Chapter 2.PDF

Chapter 2 Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development Learning Objectives After reading this chapter, you should be able to: 2.1 Describe genetic and epigenetic processes in development and the...

Chapter 2 Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development Learning Objectives After reading this chapter, you should be able to: 2.1 Describe genetic and epigenetic processes in development and the coaction of heredity and the environment in mutually influencing development. 2.2 Identify cause-and-effect relationships between factors that influence atypical development and consequential outcomes. 2.3 Describe prenatal and early postnatal brain development including brain structures and neuron structures and functions. 2.4 Explain the central role of the brain in mediating stress-induced adaptations and recognize correlations between allostatic overload and the effects of subsequent epigenetic alterations. Leo and George are identical twins. When they were born, George was a half-pound heavier than Leo, but otherwise they were so much alike that most people could not tell them apart. As they grew, friends and family used different tricks to distinguish them. If you were very observant, for instance, you might notice that George had a mole low on his left cheek, almost at the chin line. Leo also had a mole, but it was located just above his left cheekbone. Nonetheless, the boys were similar enough that they occasionally amused themselves by standing in for each other—fooling their third-grade teachers for a whole day of school or switching places with their junior prom dates. They had a shared passion for music and were gifted instrumen- talists by their late teens. Yet, the boys also began to diverge more and more, both physically and psychologically. Leo’s hair was somewhat lighter than George’s by early adolescence; George was more agile on the soccer field. Leo began to excel in math and chose astronomy as his major in college. George became a theatre major and hoped for a career as a performer. Throughout their lives, George was more placid than Leo, who was more easily agitated. In early adulthood, Leo was diag- nosed with schizophrenia. George suffered for his brother but never developed the disorder himself. 38  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 39 Identical twins will help us tell the story of heredity and environ- FIGURE 2.1 Head-to-head optical illusion. ment. They are called “identical” because they carry the same biological inheritance.You may assume that twins’ great similarity is due to their identical heredity—and that their differences must be somehow due to their environments. But what does that really mean? How can environ- ments make a difference in traits such as the location of a mole or the shade of hair color? In fact, the similarities and the differences are the outcome of both heredity and environment. Neither can work alone. The Nature–Nurture Illusion 2.1 Describe genetic and epigenetic processes in development and the coaction of heredity and the environment in mutually influencing development. Look at the image in Figure 2.1. Do you see two faces or a vase? If the figure that you focus on is the vase, the other parts of the image fade into the background or become the “ground.” If you change your focus, SOURCE: Ye Liew/Fotolia. the two faces will become the “figure” and the rest background. It is virtually impossible to maintain both perspectives simultaneously. Images like this one have been used by Gestalt psychologists to illustrate a per- ceptual phenomenon known as “figure-ground,” but we introduce it here because it provides a useful model for understanding the nature–nurture debate. No one would dispute that both heredity and environment influence human development, but when we focus on information about one of these contributors, the other seems to fade into the background. Evidence from both sides is compelling, and the helper may be persuaded to attend to one side of the argument to the exclusion of the other. The challenge is to guard against taking such a one-sided perspective, which allows for consideration of only half of the story. The most effective way that we know to avoid this kind of oversimplification is to understand the fundamentals of how gene–envi- ronment interactions function. The “take away” message, as you will see, is that genes can do nothing without environmental input—and that environmental effects are shaped by genetic constraints. For helping professionals, learning about these intricate transactions makes clear that there is little value in placing “blame” for problematic outcomes (Fruzzetti, Shenk, & Hoffman, 2005). This knowledge also improves a help- er’s ability to fashion therapeutic interventions that are realistic and valid for clients, and to help both clients and the general public to understand the complex interplay of heredity and environment in physical and behavioral outcomes (Dick & Rose, 2002). Epigenesis and Coaction In this chapter, we consider the fundamental processes that determine who we are, both physically and psychologically. We begin by examining the earliest steps in the remarkable journey of human development. You will see that heredity and environ- ment are intimate collaborators at every point along the way. Conception and Early Growth You probably know that the inheritance of traits begins with conception, when a man’s sperm fertilizes a woman’s egg, called an ovum. Fertile women usually release an ovum from one of their ovaries into a fallopian tube during every menstrual cycle. The human ovum is a giant cell with a nucleus containing 23 chromosomes, the physical structures that are the vehicles of inheritance from the mother. The sperm, in contrast, is a tiny cell, but it too carries 23 chromosomes: the father’s contribution to inheritance. The ovum’s nucleus is surrounded by a great deal of cellular material called cytoplasm; the cytoplasm is loaded with a vast array of chemicals. During fertilization, the tiny sperm penetrates the outer membrane of the ovum and makes the long journey through the 40 Chapter 2 FIGURE 2.2 Human karyotypes. Female karyotype Male karyotype 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11 12 6 7 8 9 10 11 12 13 14 15 16 17 18 13 14 15 16 17 18 19 20 21 22 19 20 21 22 23 23 X X X Y ovum’s cytoplasm to finally penetrate the nucleus, where the sperm’s outer structure disintegrates. The sperm’s chromosomes become part of the nuclear material in the fertilized ovum, which is called a zygote. The zygote contains 46 chromosomes, or more accurately, 23 pairs of chromo- somes. One member of each pair comes from the mother (ovum) and one from the father (sperm). Twenty-two of these pairs are matched and are called autosomes. In autosome pairs, the two chromosomes look and function alike. The chromosomes of the 23rd pair are called sex chromosomes, because they have an important role to play in sex determination. In female zygotes, the 23rd pair consists of two matched chromosomes, called X chromosomes, but male zygotes have a mismatched pair. They have an X chromosome from their mothers but a much smaller Y chromosome from their fathers. Figure 2.2 presents FIGURE 2.3 Cell dividing by mitosis. (Only 2 of the two karyotypes, one from a male and one from a female. A 23 pairs of chromosomes—pairs #3 and #20—are karyotype displays the actual chromosomes from human body depicted for illustration.) cells as seen under a microscope, arranged in matching pairs and then photographed. Notice the 23rd pair is matched in the #3 #3 female example but not in the male example. (See Chapter 8 for #3 a a aa #3 a fuller description of the role of sex chromosomes in human a bb b b b #20 a a #20 development.) #20 a a #20 Chromosomes for a karyotype can be taken from cells any- b a bb b b where in a person’s body, such as the skin, the liver, or the brain. #3 A duplicate copy of the original set of 46 chromosomes from the a a #3 zygote exists in nearly every body cell. How did they get there? b b #20 The chromosomes in a zygote begin to divide within hours after a a #20 conception, replicating themselves. The duplicate chromosomes b b pull apart, to opposite sides of the nucleus. The nucleus then divides along with the rest of the cell, producing two new cells, a #3 #3 which are essentially identical to the original zygote. This cell b a b division process is called mitosis (see Figure 2.3). Most impor- #20 #20 b a b a tantly, mitosis produces two new cells, each of which contains a duplicate set of chromosomes. The new cells quickly divide to produce four cells, the four cells divide to become eight cells, #3 #3 and so on. Each of the new cells also contains some of the cyto- a ab b #20 plasm of the original fertilized egg. The cell divisions continue #20 in quick succession, and before long there is a cluster of cells, b a b a each containing a duplicate set of the original 46 chromosomes.  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 41 Over a period of about two weeks, the growing organism migrates down the mother’s fallopian tube, into the uterus, and may succeed in implantation, attaching itself to the uterine lining, which makes further growth and development possible. Now it is called an embryo. Defining Epigenesis and Coaction If every new cell contains a duplicate set of the chromosomes from the zygote, and chromosomes are the carriers of heredity, then it would seem that every cell would develop in the same way. Yet cells differentiate during prenatal development and become specialized. They develop different structures and functions, depending on their surrounding environments. For example, cells located in the anterior portion of an embryo develop into parts of the head, whereas cells located in the embryo’s lateral portion develop into parts of the back, and so on. Apparently, in different cells, dif- ferent aspects of heredity are being expressed. The lesson is clear: Something in each cell’s environment must interact with hereditary material to direct the cell’s develop- mental outcome, making specialization possible. Biologists have long recognized that cell specialization must mean that heredi- tary mechanisms are not unilaterally in charge of development. Biologists first used the term epigenesis just to describe the emergence of specialized cells and systems of cells (like the nervous system or the digestive system) from an undifferentiated zygote. It was a term to describe the emergence of different outcomes from the same hereditary material, which all seemed rather mysterious (Francis, 2011). The term has evolved as biology has advanced. Biologists now define epigenesis more specifi- cally as the set of processes by which factors outside of hereditary material itself can influence how hereditary material functions (Charney, 2012). These “factors” are environmental. They include the chemicals in the cytoplasm of the cell (which constitute the immediate environment surrounding the chromosomes), factors in the cells and tissues adjacent to the cell, and factors beyond the body itself, such as heat, light, and even social interaction. The epigenome is the full set of factors, from the cell to the outside world,that controls the expression of hereditary mate- rial. “The activity of the genes can be affected through the cytoplasm of the cell by events originating at any other level in the system, including the external environ- ment” (Gottlieb, 2003, p. 7). But, as you will see, the chemicals in the cytoplasm of the cell are themselves partly determined by the hereditary material in the chromosomes. These chemicals can move beyond a cell to influence adjacent cells and ultimately to influence behav- ior in the outside environment. Heredity and environment are engaged from the very beginning in an intricate dance, a process called coaction, so that neither one ever causes any outcome on its own. Gottlieb (e.g., 1992, 2003) emphasizes coaction in his epigenetic model of development, a multidimensional theory. He expands the con- cept of epigenesis, describing it as the emergence of structural and functional proper- ties and competencies as a function of the coaction of hereditary and environmental factors, with these factors having reciprocal effects, “meaning they can influence each other”(Gottlieb, 1992, p. 161). Figure 2.4 gives you a flavor of such reciprocal effects. It will be familiar to you from Chapter 1. The Cell as the Scene of the Action Understanding epigenesis starts with the cell. The chromosomes in the nucleus of the cell are made of a remarkable organic chemical called deoxyribonucleic acid or DNA. Long strands of DNA are combined with proteins called histones, wrapped and compacted to make up the chromosomes that we can see under a microscope. Chromosomes can reproduce themselves, because DNA has the extraordinary prop- erty of self-replication. Genes are functional units or sections of DNA, and they are often called “coded” sections of DNA. For each member of a pair of chromosomes, the number and location of genes are the same. So genes, like chromosomes, come in matched pairs, half from the mother (ovum) and half from the father (sperm). 42 Chapter 2 FIGURE 2.4 An epigenetic model of gene/environment coaction. Conscious Experience e.g., self-awareness, attentional focus Cognition, Motivation, Emotion e.g., knowledge, memory, language, needs, desires Bodily Networks (of organs/glands) e.g., nervous system, cardiovascular system Cellular Processes e.g., protein production Genetic processes: e.g., gene activation, gene suppression SOURCE: Gottlieb, G. (1992). Individual development and evolution: The genesis of novel behavior. p. 186. Used by permission of the Gottlieb Estate, Nora W. Gottlieb. You may have read reports in the popular press of genetic “breakthroughs” sug- gesting that scientists have identified a gene for a trait or condition, such as depression or obesity. These reports are extremely misleading. Genes provide a code that a cell is capable of “reading” and using to help construct a protein, a complex organic chemi- cal, made up of smaller molecules called amino acids. Proteins in many forms and combinations influence physical and psychological characteristics and processes by affecting cell processes. First, let’s consider the multistage process by which a gene’s code affects protein production. The complexity of this process can be a bit overwhelming to those of us not schooled in biochemistry, so we will only examine it closely enough to get a sense of how genes and environment coact. The DNA code is a long sequence of molecules of four bases (that is, basic chemicals, not acids): adenine, cytosine, guanine, and thymine, identified as A, C, G, and T. In a process called transcription, intertwined strands of DNA separate, and one of the strands acts as a template for the synthesis of a new, single strand of messenger ribonucleic acid or mRNA. In effect, the sequence of bases (the “code”) is replicated in the mRNA. Different sections of a gene’s code can be combined in different ways in the mRNA it produces, so that a single gene can actually result in several different forms of mRNA. In a second step, called translation, the cell “reads” the mRNA code and produces a protoprotein, a substance that with a little tweaking (e.g., folding here, snipping there) can become a protein. Here again, the cell can produce several protein variations from the same protoprotein, a process  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 43 called alternative splicing (Charney, 2017). Different cell climates (combinations of chemicals) can induce different protein outcomes. One example will help here. A gene labeled the “POMC” gene is eventually translated into a protoprotein called “proopiomelanocortin” (thus the POMC abbreviation). This protein can be broken up into several different types of proteins. Cells in different parts of the body, with their different chemical workforces, do just that. In one lobe of the pituitary gland (a small gland in the brain), POMC becomes adrenocorticotropic hormone (ACTH), an important substance in the stress reaction of the body, as you will see later in this chapter. In another lobe of the pituitary gland, the cells’ chemical environments convert POMC into an opiate, called b-endorphin. In skin cells, POMC becomes a protein that promotes the production of melanin, a pigment (Francis, 2011; Mountjoy, 2015). You can see that the chemical environment of the cell affects the pro- DK Images duction of proteins at several points in the transcription and translation of coded genes. The entire transcription through translation process is referred to as gene expression. Whether or not genes will be expressed, and how often, is influenced by the environment of the cell. Most genes The moment of conception: Sperm and ovum unite to do not function full-time. Also, genes may be turned “on” in some cells create a new organism. and not in others. When a gene is on, transcription occurs and the cell manufactures the coded product or products. To understand how this works, let’s begin by noting that coded genes make up only a small portion (2% to 3%) of the DNA in a human chromosome; the rest is called “intergenic” DNA. How and when a gene’s code will be transcribed is partially regulated by sections of intergenic DNA, sometimes referred to as noncoded genes because they do not code for protein production. They function to either initiate or prevent the gene’s transcription. This process is called gene regulation. All of a person’s coded and noncoded DNA is referred to as his or her genome. Gene Regulation: The Heart of Coaction What provokes the gene regulation mechanisms to get the transcription process going? Some chemicals in the cells are transcription factors; they bind with the regulatory portions of the DNA, initiating the uncoiling of the strands of DNA at the gene loca- tion. This allows mRNA production to begin. Of course, it is more complicated than that. For example, transcription factors cannot bind to the regulatory DNA unless they first bind to another chemical called a receptor. Each kind of transcription factor binds to one or only a few receptors. Some receptors are found on the surface of a cell, bind- ing with transcription factors coming from outside the cell. Other receptors are located inside the cell. Let’s follow the functioning of one transcription factor to illustrate how gene regu- lation works. Hormones, like testosterone and estrogen, are transcription factors. We’ll focus on testosterone, produced in larger quantities by males than females. Testoster- one is primarily produced in the testes, and then it circulates widely through the body via the blood. Only cells in some parts of the body, such as the skin, skeletal muscles, the testes themselves, and some parts of the brain, have receptors for testosterone. In each of these locations, testosterone binds with a different receptor. As a result, tes- tosterone turns on different genes in different parts of the body. In a skeletal muscle, it triggers protein production that affects the growth of muscle fibers; in the testes, it turns on genes that influence sperm production. Notice the bidirectionality of the processes we have been describing. Genes in the testes must be turned on by cellular chemicals (transcription factors and receptors) to initiate testosterone production. Then testosterone acts as a transcription factor turn- ing on several different genes in different parts of the body where testosterone-friendly receptors are also produced. The cell’s chemical makeup directs the activity of the genes, and the genes affect the chemical makeup of the cell. What makes all of this much more complex is that many influences beyond the cell moderate these bidirectional processes. For example, winning a competition tends to increase testosterone production in men, whereas losing a competition tends to decrease it. The effects of winning and losing on 44 Chapter 2 testosterone are found in athletes and spectators, voters in elections, even stock traders (Carre, Campbell, Lozoya, Goetz, & Welker, 2013). Coaction is everywhere. How can factors outside of the cell, even outside the organism, influence gene regu- lation? Here again, the biochemistry of complex sequences of events can be daunting to follow, but let’s consider a few fundamental mechanisms at the cellular level. One epi- genetic change that can affect the expression of a gene is methylation, the addition of a methyl group (an organic molecule) to DNA, either to the coded gene or to regulatory DNA. Such methylation makes transcription of the gene more difficult. Heavy meth- ylation may even turn off a gene for good. Methylation is persistent, and it is passed on when chromosomes duplicate during cell division, although some events can cause demethylation. That is, methyl groups may detach from DNA. In this case, gene tran- scription is likely to increase. Another class of epigenetic changes affects histones, the proteins that bind with DNA to make up the chromosomes. How tightly bound his- tones are to DNA affects how likely it is that a coded gene will be transcribed, with looser binding resulting in more transcription. A variety of biochemicals can attach to, or detach from, histones, such as methyl groups (methylation and demethylation) and acetyl groups (acetylation and deacetylation). Each of these can affect how tightly his- tones and DNA are bound together. Methylation causes tighter binding and reduces gene transcription; demethylation causes looser binding and more transcription. Acety- lation loosens the binding, typically increasing gene transcription, and deacetylation tends to tighten the bonds again. Methylation, acetylation, and their reverse processes are common modifications of histones, but there are many others as well, each of them having some effect on the likelihood that a gene will be transcribed. In addition, other cellular components can shut down the impact of a gene, such as short sections of RNA called micro RNAs (miRNAs) that attach themselves to mRNAs and block their trans- lation into proteins. These processes are all part of the cell’s repertoire of DNA regula- tion devices (see Charney, 2012; Grigorenko, Kornilov, & Naumova, 2016). When the environment outside the organism alters gene regulation, its effects on the body must eventually influence processes like methylation inside cells, so that cer- tain genes in these cells become either more or less active. Let’s consider one example that demonstrates the impact that the social environment can have on cellular processes in the development of rat pups. There is reason to suspect that somewhat analogous processes may occur in primates as well, including humans. Rat mothers differ in the care they give their pups, specifically, in how much licking and grooming (LG) they do. In a series of studies, Michael Meaney and his colleagues (see Kaffman & Meaney, 2007; Meaney, 2010, for summaries) discovered that variations in mothers’ care during the first postnatal week alter the development of a rat pup’s hippocampus. The hip- pocampus is a part of the brain with a central role to play in reactions to stress. The offspring of “high LG” mothers grow up to be more mellow—less reactive to stress- ful events—than the offspring of “low LG” mothers. Of course, these differences could simply indicate that the “high LG” mothers pass on to their offspring genes that influ- ence low stress reactivity. But Meaney and colleagues were able to show that it is actu- ally the mothers’ care that makes the difference. They did a series of cross-­fostering studies: They gave the offspring of high LG mothers to low LG mothers to rear, and they gave the offspring of low LG mothers to high LG mothers to rear. Rat pups reared by high LG foster mothers grew up to be more mellow than rat pups reared by low LG foster mothers. When Meaney and others studied the biochemistry of the rats’ response to stress, they found that pups who receive extra maternal care respond to stress hor- mones (glucocorticoids) differently than other rats. (See later sections of this chapter for a description of the stress response in mammals, including humans.) Ordinarily, when glucocorticoids are produced, the body has been aroused for immediate action—fight or flight. But the body also launches a recovery from this arousal, reacting to reduce the further production of stress hormones. The hippocampus is the part of the brain that initiates the recovery. In rats that experience high LG as pups, just a tiny quantity of glucocorticoids is sufficient for the hippocampus to trigger a rapid reduction in the pro- duction of more stress hormones, resulting in a minimal behavioral response to stress. Now you will see the importance of epigenesis. A mother rat’s external stimula­ tion of her pup causes changes in the regulatory DNA of the pup’s hippocampus.  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 45 One of the changes is that the affected DNA is demethylated. Because of this demeth- ylation, regulatory DNA turns on a gene that produces a stress hormone receptor in hippocampus cells. With larger amounts of the stress hormone receptor, the hip- pocampus becomes more sensitive, reacting quickly to small amounts of stress hor- mone, which makes the rat pup recover quickly from stressful events, which makes it a mellow rat. So maternal rearing, an environmental factor, changes the activity of the rat pup’s DNA by demethylating it, which changes the pup’s brain, affecting its behavioral response to stress. This change is permanent after the first week of life. What is truly remarkable is that this cascade of changes has consequences for the next generation of rat pups. Mellow female rats (who have experienced extra mothering as pups) grow up to be mothers who give their pups extra grooming and licking. And so their pups are also mellow—for life. Researchers are exploring how human infants’ physiological responses to stress may be similarly calibrated by parental closeness and care (Gunnar & Sullivan, 2017; Tang, Reeb-Sutherland, Romeo, & McE- wen, 2014; see Chapter 4). Epigenesis is one reason that identical twins can have the same genotype (type of gene or genes), but not have identical phenotypes (physical and behavioral traits). Their genotypes are exactly the same because they come from a single zygote. Usually after a zygote divides for the first time, the two new cells “stick together” and continue the cell division process, leading to a multi-celled organism. But in identical twinning, after one of the early cell divisions, one or more cells sepa- rate from the rest for unknown reasons. The detached cell or cells continue(s) the cell division process. Each of the new clusters of cells that form can develop into a complete organism, producing identical, or monozygotic twins. Yet, even though they have the same genotypes, their environments may diverge, even prenatally (e.g., Ollikainen et al., 2010). Different experiences throughout their lifetimes can affect the cellular environments of the twins, and these effects can cause differences in how, and how often, some genes are expressed. As a result, as they age twins tend to diverge more and more both physically and behaviorally (Kebir, Chaumette, & Krebs, 2018). A large, longitudinal study of both monozygotic and dizygotic twins illustrates how variable epigenetic effects can be at the cellular level. Dizygotic twins, often called fraternal twins, are conceived when a mother releases two ova in the same menstrual cycle, and each ovum is fertilized by a separate sperm. Thus, these twins develop from two separate zygotes, and like any two siblings, they share about 50% of their genes on average. Wong, Caspi, and their colleagues (2010) studied a large number of both kinds of twins, taking cell samples when the children were 5 and 10 years old. For each child, the researchers measured the methylation of the regulatory DNA of three genes that affect brain function and behavior. You might expect a great deal of concordance (similarity between members of a pair of twins) in methylation, given that the mem- bers of each pair were exactly the same age and were growing up in the same fami- lies. Yet, the differences in the twins’ experiences were enough to lead to substantial discordance (differences between members of a pair of twins) in methylation for both monozygotic and dizygotic twins. The investigators also found that gene methylation tended to change for individual children from age 5 to age 10. These changes some- times involved increased methylation and sometimes involved decreased methyla- tion. Differences between twins, and changes with age within each child, could partly be a result of random processes. But much of this variation is likely to be caused by the impact that differences in life experiences have on the functioning of each child’s cells. More About Genes What significance is there to having matched pairs of genes, one from each parent? One important effect is that it increases hereditary diversity. The genes at matching locations on a pair of chromosomes often are identical, with exactly the same code, but they can also be slightly different forms of the same gene, providing somewhat dif- ferent messages to the cell. These slightly different varieties of genes at the same loca- tion or locus on the chromosome are called alleles. For example, Tom has a “widow’s peak,” a distinct point in the hairline at the center of the forehead. He inherited from one parent an allele that would usually result in a widow’s peak, but he inherited an 46 Chapter 2 TABLE 2.1 Intergenerational Transmission of Recessive Traits (by parents who are carriers) MOTHER FATHER Genotype: Ww Ww Phenotype: Widow’s peak Widow’s peak CHILD1 CHILD2 CHILD3 CHILD4 Genotype: WW Ww Ww ww Phenotype: Widow’s peak Widow’s peak Widow’s peak Straight hairline* *On average, one child in four will have the recessive trait if both parents are carriers. NOTE: W stands for the dominant widow’s peak allele; w stands for the recessive straight hairline allele. allele that usually results in a straight hairline from the other parent. These two alleles represent Tom’s genotype for hairline shape. This example illustrates that two alleles of the same gene can have a dominant- recessive relationship, with only the first affecting the phenotype. In this case, the impact of the second gene allele is essentially overpowered by the impact of the first allele, so that the phenotype does not reflect all aspects of the genotype. Tom is a carrier of a recessive gene that could “surface” in the phenotype of one of his offspring. If a child receives two recessive alleles, one from each parent, the child will have the reces- sive trait. For instance, in Table 2.1, a mother and a father both have a widow’s peak. Each of the parents has one dominant gene allele for a widow’s peak and one recessive allele for a straight hairline, so they are both carriers of the straight hairline trait. On the average, three out of four children born to these parents will inherit at least one widow’s peak allele. Even if they also inherit a straight hairline allele, they are likely to have a widow’s peak. But one child out of four, on average, will inherit two straight hairline alleles, one from each parent. Without a widow’s peak allele to suppress the effects of the straight hairline allele, such a child is likely to have a straight hairline, probably much to the surprise of the parents if they were unaware that they were carriers of the straight hairline trait! Two different alleles will not necessarily have a dominant-recessive relationship. Sometimes alleles exhibit codominance, producing a blended or additive outcome. For example, Type A blood is the result of one gene allele; Type B blood is the result of a different allele. If a child inherits a Type A allele from one parent and a Type B allele from the other parent, the outcome will be a blend—Type AB blood. Gene alleles at a single gene location can heavily influence some traits, as you have seen with hairline shape and blood type. But nearly all traits are influenced by the protein products of many different gene pairs. These genes may even be located on different chromosomes. Such polygenic effects make the prediction of traits from one generation to another very difficult and suggest that any one pair of gene alleles has a very modest influence on phenotypic outcomes. Height, skin color, and a host of other physical traits are polygenic, and most genetic influences on intelligence, personality, psychopathology, and behavior appear to be of this kind as well. One large study described 31 genes contributing to the onset of menstruation in girls, and more have been found (Tu et al., 2015). Polygenic determination on such a large scale is typical of gene influences on single traits. Do not lose sight of the importance of epigenesis in any of the gene effects we have been describing. Regulation of genes by the cellular environment, influenced by environments outside the cell, can trump dominance-recessive or codominance relationships between alleles. You will learn about some examples as we consider genetic sources of atypical development. MyLab Education Self-Check 2.1  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 47 Atypical Development 2.2 Identify cause-and-effect relationships between factors that influence atypi- cal development and consequential outcomes. Typical prenatal development is an amazing story of orderly and continuous progress from a single fertilized cell to a highly differentiated organism with many intercon- nected and efficiently functioning systems. The 9-month gestational period spans the period of the zygote (about 2 weeks), from fertilization to implantation; the period of the embryo (from about the 3rd to 8th week), when most of the body’s organ systems and structures are forming; and finally, the period of the fetus (from the 9th week until birth), when the reproductive system forms, gains in body weight occur, and the brain and nervous system continue to develop dramatically. (Figure 2.5 illustrates major developments during the periods of prenatal development.) Typical development depends on the genome to code for the products that the body needs to grow and function normally; and it depends on the environment to pro- vide a normal range of inputs, from nutrients to social interactions, in order for gene expression to be properly timed and regulated. The principle of coaction operates at every level of the developmental drama—with genes and environment in constant communication. What role does the gene/environment dance play in atypical development? Devi- ations in either the genome or the environment can push the developing organism off course. In this section you will learn about genetic and chromosomal deviations as well as environmental distortions that can alter development as early as the period of the zygote. But remember: Neither ever works alone. The effects of the genome depend on the environment and vice versa. Watch for indicators of this coaction. The Influence of Defective Gene Alleles RECESSIVE, DEFECTIVE ALLELES In sickle-cell anemia, the red blood cells are abnormally shaped, more like a half moon than the usual, round shape. The abnormal cells are not as efficient as normal cells in carrying oxygen to the tissues. Individuals with this disorder have breathing problems and a host of other difficulties that typically lead to organ malfunctions and, without treatment, to early death. Fortunately, modern treatments can substantially prolong life span. A recessive gene allele causes the malformed blood cells. If one normal gene allele is present, it will be dominant, and the individual will not have sickle-cell ane- mia. Many hereditary disorders are caused by such recessive, defective alleles, and it is estimated that most people are carriers of three to five such alleles. Yet, most of these illnesses are rare because to develop them an individual has to be unlucky enough to have both parents be carriers of the same defective allele and then to be the one in four (on average) offspring to get the recessive alleles from both parents. Table 2.2 lists some examples of these illnesses. Some recessive, defective genes are more common in certain ethnic or geographic groups than in others. The sickle-cell anemia gene, for example, is most common among people of African descent. For some of these disorders, tests are available that can identify carriers. Prospective parents who have family members with the disor- der or who come from groups with a higher than average incidence of the disorder may choose to be tested to help them determine the probable risk for their own off- spring. Genetic counselors help screen candidates for such testing, as well as provide information and support to prospective parents, helping them to understand genetic processes and to cope with the choices that confront them—choices about testing, childbearing, and parenting (e.g., Madlensky et al., 2017). DOMINANT, DEFECTIVE ALLELES Some genetic disorders are caused by dominant gene alleles, so that only one defec- tive gene need be present. Someone who has the defective gene will probably have the problem it causes, because the effects of a dominant gene allele overpower the effects FIGURE 2.5 Fetal development. age of embryo (in weeks) fetal period (in weeks) full term 48 Chapter 2 1 2 3 4 5 6 7 8 9 16 20–36 38 period of dividing indicates common site of action of teratogen. zygote, implantation brain & bilaminar embryo C.N.S. palate ear eye ear heart eye heart teeth limbs external genitalia central nervous system heart upper limbs eyes lower limbs teeth palate not external genitalia susceptible to teratogens ear prenatal death functional defects & major morphological abnormalities minor morphological abnormalities Period of greatest sensitivity to teratogens. Period of lesser sensitivity to teratogens. SOURCE: Moore, K. L., & Persaud, T.V. N. (1984). Before we are born: Basic embryology and birth defects (3rd ed.). Philadelphia, PA: Saunders. Copyright Elsevier. Reprinted with permission.  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 49 TABLE 2.2 Some Disorders Affected by Recessive, Defective Gene Alleles DISORDER DESCRIPTION Cystic fibrosis Inadequate mucus production; breathing and digestive problems; early death. Phenylketonuria (PKU) Metabolism of phenylalanines in food is insufficient; gradually compromises the nervous system, causing intellectual disability. Sickle-cell anemia Blood cells have an unusual “sickle” shape; causes heart and kidney problems. Tay-Sachs disease Enzyme disease; causes degeneration of the nervous system and death in the first few years of life. Thalassemia Blood cells abnormal; low energy, paleness, poor resistance to infection. Hemophilia Blood-clotting factor not produced; vulnerable to death by bleeding. Duchenne’s muscular Wasting of muscles produces gradual weakness, eventual death. dystrophy of a recessive allele. Suppose that such an illness causes an early death, before puberty. Then, the defective, dominant allele that causes the illness will die with the affected individual because no offspring are produced. When these alleles occur in some future generation, it must be through mutation, a change in the chemical structure of an existing gene. Sometimes mutations occur spontaneously, and sometimes they are due to environmental influences, like exposure to radiation or toxic chemicals (Strachan & Read, 2000). For example, progeria is a fatal disorder that causes rapid aging, so that by late childhood affected individuals are dying of “old age.” Individuals with pro- geria usually do not survive long enough to reproduce. When the disease occurs, it is caused by a genetic mutation during the embryonic period of prenatal development, so that while it is precipitated by a genetic defect, it does not run in families. Some disorders caused by dominant, defective alleles do not kill individuals affected by them in childhood, and thus can be passed on from one generation to another. When one parent has the disease, each child has a 50% chance of inheriting the dominant, defective gene from that parent. Some of these disorders are quite mild in their effects, such as farsightedness. Others unleash lethal effects late in life. Among the most famous is Huntington’s disease, which causes the nervous system to dete- riorate, usually beginning between 30 and 40 years of age. Symptoms include uncon- trolled movements and increasingly disordered psychological functioning, eventually ending in death. In recent years the gene responsible for Huntington’s disease has been identified, and a test is now available that will allow early detection, before symptoms appear. Unfortunately, there is no cure. The offspring of individuals with the disease face a difficult set of dilemmas, including whether to have the test and, if they choose to do so and find they have the gene, how to plan for the future. Again, genetic coun- selors may play a critical role in this process (Hines, McCarthy Veach, & LeRoy, 2010). Often, having a dominant defective allele, or two recessive, defective alleles, seems like a bullet in the heart: If you have the defective gene or genes you will develop the associated disorder. Yet epigenetic effects can alter the course of events. The disorder may not develop if epigenetic processes prevent the transcription of defective alleles or the translation of mRNA to a protein. Consider another rodent example. A fat, dia- betic yellow mouse, and a slim, healthy brown mouse can actually be identical geneti- cally. Both mice carry a dominant “Agouti” gene allele that causes the problems of the yellow mouse. But in the brown mouse, that troublesome allele is heavily methyl- ated. Dolinoy (2008) demonstrated that this epigenetic change can happen during fetal development if the mother mouse is fed a diet rich in folate, choline, and B12. Such a diet promotes methylation of the Agouti allele, shutting it down. Research on the role of epigenesis in the expression of defective genes is in its infancy (Heijmans & Mill, 2012; Mazzio & Soliman, 2012). Yet it promises to help solve some medical mysteries, such as why occasionally one monozygotic twin develops a hereditary disease but the other does not, or why some people with the same genetic 50 Chapter 2 defect have milder forms of a disease than others (e.g., Ollikainen et al., 2010). Such outcomes illustrate that coaction is always in play. This is true for behavioral disor- ders as well. For example, Caspi and his colleagues (2002) studied people with a range of variations in the “MAOA” gene. This gene provides the cell with a template for production of the MAOA enzyme, a protein that metabolizes a number of important brain chemicals called neurotransmitters, like serotonin and dopamine. (You’ll learn more about neurotransmitters later in this chapter.) Its effect is to inactivate these neu- rotransmitters, a normal process in neurological functioning. Apparently, while these neurotransmitters are critical to normal brain function, too much of them is a problem. Animals become extremely aggressive if the MAOA gene is deleted so that the enzyme cannot be produced. In humans, different alleles of the MAOA gene result in different amounts of MAOA enzyme production. Could alleles that cause low levels of produc- tion increase aggression and antisocial behavior in humans? Most research has sug- gested no such relationship. But Caspi and colleagues hypothesized that child rearing environment might affect how different gene alleles function. Specifically, they hypoth- esized that early abusive environments might make some MAOA alleles more likely to have negative effects on development. They studied a sample of New Zealand resi- dents who had been followed from birth through age 26. They identified each person’s MAOA alleles and looked at four indicators of antisocial, aggressive behavior, such as convictions for violent crimes in adulthood. Finally, they looked at each person’s child- rearing history. Caspi and colleagues did find a link between gene alleles that result in low levels of MAOA enzyme production and aggression, but only when the individual carrying such an allele had experienced abuse as a child. For people with no history of abuse, variations in the MAOA gene were not related to adult aggressive behavior. This appears to be epigenesis in action. (See Ouellet-Morin et al., 2016 for related studies.) POLYGENIC INFLUENCES As with most normal characteristics, inherited disorders are usually related to more than one gene, such that some combination of defective alleles at many chromosomal sites predisposes the individual to the illness. Like all polygenic traits, these disorders run in families, but they cannot be predicted with the precision of disorders caused by genes at a single chromosomal location. Most forms of muscular dystrophy are dis- orders of this type. Polygenic influences have also been implicated in diabetes, club- foot, some forms of Alzheimer’s disease, and multiple sclerosis, to name just a few. As we noted earlier, genetic effects on behavioral traits are typically polygenic. This appears to be true for most mental illnesses and behavioral disorders, such as alcohol- ism, schizophrenia, and clinical depression (e.g., Halldorsdottir & Binder, 2017). For example, the MAOA gene is only one of several that are associated with antisocial behavior (Ouellet-Morin et al., 2016). Genes linked to serious behavioral problems and disorders affect brain function. It will not surprise you to learn that whether and when these genes or their normal variants are expressed also depend on epigenetic modifi- cations that are associated with a person’s experiences at different points in develop- ment, and researchers have begun to identify the biochemical processes involved (e.g., Matosin, Halldorsdottir, & Binder, 2018; Shorter & Miller, 2015). The Influence of Chromosomal Abnormalities Occasionally, a zygote will form that contains too many chromosomes, or too few, or a piece of a chromosome might be missing. Problems in the production of either the ovum or the sperm typically cause these variations. Such zygotes often do not survive. When they do, the individuals usually have multiple physical or behavioral problems. The causes of chromosomal abnormalities are not well understood. Either the mother or the father could be the source, and ordinarily, the older the parent, the more likely MyLab Education that an ovum or sperm will contain a chromosomal abnormality. Among the most Video Example 2.1 common and well known of these disorders is Down syndrome (also called trisomy Down syndrome is among the most 21), caused by an extra copy of chromosome number 21. The extra chromosome in this common chromosomal abnormali- syndrome usually comes from the ovum, but about 5% of the time it comes from the ties. Consider causal factors and sperm. Children with Down syndrome experience some degree of intellectual impair- resulting developmental variants. ment, although educational interventions can have a big impact on the severity of  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 51 TABLE 2.3 Some Chromosomal Abnormalities SYNDROME CHROMOSOMAL VARIATION SOME FEATURES HELPFUL WEBSITES Cri du Chat Missing portion of chromosome #5 High pitched cry (like a cat); severe intellectual disability https://www.genome. and developmental delays; distinctive facial features (e.g., gov/19517558/ downward slant of eyes); small head; poor infant muscle https://ghr.nlm.nih.gov/condition/ tone; low birth weight; etc. cri-du-chat-syndrome Down (Trisomy 21) Extra chromosome #21 Mild to severe intellectual disability and developmental http://www.ndss.org delays; distinctive facial characteristics (e.g., flattening of http://www.nads.org features); poor infant muscle tone; increased risk of heart, digestive, hearing problems, Alzheimer’s disease, etc. Klinefelter Extra X chromosome: XXY Male; may have small testicles; low testosterone levels; http://www.aaksis.org/ delayed or incomplete puberty; breast growth; tall height; https://genetic.org/ learning disability/speech delay; etc. Triple X Extra X chromosome: XXX Female; may have tall stature; learning problems; clinodactyly https://genetic.org/ (curvature of fifth finger); seizures; kidney problems; etc. http://www.rarechromo.org/ Turner Missing X chromosome: X Female; short stature; webbed neck; infertility; some skel- https://genetic.org/ etal abnormalities; kidney or heart problems; etc. http://www.turnersyndrome.org/ XYY Extra Y chromosome: XYY Male; tall stature, low set ears; delayed motor develop- https://genetic.org/ ment; delayed speech/language; etc. http://www.rarechromo.org/ Williams Missing portion of chromosome #7 Mild to moderate intellectual disabilities; better language https://williams-syndrome.org/ production than other cognitive skills; distinctive facial http://www.williams-syndrome. features (e.g., broad forehead, short nose, wide lips); org.uk/ overfriendliness, anxiety problems; etc. https://rarediseases.info.nih.gov/ (provides information about all syndromes listed) cognitive deficits. In addition, these children are likely to have several distinctive char- acteristics, such as a flattening of facial features, poor muscle tone, small stature, and heart problems (Marchal et al., 2016). Table 2.3 provides some examples of disorders influenced by chromosomal abnormalities. Teratogenic Influences From conception, the environment is an equal partner with genes in human develop- ment. What constitutes the earliest environment beyond the cell? It is the mother’s womb, of course, but it is also everything outside of the womb—every level of the physical and social and cultural context. For example, if a mother is stressed by marital conflict, her developing fetus is likely to be influenced by the impact that her distress has on the biochemical environment of the uterus. (For simplicity, we will use the term fetus to refer to the prenatal organism in this section, even though technically it might be a zygote or an embryo.) Even the ancient Greeks, like Hippocrates who wrote 2,500 years ago, recognized that ingestion of certain drugs, particularly during the early stages of pregnancy, could “weaken” the fetus and cause it to be misshapen. Environ- mental substances and agents that can harm the developing fetus are called teratogens. The name comes from the Greek and literally means “monstrosity making.” The fetus is surrounded by a placenta, an organ that develops from the zygote along with the embryo; it exchanges blood products with the baby through the umbili- cal cord. The placenta allows nutrients and oxygen from the mother’s blood to pass into the baby’s blood and allows carbon dioxide and waste to be removed by the mother’s blood, but otherwise it usually keeps the two circulatory systems separate. Teratogens can cross the placental barrier from mother to fetus. They include some drugs and other chemicals, certain disease organisms, and radioactivity. The list of known teratogens is quite lengthy, so we have presented in Table 2.4 a summary of the main characteristics of a few of these agents. Consider, for example, alcohol. Alcohol has been called “the most prominent behav- ioral teratogen in the world” (Warren & Murray, 2013) because its use is common across 52 Chapter 2 the globe. “Behavioral” here refers to the fact that the fetus’s exposure is a result of the mother’s behavior. Conservative estimates are that 2% to 5% of babies born in the United States suffer negative effects from prenatal exposure to alcohol. Worldwide, “it is the leading cause of preventable developmental disabilities” (Hoyme et al., 2016, p. 2). Physicians have suspected the risks of drinking during pregnancy for centu- ries, but only in the last few decades has there been broad recognition of those risks (­Warren, 2013). Identifying teratogens is difficult, because their effects are variable and unpredictable. Maternal drinking during pregnancy can cause no harm to the fetus, or it can result in one or more of a wide range of problems, called fetal alcohol ­spectrum ­disorders (FASD). Most children on this spectrum experience some intellec- tual or behavioral problems. These can include specific learning disabilities, language delays, or memory problems, or more global and severe cognitive deficits, as well as ­difficulties with impulse control, hyperactivity, social understanding, and so on (­Wilhoit, Scott, & Simecka, 2017). More severe intellectual and behavioral impairments are typically accompanied by gross structural brain anomalies. Prenatal development of the brain and the face are interrelated, so it is not surprising that alcohol exposure is also associated with facial abnormalities (del Campo & Jones, 2017). The most extreme of the disorders is fetal alcohol syndrome (FAS), which is identified by a unique facial configuration with three especially likely characteristics: small eye openings so that the eyes look widely spaced, a smooth philtrum (the ridge between the nose and upper lip), and a thin upper lip. Other likely facial variations are a flattened nasal bridge, a small nose, and unusual ear ridges. Cognitive deficits are often accompanied by a small head and sometimes recurrent seizures. Children with FAS typically show growth retardation, either pre- or postnatally, both in weight and height. Many organ systems can be affected in addition to the central nervous system; problems with the heart, kidneys, and bones are common (see Table 2.4). TABLE 2.4 Selected Teratogens COMMON EFFECTS ON FETUS SAFE DOSAGE REFERENCES Legal and illegal drugs Alcohol Brain abnormalities; distinct facial structure; cardiac, skeletal, No safe dosage during Hoyme et al., 2016; Wilhoit, and urogenital abnormalities; dental abnormalities; growth pregnancy Scott, & Simecka, 2017 deficiencies; broad intellectual deficits and/or more specific attentional problems; social perception problems; language deficits; and other learning disorders. Tobacco Low birth weight due to constricted blood flow and reduced No safe dosage during Leckman & Fernandez, 2016; nutrition; prematurity; respiratory problems; cleft palate; learning pregnancy Tong et al., 2013 problems; hyperactivity; disruptive behavior; chronic tic disorders. Cocaine Prematurity or stillbirth; low birth weight; drug withdrawal after No safe dosage during Locke et al., 2016 birth including irritability, restlessness, tremors; medically and pregnancy psychologically fragile; higher rates of later learning problems and ADHD; negative temperamental traits. Marijuana Moderations in brain development and function that may make the No safe dosage during Richardson Hester, & child more vulnerable to postnatal stresses, enhancing potential for pregnancy McLemore, 2016; cognitive and emotional problems. Smith et al., 2016 Infections Rubella (German measles Cataracts and other vision abnormalities; Yazigi et al., 2017 virus) heart malformations; brain abnormalities; genitourinary disorders. Zika virus Brain abnormalities; microcephaly (small brain and head). Russo, Jungman, & Beltrão-Braga, 2017 Environmental hazards Lead Prematurity; low birth weight; brain abnormalities; cognitive Craft-Blachsheare, 2017; impairments. Nye et al., 2016 PCBs (Polychlorinated Low birth weight; cognitive impairments. Majidi, Bouchard, Gosselin, & biphenyls) Carrier, 2012  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 53 Teratogens impact fetal development by modifying both intracellular and inter- cellular activity in the placenta and in the fetus. Teratogens may sometimes actually cause mutations in coded DNA (Bishop, Witt, & Sloane, 1997). But more often they seem to operate by making epigenetic modifications to DNA and thereby altering gene expression. For example, changes in methylation patterns (both methylation of some genes and demethylation of others) have been found in children with FASD for clus- ters of genes that are important for neuro-development and behavior (e.g., Chater- Diehl, Laufer, & Singh, 2017). The teratogenic effects of alcohol are so variable, ranging from none at all to FAS, because a whole set of other factors moderates any teratogen’s impact. The unpredict- ability of teratogenic effects provides a good illustration of the multidimensionality of development. Damaging outcomes may be reduced or enhanced by the timing of pre- natal exposure, the mother’s and fetus’s genomes (genetic susceptibility), the amount of exposure (dosage), and the presence or absence of other risks to the fetus. TIMING OF EXPOSURE The likelihood and the extent of teratogenic damage depends on when in develop- ment exposure occurs (refer again to Figure 2.5). In the first few months, the structure of major organ systems is formed. Brain structures could show unusual and/or insuf- ficient development if a fetus is exposed to a teratogen like alcohol in the first trimes- ter. If the exposure occurs in the last trimester, obvious structural anomalies are not as likely, but brain and other organ functions are still in jeopardy, so that processes such as learning and behavior regulation, vision, and hearing are still vulnerable. Whereas “there is no safe trimester to drink alcohol” (Hoyme et al., 2016, p. 2), some teratogens seem to be harmful primarily at certain times. For example, thalidomide is a sedative introduced in the 1950s and widely prescribed to pregnant women for morning sick- ness. When used in the first trimester, it caused serious limb deformities (Ito, Ando, & Handa, 2011). Before thalidomide was identified as the culprit, it had affected the lives of over 10,000 children around the world. GENETIC SUSCEPTIBILITY Not all fetuses are equally susceptible to a teratogen’s effects. Both the mother’s and the baby’s genes play a role in sensitivity or resistance to a teratogen. For example, FASD is slightly more prevalent among boys than girls (May et al., 2014), and there is some indication from animal studies that maternal drinking affects males’ social behavior more than females’ (e.g., Rodriguez et al., 2016). For some teratogens, such as nicotine, researchers have identified specific genes, and gene alleles, that can increase or decrease the effects of prenatal exposure (e.g., Price, Grosser, Plomin, & Jaffee, 2010). This is, of course, an illustration of coaction. DOSAGE Larger amounts of a teratogenic agent and longer periods of exposure generally have greater effects than smaller doses and shorter periods. Alcohol’s effects are dose dependent. Mothers who drink more days per week increase their babies’ chances of FAS (Gupta, Gupta, & Shirisaka, 2016). Mothers’ binge drinking seems to be especially harmful, although no “safe” dose has been found for alcohol (May et al., 2013). Note also that the effects of any amount of alcohol ingestion are always more potent for the fetus than they are for the mother. In other words, the fetus may have crossed a toxic threshold even if the mother experiences few or very mild alcohol-related effects. Con- sequently, the U.S. Department of Health and Human Services (2015) and the Ameri- can Academy of Pediatrics (Williams & Smith, 2015) recommend that women refrain from drinking alcohol throughout a pregnancy. “No amount of alcohol intake during pregnancy can be considered safe” (Hoyme et al., 2016, p. 2). NUMBER OF RISK FACTORS As you learned in Chapter 1, risk factors are more likely to cause problems the more numerous they are. The developing organism can often correct for the impact of one 54 Chapter 2 risk factor, but the greater the number, the less likely it is that such a correction can be made. The negative effects of teratogens can be amplified when the fetus or infant is exposed to more than one. For example, poor maternal nutrition tends to increase the risk of FAS (Keen et al., 2010). Often, pregnant women who drink also smoke. They are also more likely to be poor, so it is fairly common that their babies have been exposed to multiple risks. The teratogenic effects of cocaine were once thought to include con- genital malformations until researchers recognized that pregnant women who use cocaine frequently consume other drugs, such as alcohol, tobacco, marijuana, or her- oin, and they often have poor nutrition as well. Cocaine users also tend to be poor and to experience more life stress during and after pregnancy than other women. Although prenatal cocaine exposure in the absence of other risk factors can have effects on some aspects of behavior, many of the outcomes once attributed to cocaine alone seem to result from combinations of risk factors (Terplan & Wright, 2011). Nutritional Influences Teratogens are problematic because they add something to the ordinary fetal environ- ment, intruding on the developing system and driving it off course. But what happens when contextual factors that belong in the ordinary fetal environment are missing or in short supply? When food sources are lacking in protein or essential vitamins and min- erals during prenatal and early postnatal development, an infant’s physical, socioemo- tional, and intellectual development can be compromised (e.g., Aboud & Yousafzai, 2015), and epigenetic alterations seem to be at the root of these developmental prob- lems (Champagne, 2016). In a classic intervention study, Rush, Stein, and Susser (1980) provided nutritional supplements to pregnant women whose socioeconomic circumstances indicated that they were likely to experience inadequate diets. At age 1, the babies whose mothers received a protein supplement during pregnancy performed better on measures of play behavior and perceptual habituation (which is correlated with later intelligence) than those whose mothers received a high-calorie liquid or no supplement at all. Are there longer-term behavioral consequences of inadequate prenatal nutrition? Some research does reveal enduring effects. When the fetus is unable to build ade- quate stores of iron, for example, the infant is likely to show signs of anemia by 4 to 6 months of age, and even if corrected, a history of anemia has been shown to affect later school performance. One large longitudinal study demonstrates the many long-term effects that famine can have on the developing fetus. During World War II, people in the western part of The Netherlands experienced a serious food shortage as a result of a food embargo imposed by Germany over the winter of 1944–45. At the end of the war, in 1945, scientists began studying the cohort of babies born to pregnant women who experienced the famine, comparing them either to siblings who were not born during the famine, or to another sample of Dutch people who were born in the same period, but who were not exposed to the famine (e.g., Lumey & van Poppel, 2013). Among the many long-term consequences of prenatal exposure to the famine are: higher rates of obesity by young adulthood; increased risk of schizophrenia and mood disorders, such as depression; more high blood pressure, coronary artery disease, and type II diabetes by age 50; and the list goes on (see Francis, 2011, for a summary). These long-term consequences appear to result from epigenetic changes at the cellular level. For example, one group of investigators found significant demethylation of a gene that codes for “insulin-like growth factor II” (IGF2) in individuals exposed to the famine very early in gestation, when methylation of this particular gene usually occurs (­Heijmans et al., 2008). In another study, methylation and demethylation changes in six genes were identified. The kind of change depended on the gene, the gender of the individual, and the timing of fetal exposure to the famine (Tobi et al., 2009). It is not surprising that prenatal nutrition has such effects, given what we have learned about the effects of postnatal nutrition on children’s functioning. We have known for decades that children who experience severe protein and calorie short- ages at any age may develop kwashiorkor, characterized by stunted growth, a pro- tuberant belly, and extreme apathy (Roman, 2013). Therapeutic diets can eliminate  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 55 the apathy of kwashiorkor, but cognitive impairments often persist. Some research indicates that even much less severe nutritional deficits may have impacts on chil- dren’s cognitive functioning. An intriguing study of changes in the food supplied to New York City schools provides a strong illustration (Schoenthaler, Doraz, & Wakefield, 1986). In a three-stage process, from 1978 to 1983, many food additives and foods high in sugar (sucrose) were eliminated from school meals, so that chil- dren’s consumption of “empty calories” was reduced, and, presumably, their intake of foods with a higher nutrient-to-calorie ratio increased. With each stage of this process, average achievement test scores increased in New York City schools, with improvements occurring primarily among the children who were performing worst academically. Findings such as these suggest that children whose prenatal and postnatal envi- ronments are short on protein and other essential nutrients may not achieve the levels of behavioral functioning that they could have with adequate diets. But the long-range impact of early diet, like the effects of teratogens, is altered by the presence or absence of other risk and protective factors. Some studies have found, for example, that if chil- dren experience poor early nutrition because of extreme poverty or major events such as war, they are less likely to have cognitive impairments the more well educated their parents are (e.g., Boo, 2016). As with other risk factors, the effects of poor nutrition are lessened by other more benign influences. We note again that it is in combination that risk factors do the most harm. (See Box 2.2 for further discussion of this phenomenon.) One heartening consequence is that when we intervene to reduce one risk factor, such as malnutrition, we may actually reduce the impact of other negative influences on development as well. MyLab Education Self-Check 2.2 The Developing Brain 2.3 Describe prenatal and early postnatal brain development including brain structures and neuron structures and functions. Now that you have a sense of the genetic and epigenetic processes at work in develop- ment, we can begin to examine behavioral change over time. We will first focus on the physical system that underlies behavior: the central nervous system and, especially, the brain. Helping professionals can better understand how their clients think, feel, and learn if they give some attention to the workings of this marvelously complex ­system. We will guide you through the story of prenatal and immediate postnatal brain development. Then we will examine in depth a key process mediated by the brain: the stress and adaptation system. As you will see throughout this text, stress, and individual differences in the response to stress, are at the core of what helpers must understand about human development. Early Prenatal Brain Development When you were just a 2-week-old embryo, your very existence still unknown to your parents, cells from the embryo’s upper surface began to form a sheet that rearranged itself by turning inward and curling into a neural tube. This phenomenon, called neurulation, signaled the beginning of your central nervous system’s development. Once formed, this structure was covered over by another sheet of cells, to become your skin, and was moved inside you so that the rest of your body could develop around it. Around the 25th day of your gestational life, your neural tube began to take on a pro- nounced curved shape. At the top of your “C-shaped” embryonic self, three distinct bulges appeared, which eventually became your hindbrain, midbrain, and forebrain. (See Figure 2.6.) 56 Chapter 2 FIGURE 2.6 Stages of brain development. The developing human brain viewed from the side in a succession of embryonic and fetal stages. The small figures beneath the first five embryonic stages are in proper relative proportion to the last five figures. 25 Days 35 Days 40 Days 50 Days 100 Days Four Months Six Months Seven Months Eight Months Nine Months SOURCE: Cowan, W. M. (1979). The development of the brain. In R. R. Llinas (Ed.). The workings of the brain (p. 41). Scientific American (Sept. 1979), p. 166. Illustration by Tom Prentiss. Reproduced with permission. Copyright © (1979) Scientific American, Inc. All rights reserved. Within the primitive neural tube, important events were occurring. Cells from the interior surface of the neural tube reproduced to form neurons, or nerve cells, that would become the building blocks of your brain. From about the 40th day, or 5th week, of gestation, your neurons began to increase at a staggering rate—one quarter of a mil- lion per minute for 9 months—to create the 100 billion neurons that make up a baby’s brain at birth. At least half would be destroyed later either because they were unneces- sary or were not used. We will have more to say about this loss of neurons later. Your neurons began to migrate outward from their place of birth rather like fila- ments extending from the neural tube to various sites in your still incomplete brain. Supporting cells called glial cells, stretching from the inside of the neural tube to its outside, provided a type of scaffolding for your neurons, guiding them as they ven- tured out on their way to their final destinations. Those neurons that developed first migrated only a short distance from your neural tube and were destined to become the hindbrain. Those that developed later traveled a little farther and ultimately formed the midbrain. Those that developed last migrated the farthest to populate the cerebral cortex of the forebrain. This development always progressed from the inside out, so that cells traveling the farthest had to migrate through several other already formed layers to reach their proper location. To build the six layers of your cortex, epigenetic processes pushed each neuron toward its ultimate address, moving through the bot- tom layers that had been already built up before it could get to the outside layer. (See Box 2.1 and Figures 2.7 and 2.8.) Scientists have discovered that neurons sometimes need to find their destinations (for example, on the part of the cortex specialized for vision) before that part of the  Genetics, Epigenetics, and the Brain: The Fundamentals of Behavioral Development 57 Box 2.1: The Major Structures of the Brain Multidimensional models of mental health and psychopathology sends these messages to their appropriate destinations. For now incorporate genetics and brain processes into their concep- example, the thalamus projects visual information, received via tual frameworks. Thus, a working knowledge of the brain and the optic nerve, to the occipital lobe of the cortex (discussed later its functioning should be part of a contemporary helper’s toolkit. in this box). On both sides of the thalamus are structures called Consumers of research also need this background to understand the basal ganglia. These structures, especially the nucleus studies that increasingly include brain-related measures. Here we accumbens, are involved in motivation and approach behavior. present a very short introduction to some important brain areas The hypothalamus, situated below the thalamus, is a small and describe their related functions. but important area that regulates many key bodily functions, such The complex human brain can be partitioned in various as hunger, thirst, body temperature, and breathing rate. Lesions ways. One popular way identifies three main areas that track evo- in areas of the hypothalamus have been found to produce eat- lutionary history: hindbrain, midbrain, and forebrain. Bear in mind, ing abnormalities in animals, including obesity or starvation. It is however, that brain areas are highly interconnected by neural cir- also important in the regulation of emotional responses, includ- cuitry despite attempts to partition them by structure or function. ing stress-related responses. The hypothalamus functions as an In general, the more complex, higher-order cognitive functions intermediary, translating the emotional messages received from are served by higher-level structures while lower-level structures the cortex and the amygdala into a command to the endocrine control basic functions like respiration and circulation. system to release stress hormones in preparation for fight or Beginning at the most ancient evolutionary level, the hindbrain flight. We will discuss the hypothalamus in more detail in the sec- structures of medulla, pons, cerebellum, and the reticular tion on the body’s stress systems. formation regulate autonomic functions that are outside Limbic structures (hippocampus, amygdala, septum, and our conscious control. The medulla contains nuclei that control cingulate cortex) are connected by a system of nerve pathways basic survival functions, such as heart rate, blood pressure, and (limbic system) to the cerebral cortex. Often referred to as the respiration. Damage to this area of the brain can be fatal. The “emotional brain,” the limbic system supports social and emo- pons, situated above the medulla, is involved in the regulation of tional functioning and works with the frontal lobes of the cortex the sleep–wake cycle. Individuals with sleep disturbances can to help us think and reason. The amygdala rapidly assesses the sometimes have abnormal activity in this area. The medulla and emotional significance of environmental events, assigns them a the pons are also especially sensitive to an overdose of drugs or threat value, and conveys this information to parts of the brain alcohol. Drug effects on these structures can cause suffocation that regulate neurochemical functions. The structures of the lim- and death. The pons transmits nerve impulses to the cerebellum, bic system have direct connections with neurons from the olfac- a structure that looks like a smaller version of the brain itself. The tory bulb, which is responsible for our sense of smell. It has been cerebellum is involved in the planning, coordination, and smooth- noted that pheromones, a particular kind of hormonal substance ness of complex motor activities such as hitting a tennis ball or secreted by animals and humans, can trigger particular reactions dancing, in addition to other sensorimotor functions. that affect emotional responsiveness below the level of conscious Within the core of the brainstem (medulla, pons, and mid- awareness. We will have more to say about the workings of the brain) is a bundle of neural tissue called the reticular formation emotional brain and its ties to several emotional disorders in that runs up through the midbrain. This, together with smaller Chapter 4. groups of neurons called nuclei, forms the reticular activating Other limbic structures, notably the hippocampus, are critical system, that part of the brain that alerts the higher structures for learning and memory formation. The hippocampus is espe- to “pay attention” to incoming stimuli. This system also filters cially important in processing the emotional context of experience out the extraneous stimuli that we perceive at any point in time. and sensitive to the effects of stress. Under prolonged stress, For example, it is possible for workers who share an office to hippocampal neurons shrink and new neurons are not produced. tune out the speech, music, or general background hum going The hippocampus and the amygdala are anatomically con- on around them when they are involved in important telephone nected, and together they regulate the working of the HPA axis conversations. However, they can easily “perk up” and attend if a (described later in this chapter). In general, the amygdala acti- coworker calls their name. vates this stress response system while the hippocampus inhibits The midbrain also consists of several small structures it (McEwen & Gianaros, 2010). (superior colliculi, inferior colliculi, and substantia nigra) The most recognizable aspect of the forebrain is the cere- that are involved in vision, hearing, and consciousness. These brum, which comprises two thirds of the total mass. A crevice, parts of the brain receive sensory input from the eyes and ears or fissure, divides the cerebrum into two halves, like the halves and are instrumental in controlling eye movement. of a walnut. Information is transferred between the two halves The forebrain is the largest part of the brain and includes by a network of fibers comprising the corpus callosum. the cerebrum, thalamus, hypothalamus, and limbic system These halves are referred to as the left and right hemispheres. structures. The thalamus is a primary way station for handling Research on hemispheric specialization (also called neural communication, something like “information central.” ­lateralization), pioneered by Sperry (1964), demonstrated It receives information from the sensory and limbic areas and that the left hemisphere controls functioning of the right side of (continued) 58 Chapter 2 the body and vice versa. Language functions such as vocabu- for the processing of somatosensory information such as touch, lary knowledge and speech are usually localized in the left temperature, and pain. Finally, the frontal lobe, situated at the hemisphere, and visual–spatial skills are localized on the right. top front part of each hemisphere, controls voluntary muscle Recently, this research was introduced to lay readers through movements and higher-level cognitive functions. a rash of popular books about left brain–right brain differences. The prefrontal cortex (PFC) is the part of the frontal lobe Overall, many of these publications have distorted the facts and that occupies the front or anterior portion. This area is involved oversimplified the findings. Generally the hemispheres work in processes like sustained attention, working memory, planning, together, sharing information via the corpus callosum and coop- decision making, and emotion regulation. Generally, the PFC erating with each other in the execution of most tasks. There is plays a role in regulation and can moderate an overactive amyg- no reliable evidence that underlying modes of thinking, person- dala as well as the activity of the body’s stress response system. ality traits, or cultural differences can be traced exclusively to Another important regulatory pathway involves the anterior hemispheric specialization. cingulate cortex (ACC), a structure in the middle of the brain Each hemisphere of the cerebral cortex can be further above the corpus callosum. The ACC mediates cognition and divided into lobes, or areas of functional specialization (see Fig- affect. Impaired connections between the ACC and the amyg- ure 2.8). The occipital lobe, located at the back of the head, dala are related to higher levels of anxiety and neuroticism, and handles visual information. The temporal lobe, found on the lower ACC volume has been found in depressed patients (Kaiser, sides of each hemisphere, is responsible for auditory process- Andrews-Hanna, Wager, & Piagalli, 2015). The size of the various ing. At the top of each hemisphere, behind a fissure called the brain regions and the integrity of their circuitry play a role in indi- central sulcus, is the parietal lobe. This area is responsible viduals’ cognition, affect, and behavior. FIGURE 2.7 The major structures of the brain. Hindbrain, Midbrain, and Forebrain This is a picture of the brain from the left side. Beneath the cortex are three parts of the brain: the hindbrain, the midbrain,