of optic tectum) are guided to specific targets 2 optic tectum that are arranged on the terminal surface in When half the optic tectum was destroyed the same way as the axons’ cell bodies are and the optic nerve cut, arranged on the original surface (see Cang the retinal ganglion cells & ­Feldheim, 2013; Klein & Kania, 2014; from the retina projected systematically over the Triplett, 2014). The key part of this hypoth- remaining half of the optic esis is that the growing axons are guided tectum. to their destinations by two intersecting signal gradients (e.g., an anterior–posterior M09_PINE1933_11_GE_C09.indd 244 22/01/2021 11:12  Development of the Nervous System 245 to their targets has lagged behind our understanding of how they reach them. Still, some exciting breakthroughs Journal Prompt 9.1 have been made: (1) some of the chemical signals that play Why do you think the developing nervous system would a role in the location and formation of synapses have been produce 50 percent more neurons than are required? identified (see Christensen, Shao, & Colón-Ramos, 2013; Inestrosa & Arenas, 2010; Koropouli & Kolodkin, 2014; Neuron death during development was initially Krueger et al., 2012); (2) it has been shown that spontaneous assumed to be a passive process. It was assumed that neurotransmitter release is important for synapse forma- developing neurons died when they failed to get adequate tion (see Andreae & Burrrone, 2018); and (3) cell surfaces nutrition. However, it is now clear that cell death during have been shown to interact prior to synapse formation (see development is usually active. Genetic programs inside de Wit & Ghosh, 2016). neurons are triggered and cause them to actively commit Perhaps the most exciting recent discovery about suicide. Passive cell death is called necrosis (“ne-KROE- synaptogenesis (the formation of new synapses) is that it sis”); active cell death is called apoptosis (“A-poe-toe-sis”). depends on the presence of glial cells, particularly astro- Apoptosis is safer than necrosis. Necrotic cells break apart cytes (see Bosworth & Allen, 2017) and microglia (see and spill their contents into the surrounding extracellular fluid, Stogsdill & Eroglu, 2017). Retinal ganglion cells main- and the consequence is potentially harmful inflammation. In tained in culture formed seven times more synapses when contrast, in apoptotic cell death, the internal structures of a cell astrocytes were present. Moreover, synapses formed in are cleaved apart and packaged in membranes before the cell the presence of astrocytes were quickly lost when the breaks apart. These membrane packages contain molecules astrocytes were removed. Early theories about the con- that attract microglia who engulf and consume them. tribution of astrocytes to synaptogenesis emphasized a Apoptosis removes excess neurons in a safe, neat, and nutritional role: Developing neurons need high levels orderly way. But apoptosis has a dark side as well: If genetic of cholesterol during synapse formation, and the extra programs for apoptotic cell death are blocked, the conse- cholesterol is supplied by astrocytes. However, current quence can be cancer (see Bardella et al., 2018); if the pro- evidence suggests that astrocytes play a much more com- grams are inappropriately activated, the consequence can plex role in synaptogenesis, by processing, transferring, be neurodegenerative disease. and storing information supplied by neurons (see Clarke What triggers the genetic programs that cause apoptosis & Barres, 2013). in developing neurons? There appear to be two kinds of trig- Most current research on synaptogenesis is focused on gers. First, some developing neurons appear to be genetically determining the chemical signals that must be exchanged programmed for an early death—once they have fulfilled between presynaptic and postsynaptic neurons for a syn- their functions, groups of neurons die together in the absence apse to be created (see Ou & Shen, 2010; Sheffler-Collins & of any obvious external stimulus (see Dekkers & Barde, 2013; Dalva, 2012). One complication researchers face is the pro- Underwood, 2013). Second, some developing neurons seem miscuity that developing neurons display when it comes to die because they fail to obtain the life-preserving chemi- to synaptogenesis: In vitro studies show that any type of cals that are supplied by their targets (see Deppmann et al., neuron can form synapses with any other type. However, 2008). Evidence that life-preserving chemicals are supplied once established, synapses that do not function appropri- to developing neurons by their postsynaptic targets comes ately tend to be eliminated (see Coulthard, Hawksworth, from two kinds of observations: (1) Grafting an extra target & Woodruff, 2018). structure (e.g., an extra limb) to an embryo before the period of synaptogenesis reduces the death of neurons growing into the area, and (2) destroying some of the neurons growing Neuron Death and Synapse into an area before the period of cell death increases the sur- Rearrangement vival rate of the remaining neurons. Several life-preserving chemicals that are supplied LO 9.6 Describe the processes of neuron death and to developing neurons by their targets have been identi- synapse rearrangement. Why is apoptosis fied. The most prominent class of these chemicals is the safer than necrosis? ­neurotrophins. Nerve growth factor (NGF) was the first Neuron death is a normal and important part of neurode- neurotrophin to be isolated (see Levi-Montalcini, 1952, velopment. Many more neurons—about 50 percent more— 1975); the second was brain-derived ­neurotrophic ­factor are produced than are required, and waves of large-scale (BDNF). The neurotrophins promote the growth and neuron death occur in various parts of the brain t­ hroughout s­urvival of neurons, function as axon guidance ­molecules, development. and stimulate synaptogenesis (Park & Poo, 2013). M09_PINE1933_11_GE_C09.indd 245 22/01/2021 11:12  246 Chapter 9 SYNAPSE REARRANGEMENT. Figure 9.10 The effect of synapse rearrangement on the selectivity of synaptic During the period of cell death, transmission. The synaptic contacts of each axon become focused on a smaller neurons that have established ­number of cells. incorrect connections are par- ticularly likely to die. As they die, the space they leave vacant on postsynaptic membranes is filled by the sprouting axon ter- minals of surviving neurons. Thus, cell death results in a mas- sive rearrangement of synaptic connections. This phase of syn- apse rearrangement also tends to focus the output of each neuron on a smaller number of postsyn- aptic cells, thus increasing the selectivity of transmission (see Figure 9.10). There is evidence that microglia play a role in synapse rearrangement (see Coulthard, Hawksworth, & Woodruff, 2018; Ueno & Yamashita, 2014). A diffuse pattern of synaptic A more focused pattern of contact is characteristic of early synaptic contact is present after stages of development. synapse rearrangement. Scan Your Brain Are you ready to focus on the continuing development of 3. Neural _________ the human brain after birth? To find out if you are prepared 4. Neural _________ to proceed, scan your brain by filling in the blanks in the 5. _________ aggregation following chronological list of stages of neurodevelopment. 6. Growth of neural _________ The correct answers are provided at the end of the exercise. 7. Formation of _________ Before proceeding, review material related to your errors and 8. Neuron _________ and synapse _________ omissions. (7) synapses, (8) death; rearrangement. 1. Induction of the neural _________ (4) migration, (5) Neural, (6) processes (axons and dendrites), 2. Formation of the _________ tube Scan Your Brain answers: (1) plate, (2) neural, (3) proliferation, slowly than those of other species, not achieving full matu- rity until late adolescence or early adulthood (see Crone Early Cerebral & Dahl, 2012; Fuhrmann, Knoll, & Blakemore, 2015). This Development in Humans module deals with cerebral development that occurs during both the prenatal period (the period of development before Much of our knowledge of the development of the human birth) and the early postnatal period (the period of devel- brain comes from the study of nonhuman species. This opment after birth). This module places emphasis on the fact emphasizes the value of the evolutionary perspective. development of the prefrontal cortex (see Figure 1.8), because There is, however, one way in which the development of it is the last part of the human brain to reach maturity the human brain is unique: The human brain develops more (see Giedd, 2015). M09_PINE1933_11_GE_C09.indd 246 22/01/2021 11:12  Development of the Nervous System 247 Prenatal Growth of the Human Brain Knickmeyer, & Gao, 2018), with much of the growth occur- ring in the first year (Gilmore et al., 2012; Li et al., 2015) LO 9.7 Describe what has been discovered about and continuing into the third year (see Silbereis et al., 2016). human prenatal growth of the brain. This increase in size does not result from the development As you have already learned, much of our knowledge about of additional neurons. The postnatal growth of the human neurodevelopment is inferred after examining development brain seems to result from three other kinds of growth: syn- in nonhuman animals. This was especially the case for stud- aptogenesis, myelination of axons, and increased branching ies examining prenatal growth of the brain, because such of dendrites. procedures would be invasive or otherwise unfeasible to There is a general increase in synaptogenesis in the use in developing humans. human cortex shortly after birth, but there are differences among the cortical regions. For example, in the primary visual and auditory cortexes, there is a major burst of syn- Journal Prompt 9.2 aptogenesis in the fourth postnatal month, and maximum Much of our knowledge about human neurodevelop- synapse density (150 percent of adult levels) is achieved in ment is inferred from studies of non-human animals. the seventh or eighth postnatal month. In contrast, synapto- Given that the human brain is unique in that it develops more slowly, what implications does this have for the genesis in the prefrontal cortex occurs at a relatively steady validity of our knowledge of human neurodevelopment? rate, reaching maximum synapse density in the second year. Myelination increases the speed of axonal conduc- tion, and the myelination of various areas of the human However, three major technical advances have allowed brain during development roughly parallels their func- researchers to directly examine the development of human tional development (see Purger, Gibson, & Monje, 2015). neural tissue. The first you have already learned about: The ­Myelination of sensory areas occurs in the first few months development of three-dimensional brain organoids in cul- after birth, and myelination of the motor areas follows soon ture. Brain organoids are built from human cells and have after that, whereas myelination of the prefrontal cortex con- been used to study the development of the human brain tinues into adulthood (Yap et al., 2013). Indeed, myelination (see Arlotta, 2018). For example, Quadrato and colleagues appears to be an ongoing process that changes as a func- (2017) induced the development of human photosensitive tion of experience throughout one’s lifespan (see Mount brain organoids and then used them to study the develop- & Monje, 2017). ment of the visual system. In general, the pattern of dendritic branching in the The second technical advance that has allowed us to cortex duplicates the inside-out pattern of neural migra- more directly examine prenatal human development is the tion you have already learned about, in the sense that ability to image the brains of prenatal humans. For example, dendritic branching progresses from deeper to more a small number of labs have recently imaged the functional superficial layers. Technical advances in imaging live connectivity (correlated activity between different brain regions neurons in culture are leading to insights into how den- over time) of the developing brain in utero. This line of work drites can reconfigure themselves. Most surprising is the has already revealed the development of functional connec- speed with which even mature dendritic spines (the small tions in 30- to 38-week-old fetuses (see Thomason et al., 2017). protuberances from dendrites, many of which form syn- The final technical advance that has furthered our apses with other cells) can change their shape in response understanding of the developing human brain is the char- to an animal’s experiences and current environment (see acterization of cell-level transcriptomes (a catalogue of all the Berry & Nedivi, 2017). proteins transcribed in a particular cell). T ­ ranscriptomes Early human brain development is not a one-way have now been characterized for both the developing street; there are regressive changes as well as growth (see human prefrontal cortex (see Zhong et al., 2018), and even Jernigan et al., 2011). For example, once maximum synaptic the entire human cerebral cortex (see Fan et al., 2018), in density and gray matter volume have been achieved, there human embryos. Analysis of these transcriptomes will are periods of decline. Like periods of synaptogenesis, peri- likely provide important insights into cell development in ods of synaptic and gray-matter loss occur at different times prenatal humans (see Bakken et al., 2016). in different parts of the brain. For example, cortical thin- ning occurs first in primary sensory and motor areas, pro- Postnatal Growth of the Human Brain gresses to secondary areas, and culminates in association areas (see Jernigan et al., 2011). The achievement of the adult LO 9.8 Describe the various qualities of postnatal level of gray matter in a particular cortical area is correlated growth of the human brain. with that area’s reaching functional maturity—sensory and The human brain grows substantially after birth, doubling motor areas reach functional maturity before association in volume between birth and adulthood (see Gilmore, areas (see Purger, Gibson, & Monje, 2015). M09_PINE1933_11_GE_C09.indd 247 22/01/2021 11:12  248 Chapter 9 As is true for studies of the prenatal human brain, new toy being placed. However, if, after being placed behind technologies have enhanced the rate at which researchers are the same screen on several consecutive trials, the toy was learning about the developing postnatal human brain. For placed behind the other screen (as the infant watched), most example, recent developments in infant magnetic resonance of the 7-month-old infants kept reaching for the previously imaging (MRI) and functional MRI (see Chapter 5) have correct screen rather than the screen that currently hid the allowed for a survey of structural changes and functional toy. Children tend to make this perseverative error between changes, respectively, in the human brain across development about 7 and 12 months, but not thereafter (Diamond, 1985). (see Cao, Huang, & He, 2017; Gilmore, Knickmeyer, & Gao, ­Perseveration is the tendency to continue making a for- 2018; Vijayakumar et al., 2018). That is, cognitive neuroscien- merly correct response when it is currently incorrect. tists can now examine the neural correlates of particular cog- Diamond (1991) hypothesized that the perseverative nitive capacities at different stages of early development (see errors that occur in infants between 7 and 12 months are Ellis & Turk-Browne, 2018). Another example comes from the due to a lag in prefrontal cortex development. Current development of methods for cataloguing the proteins in par- research supports this hypothesis. First, patients with dam- ticular cell types: Such methods have allowed researchers to age to the prefrontal cortex display perseveration when create a proteome (a catalogue of the proteins in different cell switching tasks: They fail to suppress previously correct types) of the postnatal human brain (see Carlyle et al., 2017). responses when the task switches such that those responses are now incorrect (see Shallice & Cipolloti, 2018). Second, the mammalian prefrontal cortex is known to be involved Development of the Prefrontal Cortex in the retention of information within working memory (see LO 9.9 Describe the functions of the prefrontal cortex Cavanagh et al., 2018), which is required in order to perform and what sorts of behaviors infants display well on Piaget’s task. Finally, the number of synapses in the prior to its development. prefrontal cortex is not maximal until the second year of life. As you have just learned, the prefrontal cortex displays the most prolonged period of development of any brain region. Its development is believed to be largely responsible for the Effects of Experience on course of human cognitive development, which occurs over the same period (see Giedd, 2015). Postnatal Development of Given the size, complexity, and heterogeneity of the prefrontal cortex, it is hardly surprising that no single theory Neural Circuits can explain its function. Nevertheless, four types of cogni- Because the human brain develops so slowly, there are tive functions have often been linked to this area in studies many opportunities for experience to influence its devel- of adults with extensive prefrontal damage. Various parts of opment. Indeed, as you will see in this module, the effects the adult prefrontal cortex seem to play roles in (1) working of experience on brain development are many and varied. memory, that is, keeping relevant information accessible for short periods of time while a task is being completed; Critical Periods vs. Sensitive Periods (2) planning and carrying out sequences of actions; (3) inhib- iting responses that are inappropriate in the current context LO 9.10 Explain the difference between a “critical but not in others; and (4) following rules for social behavior period” and a “sensitive period” of (see Fareri & Delgado, 2014; Watanabe & Yamamoto, 2015). development. These cognitive functions seem to mature during the period An important feature of the effects of experience on devel- of adolescence (often defined as 10 to 24 years of age; Patton opment is that they are time-dependent: The effect of a et al., 2018) and appear to be associated with the growth of given experience on development depends on when it dopaminergic axons into the prefrontal cortex (see Hoops & occurs during development (see Makinodan et al., 2012). Flores, 2017) and the maturation of the GABAergic system In most cases, there is a window of opportunity in which in the prefrontal cortex (see Caballero & Tseng, 2016). a particular experience can influence development. If it is One interesting line of research on prefrontal cortex absolutely essential (i.e., critical) for an experience to occur development is based on Piaget’s classic studies of psy- within a particular interval to influence development, the chological development in human babies. In his studies of interval is called a critical period. If an experience has a 7-month-old children, Piaget noticed an intriguing error. great effect on development when it occurs during a par- A small toy was shown to an infant; then, as the child ticular interval but can still have weak effects outside the watched, it was placed behind one of two screens, left or interval, the interval is called a sensitive period. Although right. After a brief delay, the infant was allowed to reach the term critical period is widely used, the vast majority of for the toy. Piaget found that almost all 7-month-old infants experiential effects on development have been found to reached for the screen behind which they had seen the occur during sensitive periods. M09_PINE1933_11_GE_C09.indd 248 22/01/2021 11:12  Development of the Nervous System 249 Early Studies of Experience and primary visual cortex (see Chapter 6) and by the development of topographic cortical maps in sensory systems. Neurodevelopment: Deprivation and OCULAR DOMINANCE COLUMNS. Depriving one eye Enrichment of input for a few days early in life has a lasting adverse LO 9.11 Explain the different effects of deprivation effect on vision in the deprived eye, but this does not hap- and enrichment on neurodevelopment. pen if the other eye is also blindfolded. When only one eye is blindfolded, the ability of that eye to activate the visual Most research on the effects of experience on the development cortex is reduced, whereas the ability of the other eye is of the brain has focused on sensory and motor systems— increased. Both of these effects occur because early monocu- which lend themselves to experiential manipulation. Much lar deprivation changes the pattern of synaptic input into of the early research focused on two general manipulations the primary visual cortex (see Jaepel et al., 2017). of experience: sensory deprivation and sensory enrichment. In many species, ocular dominance columns in layer IV The first studies of sensory deprivation assessed the of the primary visual cortex are largely developed at birth. effects of rearing animals in the dark. Rats reared from However, blindfolding one eye for just a few days during the birth in the dark were found to have fewer synapses and first few months of life reorganizes the system: The width of fewer dendritic spines in their primary visual cortex, and the columns of input from the deprived eye is decreased, and as adults they were found to have deficits in depth and pat- the width of the columns of input from the nondeprived eye tern vision. In contrast, the first studies of early exposure to is increased (Hata & Stryker, 1994; Hubel, Wiesel, & LeVay, enriched environments (e.g., environments that contain toys, 1977). The exact timing of the sensitive period for this effect running wheels, and other rats; see Sale, 2018) found that is specific to each species. Note that this is an example of a enrichment had beneficial effects. For example, rats that sensitive period, as opposed to a critical period, because during were raised in enriched (complex) group cages rather than adulthood the effect still occurs but requires longer periods by themselves in barren cages were found to have thicker of monocular deprivation (see Levelt & Hübener, 2012). cortex, with more dendritic spines and more synapses per Because the adverse effects of early monocular depriva- neuron (see Berardi, Sale, & Maffei, 2015). tion manifest themselves so quickly (i.e., in a few days), it The effects of sensory deprivation have also been studied was believed that they could not be mediated by structural in human babies born with cataracts in both eyes, which ren- changes. However, Antonini and Stryker (1993) found that der them nearly blind (Vavvas et al., 2018). When the cataracts a few days of monocular deprivation produced a massive were removed between 1 and 6 weeks after birth, their vision decrease in branching of those axons that extend from the cell was comparable to that of a newborn (Maurer & Lewis, 2018). bodies of lateral geniculate nucleus neurons to lower layer IV Thereafter, some aspects of vision improved quickly, but some of the primary visual cortex (see Figure 9.11). visual deficits (e.g., deficits in face processing) persisted into adulthood (see Maurer, 2017). Figure 9.11 The effect of a few days of early monocular deprivation on the Experience and s­ tructure of axons projecting from the lateral geniculate nucleus into lower layer IV of the primary visual cortex. Axons carrying information from the deprived eye Neurodevelopment ­displayed substantially less branching. LO 9.12 Give two examples of the effects of experience on neurodevelopment. Nondeprived eye Deprived eye Research on the effects of experience on brain development has progressed beyond simply assessing general Layer IV of sensory deprivation or enrichment. primary visual Manipulations of early experience cortex have become more selective. Many of these selective manipulations of early experience have revealed a competi- tive aspect to the effects of experience on neurodevelopment. This competi- Axon from lateral Axon from lateral tive aspect is most clearly illustrated geniculate nucleus geniculate nucleus by the disruptive effects of monocu- lar deprivation on the development Based on Antonini, A., & Stryker, M. P. (1993). Rapid re-modeling of axonal arbors in the visual cortex. Science, of ocular dominance columns in 260, 1819–1821. M09_PINE1933_11_GE_C09.indd 249 22/01/2021 11:12  250 Chapter 9 TOPOGRAPHIC SENSORY CORTEX MAPS. Some of the development: Neurogenesis (the growth of new neurons) most remarkable demonstrations of the effects of experi- does not occur in adults. The first principle appears to be ence on the organization of the nervous system come from fundamentally correct, at least when applied to me, but the research on sensory topographic maps. The following are second has been proven wrong. two such demonstrations: Prior to the early 1980s, brain development after the early developmental period was seen as a downhill slope: Roe and colleagues (1990) surgically altered the course Neurons continually die throughout a person’s life, and it of developing axons of ferrets’ retinal ganglion cells was assumed that the lost cells are never replaced by new so that the axons synapsed in the medial geniculate ones. Although researchers began to chip away at this mis- nucleus of the auditory system instead of in the lateral conception in the early 1980s, it persisted until the late 20th geniculate nucleus of the visual system. R ­ emarkably, century in neuroscience, as one of the central principles of the experience of visual input caused the auditory cor- neurodevelopment. Nevertheless, the idea persists as the tex of the ferrets to become organized retinotopically most widely held public misconception about brain func- (laid out like a map of the retina). In general, surgically tion (see Yoo & Blackshaw, 2018). attaching the inputs of one sensory system to cortex The first serious challenge to the assumption that that would normally develop into the primary cortex neurogenesis is restricted to early stages of development of another system leads that cortex to develop many, came with the discovery of the growth of new neurons in but not all, characteristics typical of the newly attached the brains of adult birds. Nottebohm and colleagues (e.g., system (see Majewska & Sur, 2006). Goldman & Nottebohm, 1983) found that brain structures Several studies have shown that early music train- involved in singing begin to grow in songbirds just before ing influences the organization of human cortex (see each mating season and that this growth results from an Miendlarzewska & Trost, 2014). For example, early increase in the number of neurons. musical training expands the area of auditory cortex that responds to complex musical tones. Journal Prompt 9.3 As you will learn in this module, even the adult brain dis- plays significant neuroplasticity. What do you think is the Neuroplasticity in Adults evolutionary significance of this adult neuroplasticity? If this text were a road trip we were taking together, at this point, we would spot the following highway sign: SLOW, Then, in the 1990s, researchers, armed with new tech- IMPORTANT VIEWPOINT AHEAD. You see, you are about niques for labelling newly born neurons, showed that adult to encounter findings that have changed how neuroscien- neurogenesis occurs in the rat hippocampus (e.g., Cameron tists think about the human brain. et al., 1993)—see Figure 9.12. And shortly thereafter, it was Neuroplasticity was once thought to be restricted to discovered that new neurons are also continually generated the developmental period. Mature brains were considered in the subventricular zone. (As you learned earlier, the sub- to be set in their ways, incapable of substantial reorgani- ventricular zone is where neural proliferation occurs during zation. Now, the accumulation of evidence has made clear early neurodevelopment.) that mature brains are continually changing and adapting. At first, reports of adult neurogenesis were not embraced Many lines of research contributed to this new view. For by a generation of neuroscientists who had been trained to now, consider the following two. You will encounter many think of the adult brain as fixed, but acceptance grew as con- more in the next two chapters. firmatory reports accumulated. Particularly influential were reports that new neurons are added to the hippocampuses Neurogenesis in Adult Mammals of primates (e.g., Kornack & Rakic, 1999), including humans (Erikkson et al., 1998), and that the number of new neurons LO 9.13 Describe the evolution in our thinking added to the adult human hippocampus is substantial, an about the birth of new neurons in the adult estimated 700 per day per hippocampus (see Kempermann, mammalian brain. Also, explain the possible 2013; Kheirbek & Hen, 2013; Spalding et al., 2013). function(s) of adult-born hippocampal In most nonhuman adult mammals, substantial neu- neurons. rogenesis seems to be restricted to the subventricular zone When I (SB) was a student, I learned two important and hippocampus—although low levels have also been principles of brain development. The first I learned observed in the hypothalamus (see Sousa-Ferreira, de through experience: The human brain starts to function in Almeida, & Cavadas, 2014), cortex (see Feliciano & B ­ ordey, the womb and never stops working until one stands up to 2012), striatum and spinal cord (see Yoo & Blackshaw, 2018). speak in public. The second I learned in a course on brain In