CHAPTER 3 Overview of Factors Influencing Brain Development Bryan Kolb University of Lethbridge, Lethbridge, AB, Canada 3.1 INTRODUCTION We saw in Chapter 1, Overview of Brain Development that brain development is a prolonged process beginning in utero and continuing in humans until the end of the third decade. Brain development is guided not only by a basic genetic blueprint but also is shaped by a wide range of experiences, ranging from sensory stimuli to social relationships to stress, throughout the lifetime (Table 3.1). Brain development in humans can be measured directly by neuroimaging (structural MRIs, functional MRIs), electrophysiology, and behavior. Behavioral measures include neuropsycho- logical measures of cognitive functioning as well as measures of motor, perceptual, and social functioning. The behavioral measures present a challenge because tests need to be minimally culturally biased and age-appropriate to allow generalizations in a global context. One difficulty is that behavioral tests are difficult to administer to young children yet we know that experience sets children on trajectories that can be seen by 2 years of age (e.g., Hart & Risley, 1995), meaning that there is a need to intervene very early to set more optimistic trajectories for children at risk. An important challenge is to identify mechanisms that may underlay modifica- tions in brain development and behavior. Ultimately, the mechanisms will be molec- ular but there is a significant gap in our understanding of how molecular changes affect behavior, presumably via changes in neural networks and/or neural activity. Nonetheless, the emergence of epigenetics is providing evidence that pre- and postnatal, and even preconception, experiences modify gene expression, both developmentally and later in life. The relationship between molecular or cellular changes, neural networks, and behavior is by no means clear and is plagued by the problems inherent in inferring causation from correlation. By its very nature, behavioral neuroscience searches for epigenetic and neural correlates of behavior. Some of the molecular and neural changes are most certainly directly associated with behavior, but others are more ambiguous. Consider an example. When a person learns to play tennis there is an The Neurobiology of Brain and Behavioral Development r 2018 Elsevier Inc. DOI: http://dx.doi.org/10.1016/B978-0-12-804036-2.00003-0 All rights reserved. 51 52 The Neurobiology of Brain and Behavioral Development Table 3.1 Summary of factors affecting brain development Environmental factors Sensory and motor experience Language and cognitive experience Music Stress Psychoactive drugs ParentÀchild and peer relationships Diet Poverty Brain injury Internal factors Microbiome Immune system obvious change in the ability to make smooth and accurate movements that become so fast that a novice player would see them as being impossible. But what is the relationship between the molecular, behavioral, and cerebral changes? We can conclude that the tennis training directly caused the behavioral change, but it is less clear how molecular changes altered the brain or how the neural changes relate to the behavior. The improved behavior may have preceded some of the changes in the brain or perhaps induced molecular changes. Thus, a common criticism of studies trying to link experience, neuronal and molecular changes, and behavior is that “they are only correlates.” This is true but it is hardly a reason to dismiss such studies. Ultimately, the proof would be in showing how the neural changes arose, which would presumably involve molecular analysis such as a change in gene transcription. For many studies using humans this would be an extremely difficult challenge and often impractical. It is our view that once we understand the “rules” that govern how different factors lead to changes in brain structure and function, we will be better able to look for molecular changes. A certain level of ambiguity in the degree of causation is perfectly justifiable at this stage of our knowledge. Understanding the precise mechanism whereby the synaptic changes might occur is not necessary to proceed with further studies aimed at improving functional outcomes in children. The goal of this chapter is to consider the manner in which a wide range of fac- tors influence both brain and behavioral development as well as how the brain responds to other experiences later in life. We begin with a brief discussion of epige- netics and how changes in gene expression can modify brain development in order to provide a general framework for understanding how experience can translate into brain and behavioral changes. Overview of Factors Influencing Brain Development 53 3.2 EPIGENETICS AND BRAIN DEVELOPMENT The genes expressed within a cell are influenced by factors inside the cell and in the cell’s environment. Cells within the body find themselves in different environments (e.g., bone, heart, brain) and this environment will determine which genes are expressed and what kind of tissue it becomes, including what type of nervous system cell. But environmental influence on cells does not end at birth because our environ- ment changes daily throughout our lives, providing opportunity to influence our gene expression (for a more extensive discussion, see Chapter 7, Epigenetics and Genetics of Brain Development). Epigenetics can be viewed as a second genetic code, the first one being the genome, which is an organism’s complete set of DNA. Epigenetics refers to the changes in gene expression that do not involve change to the DNA sequence but rather the processes whereby enzymes read the genes within the cells. Thus, epigenetics describes how a single genome can code for many phenotypes, depending upon the internal and external environments. Epigenetic mechanisms can influence protein production either by blocking a gene to prevent transcription or by unlocking a gene so that it can be transcribed (see Fig. 3.1). Chromosomes are comprised of DNA wrapped around supporting molecules Figure 3.1 Methylation alters gene expression. In the top panel methyl groups (CH3) or other molecules bind to tails of histones, either blocking them from opening (orange circles) or allowing them to open for transcription (green squares. In the bottom panel, methyl groups bind to CG base pairs to block transcription (after Kolb, Whishaw, & Teskey, 2016). 54 The Neurobiology of Brain and Behavioral Development of a protein called histone, which allows many meters of DNA to be packaged in a small space. For any gene to be transcribed into messenger (mRNA), its DNA must be unspooled from the histones. Thus, one measure of changes in gene expression is his- tone modification through methylation, phosphorylation, ubiquinylation, or acetylation. Methyl groups (CH3) or other molecules bind to the histones, either blocking them from opening or allowing them to unravel. Methylation can also occur in CpG islands on the DNA that are usually located near promoter sites for genes (see Fig. 3.1). (CpG refers to cytosine and guanine that appear in a row on a strand of DNA. The “p” refers to the phosphodiester bond between them.) When methylation occurs at CpG sites gene transcription cannot proceed. In mammals, about 60%À90% of CpG sites are methylated. Changes in the amount of methylation in a tissue thus can give an indirect estimate of the amount of gene expression. As a rule of thumb more methylation means fewer genes expressed whereas reduced methylation means more genes are expressed. Epigenetic mechanisms act to influence protein production in a cell either by blocking a gene, and thus preventing transcription, or by unlocking a gene to allow transcription. This is where experiential and environmental influences come into play to influence brain and behavior. Consider an example. There is a growing literature showing that maternal smoking during pregnancy is associated with adverse effects on neurodevelopment and abnormal cognitive development in the offspring but it has been difficult to identify a direct link until recently. Several studies now have exam- ined the epigenetic impact of a pregnant mother’s smoking on her child. For example, Joubert, Feliz, Yousefi, and Bakulski (2016) studied over 6600 mothers and their newborns, comparing which genes were methylated. The methylation pattern in the infants was similar to what is seen in adult smokers, even though the infant was never exposed directly to cigarette smoke. The newborns of smoking mothers had a methyl- ation pattern that differed from newborns of nonsmoking mothers at about 6000 locations, about half of which were associated with a particular gene. Many of these genes are related to nervous system development. Holz, Boecker, Baumeister, and Hohm (2014) examined the long-term effect of gestational exposure to smoking by measuring fMRI (functional Magnetic Resonance Imaging) activity during the performance of a test of inhibitory control in young adult participants. They found that there was reduced volume and activity in the ante- rior cingulate gyrus, inferior frontal gyrus (IFG), and the supramarginal gyrus, patterns often associated with attention-deficit hyperactivity disorder (ADHD) symptoms, in a dose-dependent manner. Other studies in laboratory animals have found decreased brain-derived neurotrophic factor mRNA and protein, which is also associated with neurodevelopmental disorders (e.g., Yochum et al., 2014). But what about smoking grandmothers? Golding, Northtone, Gregory, Miller, and Pembrey (2014) have studied a large group of over 20,000 children in whom there are data regarding smoking in grandmothers and mothers. In one study, they Overview of Factors Influencing Brain Development 55 found that if paternal grandmothers had smoked in pregnancy, but their mother had not, the girls were taller and both genders had greater bone and lean mass at 17 years of age. In contrast, if the maternal grandmother had smoked prenatally but the mother had not, the boys were heavier than expected due to lean rather than fat mass, which was reflected in increased strength and fitness.