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CHAPTER 1 Welcome to the World ofNeurobiology 21
The encoding of memory involves synaptic plasticity in each of the brain areas
identied. Research suggests that long-term memory is stored in cortical circuits
in the cerebral cortex. This means that the neocortex is involved in not only
the integration and processing of sensory, motor, and cognitive information, but
also in its storage as well.
Controlling with the executive brain
The frontal lobes are responsible for planning and executing behavior (refer to
Chapter16). During evolution there was a relative expansion of the frontal lobe
compared to the rest of the brain in humans compared to other primates, and
primates compared to other mammals.
The motor cortex controls motor neurons for regulation of contraction of skeletal
muscles. The frontal eye elds control eye movements, and Broca’s area mediates
language production. The prefrontal cortex produces executive functions for per-
forming goal-directed movements and controlling behavior.
Thinking about cognition
Several cognitive functions, including language, are lateralized in humans. The
capacity for learning language is innate in humans and involves Wernicke’s and
Broca’s areas. Neurobiology research is working to understand how human
language systems operate. Chapter 17 examines the components of the human
brain areas most important for cognitive functions.
Intelligence is the ability to acquire and apply knowledge and skills. The prefrontal
cortex is involved in higher-order cognitive processes such as working memory,
planning, decision-making, reasoning, problem-solving, and goal setting. The
prefrontal cortex also acts in behavioral self-control and emotional control. These
cognitive functions, together with your long-term declarative memory, form the
components of intelligence.
Consciousness issubjective and includes being aware of your sensations, thoughts,
experiences, and emotions. Researchers have studied brain mechanisms that may
underlie consciousness and have proposed many hypotheses about the basis of
consciousness.
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CHAPTER 2 Meeting the Building Blocks 23
Chapter2
Meeting the Building
Blocks
N
eurons and glia are cells, and like all cells in the body, they’re composed
of water, ions, and organic molecules including carbohydrates, proteins,
nucleic acids, and lipids. Surrounding the cell is the plasma membrane.
The cytoplasm contains cellular organelles where proteins are synthesized and
metabolism takes place, and the cytoskeleton keeps everything in shape and
moves things around.
The DNA is contained in the nucleus and in mitochondria outside the nucleus.
Genes are sequences of DNA.Which genes are expressed is what makes the body’s
cell types dierent from each other and distinguishes dierent types of neurons
and glia. This chapter covers the basic biochemistry and genetics relevant to neu-
rons and glia and describes what makes neurons and glial so specialized.
Introducing Molecular Building Blocks
Neurons and glia are similar to other cells because they contain water, ions, and
organic molecules (monomers and polymers) that contain carbon, hydrogen,
nitrogen, oxygen, and phosphorus. Monomers are single molecule building blocks
IN THIS CHAPTER
»
Investigating cell molecules, ions, and
proteins
»
Checking out cell organelles
»
Assembling the cell membrane with
lipids and proteins
»
Getting to know neuronal parts
»
Exploring genetics and inheritance
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24 PART 1 Getting Started with Neurobiology
that can be combined to form polymers. Sugars form polysaccharides, amino acids
form proteins, nucleotides and deoxynucleotides form the nucleic acids (RNA and
DNA), and lipids form fats and bilayers.
The following sections describe the characteristics of ions, bonds, and molecules,
and the features of the nucleic acids DNA and RNA.
Hydrating with water and electrolytes
Like other cells in the body, neurons and glia contain about 70 percent water and
many types of ions. Ions are charged atoms and molecules. They can have a posi-
tive charge (cation) or a negative charge (anion). Ions can contain one charge
(monovalent) or have more than one charge (divalent and so forth).
The most important intracellular atomic ions for signaling are sodium, potassium,
chloride, and calcium. Magnesium and iron ions are cofactors for many proteins.
Some important molecular ions are acetate, ammonia, and bicarbonate ions.
Identifying the two types of bonds
A chemical bond is formed when two or more atoms have an attraction to one
another. Two main types of bonds between atoms are as follows:
»
Covalent bonds: They’re strong bonds that involve the sharing of electrons.
They can be either polar or nonpolar. Molecules are formed by covalent
bonding between atoms. Molecules are generally stable in cells and don’t
break apart on their own.
»
Noncovalent bonds: They’re weaker bonds that involve electrostatic interac-
tions, like ionic and hydrogen bonds, or other interactions like hydrophobic
bonds between lipids.
Dissolving in water or lipids
Polar covalent bonds involve unequal sharing of the electrons, leading to a sepa-
ration of charge, called a dipole. The resulting molecule has a concentration of
positive charge in one region and negative charge in another region. Water is a
polar molecule because the two hydrogens are slightly positive, with a slightly
negative charge around the oxygen in the middle. Polar molecules are soluble in
water and are called hydrophilic. Polar molecules are found in the extracellular
uid, cytoplasm, and inside organelles.
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CHAPTER 2 Meeting the Building Blocks 25
In nonpolar covalent bonds, the electrons are shared equally between or among
the atoms. A nonpolar molecule doesn’t have a permanent dipole. Most nonpolar
molecules aren’t soluble in water and are called hydrophobic. Fatty acids like cook-
ing oils are an example. Some molecules have a region with polar bonds and a
region with nonpolar bonds. An example is a phospholipid, which forms lipid
bilayers in cellular membranes.
Covalent bonds are strong bonds that produce the stable primary sequence of
polymers such as proteins, DNA, and polysaccharides, and keep them intact in
cells. Noncovalent bonds are much weaker, but they’re important because they
give water its characteristics, produce the three-dimensional structures of pro-
teins and DNA, and underlie the formation of biological membranes.
Creating cellular subunits and polymers
The two types of metabolic pathways are as follows:
»
Catabolic pathways: They break down polymers into individual monomers
(building blocks). Most catabolic reactions are exergonic (energy releasing), and
the energy released can be used to produce ATP.
»
Anabolic pathways: They create polymers from individual monomers. Most
anabolic reactions are endergonic and require an energy input (usually from
ATP hydrolysis).
Both types of reactions require enzymes for the formation or breaking of covalent
bonds. Enzymes lower the activation energy for reactions to speed up their rate.
Replicating DNA
DNA is a nucleic acid composed of long sequences of nucleotides covalently bonded
to each other. Nucleotides contain a nitrogenous base, a pentose sugar, and a
phosphate. The bases in DNA are adenine (A), cytosine (C), guanine (G), and
thymine (T). DNA forms a double helix that binds and wraps around histone
proteins to form the chromosomes. The nucleus contains the cell’s chromosomes
and is where DNA replication and RNA transcription occur. Mitochondria contain
a small mitochondrial genome separate from the nucleus.
Replication is the synthesis of a new DNA molecule (chromosome) from a DNA
template. It occurs during mitosis for all somatic cells in the body. After the DNA
is replicated, the copies (chromosomes) are segregated, and the cellular compo-
nents undergo cell division by cytokinesis. In mitosis, each daughter cell inherits
the full genome of its parent cell as well as cytoplasm and organelles.
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26 PART 1 Getting Started with Neurobiology
Reproductive organs produce gametes by meiosis. Each gamete receives only one
copy of each chromosome. During meiosis, a new chromosome can be created
from a combination of both parent chromosomes in a process of breaking and
joining, which is called crossover. When gametes combine during fertilization, the
zygote begins with a pair of chromosomes, one from each parent that it replicates
during mitosis.
Getting Into Genes
The genotype is the genetic makeup of a cell, determined by the cell’s DNA.The
sequence of the DNA contains specic units or segments called genes that are the
basic physical and functional unit of heredity. Genes have the instructions for
producing RNA and proteins. An estimated 20,000 protein-coding genes are pres-
ent in the human genome. Only about 1.5 percent of the entire human genome is
used to code for proteins. Gene expression is the process by which information
encoded in the DNA is used to direct the synthesis of proteins.
Gene expression determines the types and levels of proteins synthesized in the
cell. The majority of functions and activities of the cell are dependent on and car-
ried out by proteins. Not all of the protein-encoding genes are expressed equally
in all cells. Dierent cells express dierent sets of genes. This is called dierential
gene expression. The types and levels of proteins a cell produces determines its
phenotype, including its morphology, physiology, and function.
Gene expression can be controlled by several mechanisms, including transcrip-
tion, the processing, export, and degradation of RNA, and the synthesis, activa-
tion, and degradation of proteins. Of these, the most widespread control of gene
expression is through transcription. The following sections address some of these
processes in greater detail.
The DNA molecule is a double-stranded helix. It’s well suited for storing and rep-
licating biological information because the two strands are complementary. This
complementary structure enables replication by splitting the two DNA strands, so
each can form a new complementary strand. The double helix is stable and resist-
ant to cleavage, allowing the body’s trillions of cells to safely store the genome.
Creating RNA in transcription
Transcription is the process of synthesis of an RNA molecule based on a DNA tem-
plate. The RNA is then used to direct the synthesis of proteins. Transcription is
regulated by transcription factors and epigenetics. Transcription factors are DNA-
binding proteins. Binding of transcription factors to a region in the gene called the
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CHAPTER 2 Meeting the Building Blocks 27
promotor can activate or inhibit transcription. About 1,500 dierent transcription
factors are encoded in the human genome.
Examining epigenetics
In the DNA within the chromosome, the base sequences of A, T, G, and C are iden-
tical in the majority of cells of the body. However, some of those bases and the
histone proteins that bind to the DNA become modied during development.
Epigenetics (meaning “above the genome”) is the covalent modication of DNA
and histones. These modications can enhance or inhibit the access of the DNA to
transcription factors and the transcription machinery. Two of the best character-
ized mechanisms that provide epigenetic control over gene expression are DNA
methylation and acetylation of the histone proteins.
During development, changes in epigenetic modications are critical for cellular
dierentiation. In development, totipotent stem cells, which are cells that can
develop into any cell type, dierentiate into hundreds of dierent cell types in the
body, such as neurons, astrocytes, muscle cells, or liver cells. Many epigenetic
modications are preserved and persist in subsequent cell divisions of that
cell line.
Even though many epigenetic modications in neurons are stable and ensure the
neuronal phenotype, others are reversible and dynamic. Dynamic epigenetic mod-
ications have been measured in the adult brain and proposed to underlie aspects
of neuroplasticity. Neuroplasticity is a feature of neurons that allows them to rewire
their connections in response to external and internal stimuli (refer to Chapter15
for more about neuroplasticity).
Focusing on transcription mechanisms
Transcription occurs in the cell nucleus. The transcription machinery reads the
sequences of bases in the DNA template to produce a matching RNA product. The
RNA strand is complementary to the DNA strand except that in RNA the nucleotide
uracil takes the place that thymine occupies in DNA.
Three types of RNA are produced in the nucleus:
»
Ribosomal RNA: It binds to proteins to form the ribosomes, the machinery
involved in protein synthesis.
»
Transfer RNA: It’s used to bind to amino acids and transfer them to a protein
as its being synthesized.
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28 PART 1 Getting Started with Neurobiology
»
Messenger RNA (mRNA): It’s used to instruct protein synthesis during
translation. The ribosome reads the mRNA sequence and inserts the specic
amino acid based on the mRNA sequence (see the next section for more
information).
The initial product of transcription is a primary mRNA transcript that’s processed
before being transported out of the nucleus. It’s modied to yield heterophilic
nuclear RNA (hnRNA). The hnRNA contains noncoding regions called introns and
coding regions called exons. The hnRNA is spliced to remove the introns. Later,
some exons may be spliced out to produce the nal mRNA.This splicing can pro-
duce dierent mRNAs called splice variants from the same gene.
Synthesizing Proteins in Translation
Twenty dierent amino acids become incorporated into proteins. Amino acids
contain a free amino group, a free carboxylic acid group, and another group called
a residue or side chain. The amino acid residues are either polar uncharged, polar
charged, or nonpolar. Polar/uncharged and polar/charged amino acids are hydro-
philic while nonpolar amino acids are hydrophobic.
Several amino acids have another important activity. They can also function as
neurotransmitters or as substrates in neurotransmitter synthesis. In addition,
neuropeptides can serve as neurotransmitters. Chapters5 and6 discuss the roles
of amino acids and neuropeptides as neurotransmitters.
Coding for proteins
A gene is a region of DNA that codes for an individual protein. A codon is a three-
nucleotide series in the DNA (and RNA) that codes for a specic amino acid. Within
each gene are many codons. The genetic code provides the information about
which amino acid will be inserted into the primary amino acid sequence of a
protein.
The primary amino acid sequence forms the backbone of the protein as the amino
acids are covalently bonded to each other during translation. Ribosomes are large
protein-RNA complexes that mediate translation. Translation of cytoplasmic pro-
teins occurs on free polyribosomes. For proteins embedded in the membrane and
secreted proteins, translation occurs in the endoplasmic reticulum (ER), called the
rough ER.We describe this more in the section “Tracking Membrane Proteins
and Signals” later in this chapter.
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CHAPTER 2 Meeting the Building Blocks 29
Folding in three dimensions
As the protein primary backbone sequence is synthesized, amino acid residues
interact with each other to form noncovalent bonds that fold the protein into the
following:
»
Secondary structures: They’re formed by hydrogen bonds between atoms in
the protein backbone. The two most common types are the alpha-helix and
beta-sheet.
»
Tertiary structures: They occur by the noncovalent bonding between the
residues on the amino acids. They ensure the three-dimensional structure of
a protein that’s essential for it to perform its function correctly.
Functioning in dierent ways
Functional categories of proteins include enzymes, transcription factors, transla-
tion factors, cytoskeletal proteins, motor proteins, ion channels, ion transporters,
receptors, cell adhesion proteins, and signaling proteins and neuropeptides.
The ribosome binds to the end of an mRNA molecule and then moves along it. The
ribosome reads the mRNA, and for each codon it reads, it inserts a specic amino
acid into the growing protein chain that was instructed by the codon.
After translation occurs, other chemical groups may be covalently attached to the
amino acid sequence of the protein, such as carbohydrates, lipids, and phosphates.
Adding phosphate groups is called phosphorylation, which is a common mecha-
nism for activating or inactivating an enzyme.
Organizing the Organelles
The plasma membrane maintains the contents of the cell, preventing necessary
molecules from exiting and unwanted toxic molecules from entering. The cytoplasm
is the aqueous part of the cell, lled with soluble and cytoskeletal proteins. It con-
tains cellular organelles, some of which are surrounded by membranes to provide
compartmentalization. The following organelles reside in neurons and glia:
»
Mitochondria: They’re self-replicating organelles that generate adenosine
triphosphate (ATP), the cell’s main energy source. In oxidative phosphorylation,
energy from electron transfer involving oxygen adds a phosphate to adenosine
diphosphate (ADP) to make ATP.Mitochondria have their own DNA and
multiply by cell division on their own.
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30 PART 1 Getting Started with Neurobiology
»
Endoplasmic reticulum (ER): The ER is an organelle composed of attened
membrane tubes. The ER has two forms:
•
Smooth ER synthesizes lipids.
•
Rough ER contains ribosomes involved in translation of membrane and
secreted proteins.
The ER also sequesters and releases calcium ions.
»
Golgi apparatus: It modies lipids and transmembrane proteins after
translation. This is also where membrane and secreted proteins are sorted for
tracking to the plasma membrane and some organelles. It’s also where
neuropeptides are packaged into vesicles.
»
Lysosomes: They contain enzymes that degrade damaged proteins, lipids
nucleic acids, and carbohydrates. Proteosomes also contain enzymes that
degrade proteins.
»
Centrosome: It’s an organizing center for microtubules important in separat-
ing chromosomes during mitosis. It also controls transport of proteins
through the RER and Golgi apparatus.
All of the activities in the organelles and cytoplasm require a constant supply of
energy, usually in the form of ATP.In the next sections we describe how neurons
and glia produce their energy.
Finding the energy
Glycolysis occurs in the cytoplasm and involves the conversion of one glucose
molecule into two pyruvates, with the net production of two molecules of ATP and
two molecules of NADH.Glycolysis doesn’t require oxygen.
Mitochondria encompass three metabolic processes:
»
Krebs cycle, also called the citric acid cycle or TCA cycle
»
Electron transport chain
»
Oxidative phosphorylation
Combined, they produce ATP from pyruvates and NADH.This is called cellular
respiration or aerobic respiration, and it depends on oxygen.
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