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Levels and Explanations
C H A P T E R
1 Levels and Explanations Understanding the relations between genes, the brain, and human behavior is a very challenging task because the three things exist at different levels (Table 1.1). Behavior and thinking are done by an individual, a whole person. The science of psychology teaches us how to define and measure mental functions and behaviors. Genes, on the other hand, are molecules contained in the nucleus of almost all cells in the body (except red blood cells). A gene, part of a DNA molecule, codes for the structure of another kind of molecule, a protein, which is a long chain of smaller amino acid molecules. The study of genes and the inheritance of DNA molecules is the domain of genetics. The genes transmitted from parents to offspring constitute the person’s genotype, whereas the characteristics that are measured constitute the phenotypes, and phenotypes can exist at several levels. Once we have a fairly good idea of how the gene works and what its protein product does, we can then begin to understand how it might be involved in brain function and behaviors. Hopefully, we will also gain some good ideas about how to ameliorate the effects of a defective gene by making adjustments to the environment or devising new medical treatments. This book explains how genes are related to thought and behavior by exploring examples in which the role of a specific gene is quite well understood. The examples show how a gene can influence behaviors, even though it does not code specifically for those behaviors. The concept is not an easy one to grasp. Real examples can guide us to a better understanding of difficult concepts.
lower level that are connected and work together. Small molecules such as water or ethanol are composed of two or more kinds of atoms connected by chemical bonds (Fig. 1.1). Macromolecules such as proteins are made up of long chains of smaller molecules known as amino acids, each of which is made of hydrogen, carbon, oxygen, nitrogen, and sometimes sulfur. Organelles are built from several kinds of macromolecules, while an entire cell such as a neuron in the brain contains many types of organelles. Several kinds of cells unite to form a specific tissue, such as the quadriceps muscle in the leg, and an assemblage of different tissues forms an organ—a liver or a brain. Combining the brain with other essential organs such as the heart, lungs, eyes, and hands, we arrive at an entire organism, the individual person, who in turn is part of a social group. The brain itself does not express behavior; it does not move. The brain itself cannot think; it needs connections with sense organs and a long tutoring in language to engage in thought and express ideas to other members of a social group. The whole person thinks and speaks. Only as parts of a social group do people have anything to say. Because the levels of reality are so different, specialized disciplines have arisen to study and explain them. Physics studies atoms such as carbon and oxygen, but it cannot tell us much about the properties of macromolecules such as genes or proteins. To be a good physicist, a scholar does not need to know anything at all about genes. Likewise, a geneticist will not be able to explain inheritance by doing an in-depth investigation of the nitrogen atom or the electron. There are many commonalities across levels in the fundamental methods of doing a scientific study and analyzing the data with mathematics, and a few broad generalizations about nature can also be made. Nevertheless, the large bulk of knowledge of a specific level is encapsulated in the texts and journals of a specific discipline. A few hybrid disciplines span several levels. Neuroscience is a prime example. Molecular neuroscience examines how small neurotransmitter molecules such
LEVELS AND SCIENTIFIC DISCIPLINES The concept of integrative levels has been applied in different ways by different fields of science, as described in a historical review by Kleineberg (2017). Here, the concept is applied to things that differ in size and the kinds of connections within and between the levels. An entity at one level is made up of several smaller things at the next
Genes, Brain Function, and Behavior https://doi.org/10.1016/B978-0-12-812832-9.00001-4
1
© 2019 Elsevier Inc. All rights reserved.
2 TABLE 1.1
1. LEVELS AND EXPLANATIONS
Levels of Explanation and Scientific Disciplines Mit
Level
Examples
Specialty
Geographic cluster
Village, province, nation
Political science
Social organization
Family, club, orchestra, hospital
Sociology
Individual
Fruit fly, mouse, dog, human being
Psychology
Organ
Eye, brain, ovary, arm
Physiology
Tissue
Retina, gums, bicep muscle
Physiology
Cell
Neuron, leucocyte, sperm
Cell biology
Organelle
Synapse, myelin, mitochondria
Neurobiology
Macromolecule
DNA (gene), protein, omega-3 fatty acid
Biochemistry, genetics
Molecule
Water, carbon dioxide, ethanol, lysine
Chemistry
Atom
Carbon, hydrogen, oxygen, iron, silver
Physics
Presynaptic terminal
och
Postsynaptic membrane
ond
ria
Receptors
Axon that s of neuron ends signa l
Vesicles
tic
Synapse
ap Syn
Neurotransmitter molecules
Dendrite of neuron that receives signal
ft
cle
FIG. 1.2 Diagram of a synapse, a specialized organelle that conveys signals from one nerve cell to another using small neurotransmitter molecules that are synthesized in one cell, stored in small vesicles and then released into the gap or cleft between the two cells, where they stimulate receptors on the next neuron. A synapse is so small that about 1000 of them placed side by side would amount to just 1 mm. Mechanisms of synaptic function are described in Chapter 4.
LEVELS AND SIZE
as dopamine are synthesized by large macromolecules called enzymes and stored in an organelle, a synapse that connects two neurons (Fig. 1.2). The enzymes needed to make dopamine arrive in the synapse, and the transmitter molecules that they synthesize are then stored in small vesicles. Things happen in the person’s environment that can stimulate the release of dopamine from the vesicles and deliver a pulse of chemical energy that influences the next nerve cell in a circuit. If enough neurons get involved in the action, this can change the individual’s behavior. Thus, a student of neuroscience needs to study sciences at different levels from molecule to mind in order to achieve a good understanding of how the entire nervous system works to regulate behavior.
Mixture of gases
Molecules of water
H H O O
H O
H
H
H
H
O
O
H
O
H
O
Dimethyl ether Highly flammable gas Liquid at –24°C Freezes at –141°C
Ethanol Drinkable liquid Gas at +78°C Freezes at –114°C
H
O H H O H
H
H
O
H
H
H
H O H
O HO
H
H H
H
H
H
O H
H
O
O
O O
FIG. 1.1
O H
(A)
O H
H
H
H H
H H
H
H
H
The sizes of parts that are involved at each level increase greatly from atom to macromolecule, to cell, to organ, to the whole person. The metric system provides a convenient way to express sizes in powers of 10 (Table 1.2). A superb illustration of the scale of size is provided by the web page maintained by the University of Utah that can be accessed using the search term “cell size and scale.” A diagram (Fig. 1.3) shows the range of things that can be seen with the unaided eye, a light microscope, and an electron microscope. Living organisms can be relatively small, such as a minute HIV virus (125 nm) or the familiar Escherichia coli bacterium (1.5 4 μm) that populates our digestive tract. A bacterium is a single cell and is much smaller than just one nerve cell in a human brain that can grow to have a cell body with a diameter of 40 μm or microns (Herndon,
H
H
H
C
C
H
H
H O
H
H
C H
H O
C
H
H
Isomers
(B)
Atoms of carbon, hydrogen, and oxygen are shown as the letters C, H, and O, respectively. Chemical bonds are shown as small lines, and a double bond is two lines. Hydrogen can form just one bond, oxygen two, and carbon four. (A) When each atom of H or O is bound to another of the same kind, the two kinds form a mixture of gases. When a spark triggers oxidation of the hydrogen, the result from the same atoms arranged differently is liquid water. (B) The isomers ethyl alcohol and dimethyl ether both have the chemical formula C2H6O, but the properties of the molecules differ greatly when the oxygen is in a different position.
PROPERTIES AND CONNECTIONS
TABLE 1.2 The Metric System and Powers of 10 Prefix
Multiplier
Power of 10
Examples
Giga
1,000,000,000
109
Gigabyte
Mega
1,000,000
106
Megaton
Kilo
1000
103
Kilometer
One
1
1
Gram
Centi
0.01
102
Centimeter
Milli
0.001
103
Millisecond
Micro
0.000001
106
Microgram
Nano
0.000000001
109
Nanometer
Human eye
1 cm
Mosquito Red ant Flea
1 mm
Large neuron Paramecium
Light microscope
100 µm
1-cell zygote Human hair
10 µm
Red blood cell E. coli bacterium
Electron microscope
1 µm
100 nm
10 nm
1 nm
Synapse
3
their forms and functions. An entire blue whale can reach 180 Mt (1 t ¼ 1000 kg), more than the combined mass of 7 million 25 g mice. Nevertheless, the nervous systems of whale, mouse, and other mammals are remarkably similar. Size by itself does not tell us much about the individual parts or the internal organization of an organism. Gravity provides a good example of levels and size. Isaac Newton made the fundamental discovery that every speck of matter in the universe attracts every other speck. The amount of matter in a body is indicated by its mass in grams or kilograms. Newton showed that the force of gravitational attraction between a person and the earth is determined by the mass of a person (m1) multiplied by the mass of the earth (m2) and divided by the square of the distance of the person from the center of the earth (d). We experience the force of gravitational attraction toward the center of the earth as body weight and measure it with a bathroom scale. In the era of space travel, astronauts who visited the moon testified that the force of gravity there is far less than on earth because the moon is so much less massive. Gravitation applies equally well to a simple rain drop falling to earth and immense galaxies of stars involving vast distances. For gravitational attraction, it makes no difference how the atoms that comprise one body are joined together; the important thing is simply how many atoms of which elements it contains. The scientific explanation of gravity involves things that transpire at the atomic level. The formula for computing the force of gravity is F ¼ C(m1 m2/d2), where the number C is the gravitational constant.
HIV
PROPERTIES AND CONNECTIONS Hemoglobin DNA diameter Ethanol molecule Carbon atom
0.1 nm
FIG. 1.3 Sizes of things, ranging from small animals that can be seen with the unaided eye to a single atom. The smallest object that most people can see without a microscope is in the range 0.1–0.2 mm. One micrometer (μm) or micron is 0.000001 m or 0.001 mm. One nanometer (nm) is one millionth of a millimeter or 0.000001 mm. A very large protein such as hemoglobin, when folded into a ball, is about 7 nm in diameter, which means that about 140 of them side by side would amount to 1 μm and 140,000 of them side by side would span 1 mm.
1963) and branches extending outward >250 μm (0.25 mm). As we proceed above the level of cells, most things can be seen by the unaided eye, and it thus is easier to know
When we study a group of objects at one level, we can see how the properties of a group often depend on how the parts are connected with each other. There are situations in which the same parts are connected differently, which results in very different properties. Several of these are quite familiar. Consider the atoms hydrogen and oxygen (Fig. 1.1A). Each can exist as a colorless, odorless gas wherein pairs of atoms of one kind are loosely bound to each other and free to float in a container. They are so small that gravity has little effect, and the gas particles fill the container from top to bottom. When a spark is sent through the mixture of gases, this triggers oxidation with a loud pop and flash. Suddenly, the hydrogen and oxygen atoms recombine into a familiar molecule: water or H2O. It is a clear liquid, and gravity draws most of it to the bottom of the container. The water will freeze into solid ice at 0°C, whereas the mixture of gases will not freeze at all at any temperature people are likely to experience. Thus, although the constituent parts—the atoms—are the same in the mixture of gases and the pool
4
1. LEVELS AND EXPLANATIONS
of liquid water, the properties of the mixture of gases and the water molecule are radically different. Whether the water actually exists as liquid, solid, or gaseous water vapor depends on the temperature of the molecules’ environment. The freezing point of a molecule in turn depends on the number and kinds of its atoms as well as how they are interconnected. Water freezes at 0°C, whereas ethanol freezes at 114°C. Thus, the properties of a particular kind of substance depend on both its internal structure formed from interconnected atoms and its external environment. It makes no sense at all to say that its existence as a gas, liquid, or solid depends more on the internal than the external factor. Both must be fully taken into account in order to understand the properties of the whole. Many kinds of molecules are isomers in which the same constituent atoms are interconnected in different ways. Fig. 1.1B shows ethanol, a liquid at room temperature, and dimethyl ether, a highly flammable gas. Both have the chemical composition C2H6O. Only the location of the oxygen atom differs, but this changes the properties of the two molecules dramatically.
LEVELS AND GENES Here, we are mainly interested in medical disorders and complex behaviors, not basic physics. Nevertheless, some of the same principles seem to be involved, albeit at different levels. Consider diabetes, a common malady. Blood sugar levels become very high. Untreated, the high blood sugar contributes to obesity, the loss of vision, kidney damage, poor circulation in the feet, and many other symptoms. Type 1 diabetes results from insufficient insulin production from the type B cells of the islet of Langerhans that are distributed throughout the pancreas, and it is treated with insulin injections. Insulin stimulates the absorption of glucose from the blood into the muscle by activating a small structure on the surface of the muscle fiber, the insulin receptor. Type 2 diabetics have enough insulin, but the receptor does not respond well to it, so there is insulin insensitivity or resistance, and blood sugar levels rise to unhealthy levels when enough glucose cannot get into the muscle fibers. Mice sometimes are diabetic and obese too, and they show almost the same array of symptoms we term diabetes in humans. In 1950, a new genetic mutation was discovered in lab mice that led to extreme overeating and obesity, and it was named the obese gene (Ingalls, Dickie, & Snell, 1950), abbreviated ob. A mouse had to have two copies of the mutation and have genotype ob/ob in order to show the extreme weight gain, the obesity phenotype. In the 1950s in mouse genetics, it was customary to name a gene for an abnormal phenotype, the disease that appeared when it was mutated. The normal
form of the gene was symbolized +. A few years later, another gene was discovered that also resulted in obesity and rapid onset of diabetes, and it was named the diabetes gene, abbreviated db (Hummel, Dickie, & Coleman, 1966). It turned out that the insulin receptor was normal in both kinds of mice. The problems in the mutant mice originated in unknown molecules. For the diabetic mice (Fig. 1.4A), one of the phenotypes was behavioral: overeating. The diabetic mice (db/db) ate far more than their normal siblings and became obese. So, researchers employed a psychological method called pairfeeding. A normal mouse (+/+) was housed by itself in a cage, and its daily food intake was measured. The next day a db/db mouse housed in an adjacent cage was given only the amount of food the normal mouse had consumed the previous day. There was also a cage with a db/db mouse that was allowed to eat all it wanted. When restricted to the same amount of food as normal mice, the db/db mouse did not become obese, and it did not show elevated glucose (Lee & Bressler, 1981). Thus, the physiological symptoms we call diabetes depended on a psychological phenomenon—appetite. Whether the db/db mice were actually diabetic depended on how much food they ate. The gene had been named diabetes, but in fact, it does not code for phenotypic diabetes. If we simply limit how much the creatures consume, there is no diabetes. After years of investigation, other researchers discovered a new hormone that is encoded by the obese gene and is deficient in ob/ob mice (Halaas et al., 1995). Injecting it into the ob/ob mice greatly reduced the overeating. Later, the hormone was named leptin, and it provided a crucial part of the puzzle of diabetes (Fig. 1.4B). It was discovered that leptin is made in white fat cells, and the more fat has been stored, the more leptin enters the bloodstream. Like all hormones, leptin is detected by specific receptor molecules. The leptin receptor was also identified, and it is located on cells in a part of the brain called the hypothalamus that regulates many bodily functions, including appetite. When leptin levels in blood rise, appetite and eating are reduced. Further studies revealed that the obese mutation actually codes for an abnormal form of the gene that codes for leptin, while the diabetic mutation codes for a defective leptin receptor. Researchers then injected leptin into the two kinds of mutant mice. The leptin injections had no effect on the diabetic mice because their defective leptin receptor could not detect it (Schwartz, Seeley, Campfield, Burn, & Baskin, 1996), but they greatly reduced diabetic symptoms in the obese mice because the injected leptin reduced their appetites for food. After the functions of the two genes were known, they were renamed. In mice, the one that coded for the leptin hormone was officially designated the leptin gene (Lep), whereas the other became the leptin receptor gene (Lepr). The normal leptin gene was symbolized Lep+, and the mutation became Lepob. The normal gene
5
ANIMAL MODELS
+/ +
LEPR
db/db
NPY Other POMC
Genotypes: +/+ Feeding: Free
db/db Free Obese
db/db Paired
Blood glucose Normal
Very high
Normal
Plasma insulin Normal
Extreme
Elevated
Body weight Normal
Normal Diabetic
Phenotypes (A)
NPYR MC4R
Leptin
Normal
Not diabetic
Appetite
Hypothalamus
"Diabetic"
Normal
Overeating
LEP
Muscle INSR
White fat
Insulin
INS Islets of Langerhans
Glucose
(B)
(A) When allowed to feed freely, mice with two copies of a mutant gene named “diabetic” (db) became obese and showed symptoms of severe diabetes, whereas mice with two normal copies of the gene (+/+) remained lean and healthy. When the (db/db) mice were restricted to only the amount of food eaten daily by their lean siblings (pair-fed), they did not become obese or show symptoms of diabetes, even though they carried abnormal forms of the gene (Lee & Bressler, 1981). Data shown are relative to +/+ baseline values. (B) Further study revealed that appetite, obesity, and diabetes are regulated by a complex system involving several genes in both humans and mice acting in several organs at several different levels, including behavior. The gene formerly known as “obese” codes for the hormone leptin and is now named LEP, while the old gene named “diabetes” codes for the leptin receptor (LEPR). Several genes are part of the circuit in the hypothalamus that includes neuropeptide Y (NPY) and its receptor (NPYR). Connections that involve activation are shown by arrows, whereas those inhibiting the downstream process end in a bar. Normally, obesity is prevented by a feedback loop whereby excess eating grows more white fat that in turn synthesizes more leptin that then stimulates the leptin receptor and turns down the appetite control.
FIG. 1.4
encoding the receptor became Lepr+, and the mutation became Leprdb. The genotypes of what were formerly known as the obese and diabetes mice were in all subsequent research symbolized as Lepob/Lepob and Leprdb/ Leprdb, respectively. The genes were also found in humans and named using capital letters (LEP and LEPR; see Fig. 1.4B). Thus, the modern practice in naming genes is to name them for what they normally do at the molecular level, not for a phenotypic disease that sometimes appears under certain conditions. This example demonstrates the importance of knowing how things work at several levels in order to comprehend the origins of disease symptoms and learn how to treat them. Although genetic mutations were the original sources of the problems, they act via a complex, multilevel system that involves a psychological process—appetite— and the animals’ nutritional environment. A behavioral method, pair-feeding, helped to understand the origins of the obesity and diabetes. The genes are macromolecules, but the disease we call diabetes is not simply a molecular issue and cannot always be treated by administering some specific molecule. The disease is a multilevel phenotype.
ANIMAL MODELS Conducting experiments with lab animals is far easier than doing so with humans because their environments and breeding can be strictly controlled and many things
can be done that would be impossible with humans for both practical and ethical reasons. Research in neuroscience relies heavily on the study of animal models. Four of the most commonly studied species in the genetic analysis of the nervous system and behavior are listed in Table 1.3. We hope the findings for animals will give us a pretty good idea of what is taking place in humans as well, but caution is warranted when comparing species. How well results are likely to generalize across species depends strongly on the level at which we are making the comparisons. The tiny nematode worm about 1 mm long that is abundant in garden soil has only 302 nerve cells, yet it has about as many different genes as humans. A large fraction of nematode genes are counterparts of human genes that have very similar chemical structures and must have been inherited from a common ancestor long ago. About half of proteins that occur in those worms are also found in humans, sometimes with minor variations in structures, and about 40% of genes known to be important for human diseases have counterparts in the worms (Corsi, Wightman, & Chalfie, 2015). Many of the large molecules that are so important for human brain function also occur in nematodes (Hobert, 2013), but the synapses that connect one nerve cell to another are different from ours, and the overall structure of the two nervous systems and the kinds of nerve cells they contain are very different indeed. Nematodes show a number of simple reflexes that are quite easy to study, and they are also capable of learning and remembering things that happen in their
6 TABLE 1.3
1. LEVELS AND EXPLANATIONS
Features of Four Species Commonly Studied in the Field of Genes, the Brain, and Behaviora
Scientific name
Caenorhabditis elegans
Drosophila melanogaster
Mus musculus domesticus
Homo sapiens
Common name
Nematode worm
Fruit fly
House mouse
Human
Adult size
1 mm
2.5 mm
15–25 g
150–180 cm
Reproduction
Self-fertilizing
Sexual
Sexual
Sexual
Age at first reproduction
3 days
7–20 days
46–62 days
14–20 years
Life span or expectancy
18–20 days
30 days
600–800 days
60–85 years
Number of neurons
302
340,000
100 million
100 billion
Kinds of chromosomes
6
4
21
23
Genome (million bases)
100.3
175
2803.6
3257.3
Protein-encoding genes
20,444
17,717
23,202
<20,000
a
Sources of information (will change with future updates of databases): Nematode worm: search terms WormBook and WormBase; Fruit fly: search term FlyBase; Mouse: search terms Mouse Genome Informatics and MGI 6.11 Introduction to Mouse Genetics; Human: search terms Genetics Home Reference and Human Genome Assembly GRCh38.p12.
environments (Ardiel & Rankin, 2010). Nevertheless, at the level of behavior, there is a wide divergence between worms and people. The nematodes eat bacteria living on the same broth as the worm. They can move by undulating in S-shaped curves, but they have no legs or arms for propulsion. Neither do they have eyes or visual organs. The life span is short, and social interactions are rudimentary. Thus, they are remarkably similar to humans at the level of macromolecules but diverge at higher levels. The ubiquitous fruit fly has a much larger nervous system than nematodes and well-developed vision plus remarkable capacities for flight. The adults engage in a kind of courtship during mating. Both the larvae and adults are capable of learning and memory. The flies share thousands of genes in common with humans that are implicated in some kind of disease (Hu et al., 2011). Nevertheless, the structure of their nervous system and behavioral repertoire are substantially unlike humans. The humble house mouse is a mammal with much greater similarity to us. Its genome is almost as large as humans, and it has just as many genes (Table 1.3). Mice have 17,098 genes that are very similar to human genes, and there are more than 1300 human diseases for which there is a fairly good mouse model of the disease process (Mouse Genome Informatics). Young mice are born hairless with their eyes closed, and they rely on care by the mother for several weeks. The nervous system of mice has many regions that are essentially the same as humans in their locations and connections with other parts of the brain, including the cerebellum, hypothalamus, hippocampus, and corpus callosum (Chapter 4). The eye and retina are very similar, but color vision is more highly developed in humans. The human cerebral cortex is folded extensively and contains many more nerve cells relative to the rest of the brain, while the mouse cortex is smooth and relatively smaller, but the layers and connections are strikingly similar in the two species. A wide
variety of tests of complex behaviors are available for mice (Crawley, 2007; Wahlsten, 2011). Mice do not have our kind of language, but there is evidence that they emit patterns of sounds in the ultrasonic range, especially during courtship, that resemble songs (Arriaga, Zhou, & Jarvis, 2012; Chabout, Sarkar, Dunson, & Jarvis, 2015). As a general pattern, similarities of nervous system anatomy and behavioral functions are greater in animals that are more closely related to humans because of more recent evolution from a common ancestor. All species of animals have DNA that encodes genetic information, and the mechanisms by which that information is processed are the same throughout the animal kingdom. The relations between DNA and proteins are also essentially the same. Thus, we expect experiments that are done at the molecular level will yield similar results for a wide range of species, while studies of complex behaviors are likely to reveal many things that are unique to a particular species. Whatever the level of a research project, results always need to be confirmed in humans. An animal model of a human function is not a substitute for investigation of the human condition. It needs to be verified. Nevertheless, many kinds of exploratory studies are far easier and more efficient to do with animal models. Landmark studies of genes and the basic processes of brain development and nervous system function were virtually all done with experiments on animals and then later confirmed in work with humans.
THE EXPERIENCE OF PAIN It is interesting to inquire whether animals experience pain the way we do. This is an important question from the standpoints of ethical treatment of animals and the use of animal models in research on pain. Without a
7
HIGHLIGHTS
doubt, pain has important cognitive aspects in people that involve language, and these higher-level thought processes are just about impossible to model with mice or rats. At the same time, the way pain is processed in the nervous system is remarkably similar for all mammals, and many of the drugs used to treat pain in people are also effective for aiding mice. Receptors in the brain that detect pain signals are encoded by genes that are very similar, and the manner of synthesizing chemicals in the brain that signal pain is virtually the same as well. The nerve endings that sense damage to peripheral tissue are very similar, as are the pain pathways via nerves from the periphery into the brain (Chapter 4). Nevertheless, the assessment of pain in people often involves verbal communication with medical personnel who make judgments of pain intensity based upon how their patients rate their own pain levels. When children are not able to rate the pain on many dimensions, they may be rated by the Wong-Baker FACES pain rating scale that asks a child to point to a symbol on a card showing smiling and frowning faces (Wong & Baker, 1988). There are six faces ranging from a score of 0 (no hurt at all) to 10 (hurts worst of all). Several versions of this scale are returned by a Google Images search, one of which is sanctioned by the Wong-Baker FACES Foundation. Mice can obviously not be rated in this way, but a clever adaptation of pained faces has been used to construct a rating scale for mice that looks closely at their faces. Investigators with extensive experience studying pain in mice had noticed that animals tended to grimace during the period following a surgical operation. They devised the mouse grimace scale in which video images are collected of the face and then rated with regard to the eyes, nose, cheek, ear, and whiskers (Langford et al., 2010). Each feature is scored as 0 ¼ grimace not present, 1 ¼ moderately visible, and 2 ¼ severe, and the five numbers are added to obtain an index ranging from 0 to 10. The scale proved to be very effective in rating postoperative pain and assessing the effects of analgesic drugs (Matsumiya et al., 2012). The grimace scale has a major advantage over the scales used in clinical practice with people because the ratings of mice from video images are done “blind” by technicians who do not know what treatments the mice had received, thereby avoiding possible biases in making judgments. A number of psychological and social factors have major impacts on the human experience of pain. People who experience greater social support from family, friends, and the helping professions report less severe pain from cancer and during childbirth, and they require lower doses of analgesic drugs to achieve acceptable levels of pain control. The “placebo effect” that alleviates pain when the substance given to patients actually has no active ingredient also highlights the role of psychological processes (Kaptchuk & Miller, 2015). Thus, for anyone
interested in the origins and amelioration of pain, understanding the phenomenon at several levels is essential.
EXPERTISE AND APPLICATIONS There is far too much knowledge embodied in the disciplines in Table 1.1 for one person to understand them all in depth, but deep knowledge, real expertise, is not necessary for many people, including readers of this book. We need enough knowledge to answer the main questions we ask about genes, brains, and behaviors. This is sometimes referred to as reading knowledge. One can read an essay, a news article, or a book written for nonspecialists and grasp the general ideas of how things work. Perhaps, one might even be able to discern when an article in a newspaper contains a serious error and then write a letter to the editor. But this depth of knowledge would not be enough to apply it in biomedical or psychological practice. It would not enable a person to make a formal diagnosis of a behavioral disorder or prescribe a drug to treat it, even though the person might have a pretty good idea of how a drug is supposed to function in the brain. A practitioner must also know about making fine distinctions among several possible diagnoses that involve similar symptoms, the merits of alternative therapies, a diverse array of possible side effects of a drug (Chapter 17), and the realities of family dynamics and other social factors. If and when the time comes for we ourselves to be examined and possibly treated for some kind of biochemical defect or a mental disorder, many of us want it to be done by genuine experts. It is possible to read this chapter without knowing just what a gene is. The term is used several times here, and simply knowing that it is a very big molecule that codes for the structure of a protein is enough to get the gist of these paragraphs. To go further with the story of genes, the brain, and behavior, we must gain a deeper understanding of genes.
HIGHLIGHTS • Things exist at different levels, ranging from atoms to molecules, to cells, to organs, then upward to an entire organism living in a society. • Each level is studied by a specialized field of science using terms and methods that are appropriate for that level. • The properties of something existing at a specific level depend on the natures of its parts and the pattern of interconnections among them. • A gene is a portion of a large molecule (DNA) and functions at the molecular level.
8
1. LEVELS AND EXPLANATIONS
• A person’s genotype is the set of genes transmitted by the parents, whereas phenotypes at other levels are characteristics that develop and can be measured. • A gene is usually named for what it normally does at the molecular level, not a disease that may occur when there is a defect in the gene. The actual occurrence of disease often depends not only on the genotype but also on features of other levels, including the individual’s environment. • Different species of animals are very similar at the molecular level but often differ greatly at the level of behavior. Lab animals provide good models of things that happen at the molecular level, and at that level, they are very similar to humans. • To understand complex behavioral phenomena such as hunger or pain, it is important to study them at different levels ranging from the molecular to behavioral and to consider the social context of behavior.
References Ardiel, E. L., & Rankin, C. H. (2010). An elegant mind: learning and memory in Caenorhabditis elegans. Learning and Memory, 17, 191–201. Arriaga, G., Zhou, E. P., & Jarvis, E. D. (2012). Of mice, birds, and men: the mouse ultrasonic song system has some features similar to humans and song-learning birds. PLoS One, 7, e46610. Chabout, J., Sarkar, A., Dunson, D. B., & Jarvis, E. D. (2015). Male mice song syntax depends on social contexts and influences female preferences. Frontiers in Behavioral Neuroscience, 9, 76. Corsi, A. K., Wightman, B., & Chalfie, M. (2015). A transparent window into biology: a primer on Caenorhabditis elegans. Genetics, 200, 387–407.
Crawley, J. N. (2007). What’s wrong with my mouse?: Behavioral phenotyping of transgenic and knockout mice (2nd ed.). New York: Wiley. Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., et al. (1995). Weight-reducing effects of the plasma protein encoded by the obese gene. Science, 269, 543–546. Herndon, R. M. (1963). The fine structure of the Purkinje cell. Journal of Cell Biology, 18, 167–180. Hobert, O. (2013). The neuronal genome of Caenorhabditis elegans. In vol. 13. WormBook: The online review of C. elegans biology (pp. 1–106). Pasadena, CA: WormBook. Hu, Y., Flockhart, I., Vinayagam, A., Bergwitz, C., Berger, B., Perrimon, N., & Mohr, S. E. (2011). An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics, 12, 357. Hummel, K. P., Dickie, M. M., & Coleman, D. L. (1966). Diabetes, a new mutation in the mouse. Science, 153, 1127–1128. Ingalls, A. M., Dickie, M. M., & Snell, G. D. (1950). Obese, a new mutation in the house mouse. Journal of Heredity, 41, 317–318. Kaptchuk, T. J., & Miller, F. G. (2015). Placebo effects in medicine. New England Journal of Medicine, 373, 8–9. Kleineberg, M. (2017). Integrative levels. Knowledge Organization, 44, 349–379. Langford, D. J., Bailey, A. L., Chanda, M. L., Clarke, S. E., Drummond, T. E., Echols, S., et al. (2010). Coding of facial expressions of pain in the laboratory mouse. Nature Methods, 7, 447–449. Lee, S. M., & Bressler, R. (1981). Prevention of diabetic nephropathy by diet control in the db/db mouse. Diabetes, 30, 106–111. Matsumiya, L. C., Sorge, R. E., Sotocinal, S. G., Tabaka, J. M., Wieskopf, J. S., Zaloum, A., et al. (2012). Using the Mouse Grimace Scale to reevaluate the efficacy of postoperative analgesics in laboratory mice. Journal of the American Association for Laboratory Animal Science, 51, 42–49. Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P., & Baskin, D. G. (1996). Identification of targets of leptin action in rat hypothalamus. Journal of Clinical Investigation, 98, 1101. Wahlsten, D. (2011). Mouse behavioral testing. London, UK: Elsevier. Wong, D. L., & Baker, C. M. (1988). Pain in children: comparison of assessment scales. Pediatric Nursing, 14, 9–17.
1 Levels and Explanations Understanding the relations between genes, the brain, and human behavior is a very challenging task because the three things exist at different levels (Table 1.1). Behavior and thinking are done by an individual, a whole person. The science of psychology teaches us how to define and measure mental functions and behaviors. Genes, on the other hand, are molecules contained in the nucleus of almost all cells in the body (except red blood cells). A gene, part of a DNA molecule, codes for the structure of another kind of molecule, a protein, which is a long chain of smaller amino acid molecules. The study of genes and the inheritance of DNA molecules is the domain of genetics. The genes transmitted from parents to offspring constitute the person’s genotype, whereas the characteristics that are measured constitute the phenotypes, and phenotypes can exist at several levels. Once we have a fairly good idea of how the gene works and what its protein product does, we can then begin to understand how it might be involved in brain function and behaviors. Hopefully, we will also gain some good ideas about how to ameliorate the effects of a defective gene by making adjustments to the environment or devising new medical treatments. This book explains how genes are related to thought and behavior by exploring examples in which the role of a specific gene is quite well understood. The examples show how a gene can influence behaviors, even though it does not code specifically for those behaviors. The concept is not an easy one to grasp. Real examples can guide us to a better understanding of difficult concepts.
lower level that are connected and work together. Small molecules such as water or ethanol are composed of two or more kinds of atoms connected by chemical bonds (Fig. 1.1). Macromolecules such as proteins are made up of long chains of smaller molecules known as amino acids, each of which is made of hydrogen, carbon, oxygen, nitrogen, and sometimes sulfur. Organelles are built from several kinds of macromolecules, while an entire cell such as a neuron in the brain contains many types of organelles. Several kinds of cells unite to form a specific tissue, such as the quadriceps muscle in the leg, and an assemblage of different tissues forms an organ—a liver or a brain. Combining the brain with other essential organs such as the heart, lungs, eyes, and hands, we arrive at an entire organism, the individual person, who in turn is part of a social group. The brain itself does not express behavior; it does not move. The brain itself cannot think; it needs connections with sense organs and a long tutoring in language to engage in thought and express ideas to other members of a social group. The whole person thinks and speaks. Only as parts of a social group do people have anything to say. Because the levels of reality are so different, specialized disciplines have arisen to study and explain them. Physics studies atoms such as carbon and oxygen, but it cannot tell us much about the properties of macromolecules such as genes or proteins. To be a good physicist, a scholar does not need to know anything at all about genes. Likewise, a geneticist will not be able to explain inheritance by doing an in-depth investigation of the nitrogen atom or the electron. There are many commonalities across levels in the fundamental methods of doing a scientific study and analyzing the data with mathematics, and a few broad generalizations about nature can also be made. Nevertheless, the large bulk of knowledge of a specific level is encapsulated in the texts and journals of a specific discipline. A few hybrid disciplines span several levels. Neuroscience is a prime example. Molecular neuroscience examines how small neurotransmitter molecules such
LEVELS AND SCIENTIFIC DISCIPLINES The concept of integrative levels has been applied in different ways by different fields of science, as described in a historical review by Kleineberg (2017). Here, the concept is applied to things that differ in size and the kinds of connections within and between the levels. An entity at one level is made up of several smaller things at the next
Genes, Brain Function, and Behavior https://doi.org/10.1016/B978-0-12-812832-9.00001-4
1
© 2019 Elsevier Inc. All rights reserved.
2 TABLE 1.1
1. LEVELS AND EXPLANATIONS
Levels of Explanation and Scientific Disciplines Mit
Level
Examples
Specialty
Geographic cluster
Village, province, nation
Political science
Social organization
Family, club, orchestra, hospital
Sociology
Individual
Fruit fly, mouse, dog, human being
Psychology
Organ
Eye, brain, ovary, arm
Physiology
Tissue
Retina, gums, bicep muscle
Physiology
Cell
Neuron, leucocyte, sperm
Cell biology
Organelle
Synapse, myelin, mitochondria
Neurobiology
Macromolecule
DNA (gene), protein, omega-3 fatty acid
Biochemistry, genetics
Molecule
Water, carbon dioxide, ethanol, lysine
Chemistry
Atom
Carbon, hydrogen, oxygen, iron, silver
Physics
Presynaptic terminal
och
Postsynaptic membrane
ond
ria
Receptors
Axon that s of neuron ends signa l
Vesicles
tic
Synapse
ap Syn
Neurotransmitter molecules
Dendrite of neuron that receives signal
ft
cle
FIG. 1.2 Diagram of a synapse, a specialized organelle that conveys signals from one nerve cell to another using small neurotransmitter molecules that are synthesized in one cell, stored in small vesicles and then released into the gap or cleft between the two cells, where they stimulate receptors on the next neuron. A synapse is so small that about 1000 of them placed side by side would amount to just 1 mm. Mechanisms of synaptic function are described in Chapter 4.
LEVELS AND SIZE
as dopamine are synthesized by large macromolecules called enzymes and stored in an organelle, a synapse that connects two neurons (Fig. 1.2). The enzymes needed to make dopamine arrive in the synapse, and the transmitter molecules that they synthesize are then stored in small vesicles. Things happen in the person’s environment that can stimulate the release of dopamine from the vesicles and deliver a pulse of chemical energy that influences the next nerve cell in a circuit. If enough neurons get involved in the action, this can change the individual’s behavior. Thus, a student of neuroscience needs to study sciences at different levels from molecule to mind in order to achieve a good understanding of how the entire nervous system works to regulate behavior.
Mixture of gases
Molecules of water
H H O O
H O
H
H
H
H
O
O
H
O
H
O
Dimethyl ether Highly flammable gas Liquid at –24°C Freezes at –141°C
Ethanol Drinkable liquid Gas at +78°C Freezes at –114°C
H
O H H O H
H
H
O
H
H
H
H O H
O HO
H
H H
H
H
H
O H
H
O
O
O O
FIG. 1.1
O H
(A)
O H
H
H
H H
H H
H
H
H
The sizes of parts that are involved at each level increase greatly from atom to macromolecule, to cell, to organ, to the whole person. The metric system provides a convenient way to express sizes in powers of 10 (Table 1.2). A superb illustration of the scale of size is provided by the web page maintained by the University of Utah that can be accessed using the search term “cell size and scale.” A diagram (Fig. 1.3) shows the range of things that can be seen with the unaided eye, a light microscope, and an electron microscope. Living organisms can be relatively small, such as a minute HIV virus (125 nm) or the familiar Escherichia coli bacterium (1.5 4 μm) that populates our digestive tract. A bacterium is a single cell and is much smaller than just one nerve cell in a human brain that can grow to have a cell body with a diameter of 40 μm or microns (Herndon,
H
H
H
C
C
H
H
H O
H
H
C H
H O
C
H
H
Isomers
(B)
Atoms of carbon, hydrogen, and oxygen are shown as the letters C, H, and O, respectively. Chemical bonds are shown as small lines, and a double bond is two lines. Hydrogen can form just one bond, oxygen two, and carbon four. (A) When each atom of H or O is bound to another of the same kind, the two kinds form a mixture of gases. When a spark triggers oxidation of the hydrogen, the result from the same atoms arranged differently is liquid water. (B) The isomers ethyl alcohol and dimethyl ether both have the chemical formula C2H6O, but the properties of the molecules differ greatly when the oxygen is in a different position.
PROPERTIES AND CONNECTIONS
TABLE 1.2 The Metric System and Powers of 10 Prefix
Multiplier
Power of 10
Examples
Giga
1,000,000,000
109
Gigabyte
Mega
1,000,000
106
Megaton
Kilo
1000
103
Kilometer
One
1
1
Gram
Centi
0.01
102
Centimeter
Milli
0.001
103
Millisecond
Micro
0.000001
106
Microgram
Nano
0.000000001
109
Nanometer
Human eye
1 cm
Mosquito Red ant Flea
1 mm
Large neuron Paramecium
Light microscope
100 µm
1-cell zygote Human hair
10 µm
Red blood cell E. coli bacterium
Electron microscope
1 µm
100 nm
10 nm
1 nm
Synapse
3
their forms and functions. An entire blue whale can reach 180 Mt (1 t ¼ 1000 kg), more than the combined mass of 7 million 25 g mice. Nevertheless, the nervous systems of whale, mouse, and other mammals are remarkably similar. Size by itself does not tell us much about the individual parts or the internal organization of an organism. Gravity provides a good example of levels and size. Isaac Newton made the fundamental discovery that every speck of matter in the universe attracts every other speck. The amount of matter in a body is indicated by its mass in grams or kilograms. Newton showed that the force of gravitational attraction between a person and the earth is determined by the mass of a person (m1) multiplied by the mass of the earth (m2) and divided by the square of the distance of the person from the center of the earth (d). We experience the force of gravitational attraction toward the center of the earth as body weight and measure it with a bathroom scale. In the era of space travel, astronauts who visited the moon testified that the force of gravity there is far less than on earth because the moon is so much less massive. Gravitation applies equally well to a simple rain drop falling to earth and immense galaxies of stars involving vast distances. For gravitational attraction, it makes no difference how the atoms that comprise one body are joined together; the important thing is simply how many atoms of which elements it contains. The scientific explanation of gravity involves things that transpire at the atomic level. The formula for computing the force of gravity is F ¼ C(m1 m2/d2), where the number C is the gravitational constant.
HIV
PROPERTIES AND CONNECTIONS Hemoglobin DNA diameter Ethanol molecule Carbon atom
0.1 nm
FIG. 1.3 Sizes of things, ranging from small animals that can be seen with the unaided eye to a single atom. The smallest object that most people can see without a microscope is in the range 0.1–0.2 mm. One micrometer (μm) or micron is 0.000001 m or 0.001 mm. One nanometer (nm) is one millionth of a millimeter or 0.000001 mm. A very large protein such as hemoglobin, when folded into a ball, is about 7 nm in diameter, which means that about 140 of them side by side would amount to 1 μm and 140,000 of them side by side would span 1 mm.
1963) and branches extending outward >250 μm (0.25 mm). As we proceed above the level of cells, most things can be seen by the unaided eye, and it thus is easier to know
When we study a group of objects at one level, we can see how the properties of a group often depend on how the parts are connected with each other. There are situations in which the same parts are connected differently, which results in very different properties. Several of these are quite familiar. Consider the atoms hydrogen and oxygen (Fig. 1.1A). Each can exist as a colorless, odorless gas wherein pairs of atoms of one kind are loosely bound to each other and free to float in a container. They are so small that gravity has little effect, and the gas particles fill the container from top to bottom. When a spark is sent through the mixture of gases, this triggers oxidation with a loud pop and flash. Suddenly, the hydrogen and oxygen atoms recombine into a familiar molecule: water or H2O. It is a clear liquid, and gravity draws most of it to the bottom of the container. The water will freeze into solid ice at 0°C, whereas the mixture of gases will not freeze at all at any temperature people are likely to experience. Thus, although the constituent parts—the atoms—are the same in the mixture of gases and the pool
4
1. LEVELS AND EXPLANATIONS
of liquid water, the properties of the mixture of gases and the water molecule are radically different. Whether the water actually exists as liquid, solid, or gaseous water vapor depends on the temperature of the molecules’ environment. The freezing point of a molecule in turn depends on the number and kinds of its atoms as well as how they are interconnected. Water freezes at 0°C, whereas ethanol freezes at 114°C. Thus, the properties of a particular kind of substance depend on both its internal structure formed from interconnected atoms and its external environment. It makes no sense at all to say that its existence as a gas, liquid, or solid depends more on the internal than the external factor. Both must be fully taken into account in order to understand the properties of the whole. Many kinds of molecules are isomers in which the same constituent atoms are interconnected in different ways. Fig. 1.1B shows ethanol, a liquid at room temperature, and dimethyl ether, a highly flammable gas. Both have the chemical composition C2H6O. Only the location of the oxygen atom differs, but this changes the properties of the two molecules dramatically.
LEVELS AND GENES Here, we are mainly interested in medical disorders and complex behaviors, not basic physics. Nevertheless, some of the same principles seem to be involved, albeit at different levels. Consider diabetes, a common malady. Blood sugar levels become very high. Untreated, the high blood sugar contributes to obesity, the loss of vision, kidney damage, poor circulation in the feet, and many other symptoms. Type 1 diabetes results from insufficient insulin production from the type B cells of the islet of Langerhans that are distributed throughout the pancreas, and it is treated with insulin injections. Insulin stimulates the absorption of glucose from the blood into the muscle by activating a small structure on the surface of the muscle fiber, the insulin receptor. Type 2 diabetics have enough insulin, but the receptor does not respond well to it, so there is insulin insensitivity or resistance, and blood sugar levels rise to unhealthy levels when enough glucose cannot get into the muscle fibers. Mice sometimes are diabetic and obese too, and they show almost the same array of symptoms we term diabetes in humans. In 1950, a new genetic mutation was discovered in lab mice that led to extreme overeating and obesity, and it was named the obese gene (Ingalls, Dickie, & Snell, 1950), abbreviated ob. A mouse had to have two copies of the mutation and have genotype ob/ob in order to show the extreme weight gain, the obesity phenotype. In the 1950s in mouse genetics, it was customary to name a gene for an abnormal phenotype, the disease that appeared when it was mutated. The normal
form of the gene was symbolized +. A few years later, another gene was discovered that also resulted in obesity and rapid onset of diabetes, and it was named the diabetes gene, abbreviated db (Hummel, Dickie, & Coleman, 1966). It turned out that the insulin receptor was normal in both kinds of mice. The problems in the mutant mice originated in unknown molecules. For the diabetic mice (Fig. 1.4A), one of the phenotypes was behavioral: overeating. The diabetic mice (db/db) ate far more than their normal siblings and became obese. So, researchers employed a psychological method called pairfeeding. A normal mouse (+/+) was housed by itself in a cage, and its daily food intake was measured. The next day a db/db mouse housed in an adjacent cage was given only the amount of food the normal mouse had consumed the previous day. There was also a cage with a db/db mouse that was allowed to eat all it wanted. When restricted to the same amount of food as normal mice, the db/db mouse did not become obese, and it did not show elevated glucose (Lee & Bressler, 1981). Thus, the physiological symptoms we call diabetes depended on a psychological phenomenon—appetite. Whether the db/db mice were actually diabetic depended on how much food they ate. The gene had been named diabetes, but in fact, it does not code for phenotypic diabetes. If we simply limit how much the creatures consume, there is no diabetes. After years of investigation, other researchers discovered a new hormone that is encoded by the obese gene and is deficient in ob/ob mice (Halaas et al., 1995). Injecting it into the ob/ob mice greatly reduced the overeating. Later, the hormone was named leptin, and it provided a crucial part of the puzzle of diabetes (Fig. 1.4B). It was discovered that leptin is made in white fat cells, and the more fat has been stored, the more leptin enters the bloodstream. Like all hormones, leptin is detected by specific receptor molecules. The leptin receptor was also identified, and it is located on cells in a part of the brain called the hypothalamus that regulates many bodily functions, including appetite. When leptin levels in blood rise, appetite and eating are reduced. Further studies revealed that the obese mutation actually codes for an abnormal form of the gene that codes for leptin, while the diabetic mutation codes for a defective leptin receptor. Researchers then injected leptin into the two kinds of mutant mice. The leptin injections had no effect on the diabetic mice because their defective leptin receptor could not detect it (Schwartz, Seeley, Campfield, Burn, & Baskin, 1996), but they greatly reduced diabetic symptoms in the obese mice because the injected leptin reduced their appetites for food. After the functions of the two genes were known, they were renamed. In mice, the one that coded for the leptin hormone was officially designated the leptin gene (Lep), whereas the other became the leptin receptor gene (Lepr). The normal leptin gene was symbolized Lep+, and the mutation became Lepob. The normal gene
5
ANIMAL MODELS
+/ +
LEPR
db/db
NPY Other POMC
Genotypes: +/+ Feeding: Free
db/db Free Obese
db/db Paired
Blood glucose Normal
Very high
Normal
Plasma insulin Normal
Extreme
Elevated
Body weight Normal
Normal Diabetic
Phenotypes (A)
NPYR MC4R
Leptin
Normal
Not diabetic
Appetite
Hypothalamus
"Diabetic"
Normal
Overeating
LEP
Muscle INSR
White fat
Insulin
INS Islets of Langerhans
Glucose
(B)
(A) When allowed to feed freely, mice with two copies of a mutant gene named “diabetic” (db) became obese and showed symptoms of severe diabetes, whereas mice with two normal copies of the gene (+/+) remained lean and healthy. When the (db/db) mice were restricted to only the amount of food eaten daily by their lean siblings (pair-fed), they did not become obese or show symptoms of diabetes, even though they carried abnormal forms of the gene (Lee & Bressler, 1981). Data shown are relative to +/+ baseline values. (B) Further study revealed that appetite, obesity, and diabetes are regulated by a complex system involving several genes in both humans and mice acting in several organs at several different levels, including behavior. The gene formerly known as “obese” codes for the hormone leptin and is now named LEP, while the old gene named “diabetes” codes for the leptin receptor (LEPR). Several genes are part of the circuit in the hypothalamus that includes neuropeptide Y (NPY) and its receptor (NPYR). Connections that involve activation are shown by arrows, whereas those inhibiting the downstream process end in a bar. Normally, obesity is prevented by a feedback loop whereby excess eating grows more white fat that in turn synthesizes more leptin that then stimulates the leptin receptor and turns down the appetite control.
FIG. 1.4
encoding the receptor became Lepr+, and the mutation became Leprdb. The genotypes of what were formerly known as the obese and diabetes mice were in all subsequent research symbolized as Lepob/Lepob and Leprdb/ Leprdb, respectively. The genes were also found in humans and named using capital letters (LEP and LEPR; see Fig. 1.4B). Thus, the modern practice in naming genes is to name them for what they normally do at the molecular level, not for a phenotypic disease that sometimes appears under certain conditions. This example demonstrates the importance of knowing how things work at several levels in order to comprehend the origins of disease symptoms and learn how to treat them. Although genetic mutations were the original sources of the problems, they act via a complex, multilevel system that involves a psychological process—appetite— and the animals’ nutritional environment. A behavioral method, pair-feeding, helped to understand the origins of the obesity and diabetes. The genes are macromolecules, but the disease we call diabetes is not simply a molecular issue and cannot always be treated by administering some specific molecule. The disease is a multilevel phenotype.
ANIMAL MODELS Conducting experiments with lab animals is far easier than doing so with humans because their environments and breeding can be strictly controlled and many things
can be done that would be impossible with humans for both practical and ethical reasons. Research in neuroscience relies heavily on the study of animal models. Four of the most commonly studied species in the genetic analysis of the nervous system and behavior are listed in Table 1.3. We hope the findings for animals will give us a pretty good idea of what is taking place in humans as well, but caution is warranted when comparing species. How well results are likely to generalize across species depends strongly on the level at which we are making the comparisons. The tiny nematode worm about 1 mm long that is abundant in garden soil has only 302 nerve cells, yet it has about as many different genes as humans. A large fraction of nematode genes are counterparts of human genes that have very similar chemical structures and must have been inherited from a common ancestor long ago. About half of proteins that occur in those worms are also found in humans, sometimes with minor variations in structures, and about 40% of genes known to be important for human diseases have counterparts in the worms (Corsi, Wightman, & Chalfie, 2015). Many of the large molecules that are so important for human brain function also occur in nematodes (Hobert, 2013), but the synapses that connect one nerve cell to another are different from ours, and the overall structure of the two nervous systems and the kinds of nerve cells they contain are very different indeed. Nematodes show a number of simple reflexes that are quite easy to study, and they are also capable of learning and remembering things that happen in their
6 TABLE 1.3
1. LEVELS AND EXPLANATIONS
Features of Four Species Commonly Studied in the Field of Genes, the Brain, and Behaviora
Scientific name
Caenorhabditis elegans
Drosophila melanogaster
Mus musculus domesticus
Homo sapiens
Common name
Nematode worm
Fruit fly
House mouse
Human
Adult size
1 mm
2.5 mm
15–25 g
150–180 cm
Reproduction
Self-fertilizing
Sexual
Sexual
Sexual
Age at first reproduction
3 days
7–20 days
46–62 days
14–20 years
Life span or expectancy
18–20 days
30 days
600–800 days
60–85 years
Number of neurons
302
340,000
100 million
100 billion
Kinds of chromosomes
6
4
21
23
Genome (million bases)
100.3
175
2803.6
3257.3
Protein-encoding genes
20,444
17,717
23,202
<20,000
a
Sources of information (will change with future updates of databases): Nematode worm: search terms WormBook and WormBase; Fruit fly: search term FlyBase; Mouse: search terms Mouse Genome Informatics and MGI 6.11 Introduction to Mouse Genetics; Human: search terms Genetics Home Reference and Human Genome Assembly GRCh38.p12.
environments (Ardiel & Rankin, 2010). Nevertheless, at the level of behavior, there is a wide divergence between worms and people. The nematodes eat bacteria living on the same broth as the worm. They can move by undulating in S-shaped curves, but they have no legs or arms for propulsion. Neither do they have eyes or visual organs. The life span is short, and social interactions are rudimentary. Thus, they are remarkably similar to humans at the level of macromolecules but diverge at higher levels. The ubiquitous fruit fly has a much larger nervous system than nematodes and well-developed vision plus remarkable capacities for flight. The adults engage in a kind of courtship during mating. Both the larvae and adults are capable of learning and memory. The flies share thousands of genes in common with humans that are implicated in some kind of disease (Hu et al., 2011). Nevertheless, the structure of their nervous system and behavioral repertoire are substantially unlike humans. The humble house mouse is a mammal with much greater similarity to us. Its genome is almost as large as humans, and it has just as many genes (Table 1.3). Mice have 17,098 genes that are very similar to human genes, and there are more than 1300 human diseases for which there is a fairly good mouse model of the disease process (Mouse Genome Informatics). Young mice are born hairless with their eyes closed, and they rely on care by the mother for several weeks. The nervous system of mice has many regions that are essentially the same as humans in their locations and connections with other parts of the brain, including the cerebellum, hypothalamus, hippocampus, and corpus callosum (Chapter 4). The eye and retina are very similar, but color vision is more highly developed in humans. The human cerebral cortex is folded extensively and contains many more nerve cells relative to the rest of the brain, while the mouse cortex is smooth and relatively smaller, but the layers and connections are strikingly similar in the two species. A wide
variety of tests of complex behaviors are available for mice (Crawley, 2007; Wahlsten, 2011). Mice do not have our kind of language, but there is evidence that they emit patterns of sounds in the ultrasonic range, especially during courtship, that resemble songs (Arriaga, Zhou, & Jarvis, 2012; Chabout, Sarkar, Dunson, & Jarvis, 2015). As a general pattern, similarities of nervous system anatomy and behavioral functions are greater in animals that are more closely related to humans because of more recent evolution from a common ancestor. All species of animals have DNA that encodes genetic information, and the mechanisms by which that information is processed are the same throughout the animal kingdom. The relations between DNA and proteins are also essentially the same. Thus, we expect experiments that are done at the molecular level will yield similar results for a wide range of species, while studies of complex behaviors are likely to reveal many things that are unique to a particular species. Whatever the level of a research project, results always need to be confirmed in humans. An animal model of a human function is not a substitute for investigation of the human condition. It needs to be verified. Nevertheless, many kinds of exploratory studies are far easier and more efficient to do with animal models. Landmark studies of genes and the basic processes of brain development and nervous system function were virtually all done with experiments on animals and then later confirmed in work with humans.
THE EXPERIENCE OF PAIN It is interesting to inquire whether animals experience pain the way we do. This is an important question from the standpoints of ethical treatment of animals and the use of animal models in research on pain. Without a
7
HIGHLIGHTS
doubt, pain has important cognitive aspects in people that involve language, and these higher-level thought processes are just about impossible to model with mice or rats. At the same time, the way pain is processed in the nervous system is remarkably similar for all mammals, and many of the drugs used to treat pain in people are also effective for aiding mice. Receptors in the brain that detect pain signals are encoded by genes that are very similar, and the manner of synthesizing chemicals in the brain that signal pain is virtually the same as well. The nerve endings that sense damage to peripheral tissue are very similar, as are the pain pathways via nerves from the periphery into the brain (Chapter 4). Nevertheless, the assessment of pain in people often involves verbal communication with medical personnel who make judgments of pain intensity based upon how their patients rate their own pain levels. When children are not able to rate the pain on many dimensions, they may be rated by the Wong-Baker FACES pain rating scale that asks a child to point to a symbol on a card showing smiling and frowning faces (Wong & Baker, 1988). There are six faces ranging from a score of 0 (no hurt at all) to 10 (hurts worst of all). Several versions of this scale are returned by a Google Images search, one of which is sanctioned by the Wong-Baker FACES Foundation. Mice can obviously not be rated in this way, but a clever adaptation of pained faces has been used to construct a rating scale for mice that looks closely at their faces. Investigators with extensive experience studying pain in mice had noticed that animals tended to grimace during the period following a surgical operation. They devised the mouse grimace scale in which video images are collected of the face and then rated with regard to the eyes, nose, cheek, ear, and whiskers (Langford et al., 2010). Each feature is scored as 0 ¼ grimace not present, 1 ¼ moderately visible, and 2 ¼ severe, and the five numbers are added to obtain an index ranging from 0 to 10. The scale proved to be very effective in rating postoperative pain and assessing the effects of analgesic drugs (Matsumiya et al., 2012). The grimace scale has a major advantage over the scales used in clinical practice with people because the ratings of mice from video images are done “blind” by technicians who do not know what treatments the mice had received, thereby avoiding possible biases in making judgments. A number of psychological and social factors have major impacts on the human experience of pain. People who experience greater social support from family, friends, and the helping professions report less severe pain from cancer and during childbirth, and they require lower doses of analgesic drugs to achieve acceptable levels of pain control. The “placebo effect” that alleviates pain when the substance given to patients actually has no active ingredient also highlights the role of psychological processes (Kaptchuk & Miller, 2015). Thus, for anyone
interested in the origins and amelioration of pain, understanding the phenomenon at several levels is essential.
EXPERTISE AND APPLICATIONS There is far too much knowledge embodied in the disciplines in Table 1.1 for one person to understand them all in depth, but deep knowledge, real expertise, is not necessary for many people, including readers of this book. We need enough knowledge to answer the main questions we ask about genes, brains, and behaviors. This is sometimes referred to as reading knowledge. One can read an essay, a news article, or a book written for nonspecialists and grasp the general ideas of how things work. Perhaps, one might even be able to discern when an article in a newspaper contains a serious error and then write a letter to the editor. But this depth of knowledge would not be enough to apply it in biomedical or psychological practice. It would not enable a person to make a formal diagnosis of a behavioral disorder or prescribe a drug to treat it, even though the person might have a pretty good idea of how a drug is supposed to function in the brain. A practitioner must also know about making fine distinctions among several possible diagnoses that involve similar symptoms, the merits of alternative therapies, a diverse array of possible side effects of a drug (Chapter 17), and the realities of family dynamics and other social factors. If and when the time comes for we ourselves to be examined and possibly treated for some kind of biochemical defect or a mental disorder, many of us want it to be done by genuine experts. It is possible to read this chapter without knowing just what a gene is. The term is used several times here, and simply knowing that it is a very big molecule that codes for the structure of a protein is enough to get the gist of these paragraphs. To go further with the story of genes, the brain, and behavior, we must gain a deeper understanding of genes.
HIGHLIGHTS • Things exist at different levels, ranging from atoms to molecules, to cells, to organs, then upward to an entire organism living in a society. • Each level is studied by a specialized field of science using terms and methods that are appropriate for that level. • The properties of something existing at a specific level depend on the natures of its parts and the pattern of interconnections among them. • A gene is a portion of a large molecule (DNA) and functions at the molecular level.
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1. LEVELS AND EXPLANATIONS
• A person’s genotype is the set of genes transmitted by the parents, whereas phenotypes at other levels are characteristics that develop and can be measured. • A gene is usually named for what it normally does at the molecular level, not a disease that may occur when there is a defect in the gene. The actual occurrence of disease often depends not only on the genotype but also on features of other levels, including the individual’s environment. • Different species of animals are very similar at the molecular level but often differ greatly at the level of behavior. Lab animals provide good models of things that happen at the molecular level, and at that level, they are very similar to humans. • To understand complex behavioral phenomena such as hunger or pain, it is important to study them at different levels ranging from the molecular to behavioral and to consider the social context of behavior.
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