Lou Gehrig was born in New York City in 1903 to German immigrant jf parents. After attending Columbia University he joined the Yankees * J as first baseman, where he earned the nickname “Iron Horse” for the strength and power of his game and his endurance even in the face of multiple injuries. His record, only recently broken, of playing 2130 consecutive games despite injuries, multiple bone breaks, and back spasms attests to his determination and fortitude. He was beloved among fans for his humility and character. Gehrig and his teammate Babe Ruth formed the core of the most incredible hitting team known to baseball. All of that ended in 1938 when it became evident that Gehrig was gradually losing the strength to swing the bat and his gait had deteriorated to a sliding of his feet along the ground. Not long after, he was diagnosed with amyotrophic lateral sclerosis (ALS), now most often called Lou Gehrig’s disease.
This neurological disorder begins with muscle weakness, loss of muscle control, atrophy, and fatigue, and rapidly progresses so that all motor function is ultimately lost, leaving the individual unable to walk, speak, swallow, or breathe. Perhaps most devastating is that although both motor neurons from the spinal cord to skeletal muscles and descending motor neurons in the frontal lobe of the cerebral cortex degenerate, almost all other functions remain intact, including cognitive function, leaving the individual mentally alert and fully aware of his wasting away and ultimate total paralysis.
Symptoms of ALS do not show spontaneous remission, and no available treatment does more than slow the progression of the disease by a few months. At this time there is no known cause for ALS, nor is the cellular mechanism of nerve degeneration clear. However, both the cause and cure of ALS will be identified with further research into the fundamental functions of neurons and their interaction
As we already know, psychopharmacology is the study of how drugs affect emotion, memory, thinking, and behavior. Drugs can produce these widespread effects because they modify the function of the human brain, most often by altering the chemical nature of the nervous system. For an understanding of drug action we first need to know a bit about individual nerve cell structure and electrochemical function. Second, we need to have an essential understanding of how these individual cells form the complex circuits that represent the anatomical basis for behavior.
All tissues in the body are composed of cells, and the special characteristics of those cells determine the structure and function of the tissue or organ. In the nervous system there are two primary types of cells, nerve cells called neurons and supporting cells called glial cells that provide metabolic support, protection, and insulation for neurons. The principal function of neurons is to transmit information in the form of electrical signaling over long distances. Sensory neurons, sensitive to environmental stimuli, convert the physical stimuli in the world around us and in our internal environment into an electrical signal and transmit that information to circuits of interneurons, which are nerve cells within the brain and spinal cord. Interneurons form complex interacting neural circuits and are responsible for conscious sensations, recognition, memory, decision making, and cognition. In turn, motor neurons direct a biobehavioral response appropriate for the situation. Although these neurons have common features, their structural arrangements and sizes vary according to their specific functions. The many possible shapes of neurons that were first described by the nineteenth-century histological studies of the Spanish neuroanatomist Ramon y Cajal. For much of the twentieth century, neuroscientists relied on the same set of techniques developed by the early neuroanatomists to describe and categorize the diversity of cell types in the nervous system. However, from the late 1970s onward, remarkable new technologies (see Chapter 4) in cell biology and molecular biology provided investigators with many additional tools to identify minute differences in the structural features of neurons, trace their multiple connections, and evaluate physiological responses.
Neurons have three major external features
Although neurons come in a variety of shapes and sizes and utilize various neurochemicals, they have several principal external features in common. These features include (1) the cell body, or soma, containing the nucleus and other organelles that maintain cell metabolic function; (2) the dendrites, which are treelike projections from the soma that receive information from other cells; and (3) the axon, the single tubular extension that conducts the electrical signal from the cell body to the terminal buttons on the axon terminals. Like all other cells, neurons are enclosed by a semipermeable membrane and are filled with a salty, gelatinous fluid, the cytoplasm. Neurons are also surrounded by salty fluid (extracellular fluid), from which they take oxygen, nutrients, and drugs and into which they secrete metabolic waste products that ultimately reach the blood and then are filtered out by the kidneys (see Chapter 1). Like other cells, neurons have mitochondria, which are responsible for generating energy from glucose in the form of adenosine triphosphate (ATP). Mitochondria are found throughout the cell but particularly where energy needs are great. Since neurons use large quantities of ATP, mitochondrial function is critical for survival, and ATP is synthesized continually to support neuron function. The assumption that the rate of synthesis of ATP reflects neuron activity is an underlying premise of several neurobiological techniques that give us the opportunity to visualize the functioning of brain cells (see Chapter 4 for a discussion of positron emission tomography [PET] and functional magnetic resonance imaging [fMRI]).
Dendrites The general pattern of neuron function involves the dendrites and soma receiving information from other cells across the gap between them, called the synapse. On the dendrites of a single neuron as well as on the soma there may be thousands of receptors, which respond to neurochemicals released by other neurons. Depending on the changes produced in the receiving cell, the overall effect may be either excitatory or inhibitory. Hence each neuron receives and integrates a vast amount of information from many cells, a function called convergence. The integrated information can in turn be transmitted to a few neurons or thousands of other neurons, a process known as divergence. If we look a bit more carefully using higher magnification, we see that the dendrites are usually covered with short dendritic spines that dramatically increase the receiving surface area.
The dendrites and their spines exhibit the special feature of being constantly modified and can change shape rapidly in response to changes in synaptic transmission (Fischer et al., 1998). These changes occur throughout life and permit us to continue to learn new associations as we interact with our environment.
Axons and terminal buttons The single long extension from the soma is the axon. Axons are tubular in structure and are filled with axoplasm (i.e., cytoplasm within the axon). Axons vary significantly in both length and diameter. Their function is to transmit the electrical signal (action potential) that is generated at the axon hillock down the length of the axon to the terminals. The axon hillock is that portion of the axon that is adjacent to the cell body.
Although there is usually only one axon for a given neuron, axons split or bifurcate into numerous branches called axon collaterals, providing the capacity to influence many more cells. At the end of the axons, there are small enlargements called terminal buttons, which are located near other cells’ dendrites or somas. Terminal buttons are also called boutons or axon terminals. The terminal buttons contain small packets (synaptic vesicles) of neurochemicals (called neurotransmitters) that provide the capacity for chemical transmission of information across the synapse to the adjacent cells or target organ. Neurons are frequently named according to the neurotransmitter they synthesize and release. Hence cells that release dopamine are dopaminergic neurons, those that release serotonin are serotonergic, and so forth.
Most axons are wrapped with a fatty insulating coating, called myelin, created by concentric layers of glial cells. Those glial cells that are responsible are of two types: Schwann cells, which myelinate peripheral nerves that serve muscles, organs, and glands; and oligodendroglia, which myelinate nerves within the brain and spinal cord. The myelin sheath provided by both types of glial cells is not continuous along the axon but has breaks in it where the axon is bare to the extracellular fluid. These bare spots are called nodes of Ranvier and are the sites where the action potential is regenerated during the conduction of the electrical signal along the length of the axon. The myelin sheath increases the speed of conduction along the axon; in fact, the thicker the myelin, the quicker the conduction. While a small number of neurons are unmyelinated and conduct slowly, others are thinly wrapped, and some rapidly conducting neurons may have a hundred or more wraps. Myelination also saves energy by reducing the effort required to restore the neuron to its resting state following the transmission of the electrical signal.
Soma The cell body is responsible for the metabolic care of the neuron. Among its important functions is the synthesis of proteins that are needed throughout the cell for growth and maintenance. The proteins include such things as enzymes, receptors, and components of the cell membrane. Within the nucleus are pairs of chromosomes that we inherited from our parents. Chromosomes are long strands of DNA, and genes are small portions of chromosomes that code for the manufacture of a specific protein molecule. Hence the coding region of a gene provides the “recipe” for a specific protein such as a receptor or enzyme. Although every cell in the body contains the full genetic library of information, each cell type manufactures only those proteins needed for its specific function. Hence liver cells manufacture enzymes to metabolize toxins, while neurons manufacture enzymes needed to synthesize neurotransmitters and carry out functions necessary for neural transmission. In addition, which specific genes are activated is also determined in part by our day-to-day experience. Neurobiologists are finding that experiences such as prolonged stress or chronic drug use may turn on or turn off the production of particular proteins by modifying transcription factors. Transcription factors are nuclear proteins that direct protein production. Transcription factors such as CREB bind to the promotor region of the gene adjacent to the coding region, modifying its rate of transcription.
Transcription occurs in the nucleus, where messenger RNA (mRNA) makes a complementary copy of the active gene. After moving from the nucleus to the cytoplasm, mRNA attaches to organelles called ribosomes, which decode the recipe and link the appropriate amino acids together to form the protein. This process is called translation.
Having said that proteins are synthesized within the soma and knowing that the proteins are needed throughout the neuron, we must consider how the proteins are moved to the required destination. The process is called axoplasmic transport and it depends on structures of the cytoskeleton. The cytoskeleton, as the name suggests, is a matrix composed of tubular structures, which include microtubules and neurofilaments that form a mesh-like mass that provides shape for the cell. In addition, the microtubules, which run longitudinally down the axon, provide a stationary track along which small packets of newly synthesized protein are carried by specialized motor proteins. The movement of materials occurs in both directions. Newly synthesized proteins are packaged in the soma and transported in an anterograde direction toward the axon terminals. At the terminals the contents are released, and retrograde axonal transport carries waste materials from the axon terminals back to the soma for recycling.
Characteristics of the cell membrane are critical for neuron function
One of the more important characteristics of neurons is the cell membrane. In addition to the phospholipids, membranes also have proteins inserted into the bilayer. Many of these proteins are receptors, large molecules that are the initial sites of action of neurotransmitters, hormones, and drugs. Other important proteins associated with the membrane are enzymes that catalyze biochemical reactions in the cell. The third important group of proteins are ion channels and transporters. Because the membrane is not readily permeable to charged molecules, special devices are needed to move molecules such as amino acids, glucose, and metabolic products across the membrane. Movement of these materials is achieved by transporter proteins, which are described further in Chapter 3. In addition, charged particles (ions), such as potassium (K+), sodium (Na+), chloride (Cl“), and calcium (Ca2+), that are needed for neuron function can be moved through the membrane only via ion channels. These channels are protein molecules that penetrate through the cell membrane and have a water-filled pore through which ions can pass.
Ion channels have several important characteristics. First, they are relatively specific for a particular ion, although some allow more than one type of ion to pass through. Second, most channels are not normally open to allow free passage of the ions, but are in a closed configuration that can be opened momentarily by specific stimuli. These channels are referred to as gated channels. The two types of channels of immediate interest to us are the ligand-gated channels and the voltage-gated channels. When a drug, hormone, or neurotransmitter binds to a receptor that recognizes the ligand, the channel protein changes shape and opens the gate, allowing a flow of a specific ion to move either into or out of the cell. The direction in which an ion moves is determined by its relative concentration; it always travels from high to low concentration. Hence, given an open gate, Na+, Cl”, and Ca2+ will move into the cell, while K+ moves out. A second type of channel, which will be of importance later in this chapter, is the type that is opened by voltage differences across the membrane. These channels are opened not by ligands but by the application of a small electrical charge to the membrane surrounding the channel. Other channels are modified by second messengers. Regardless of the stimulus opening the channel, it opens only briefly and then closes again, limiting the total amount of ion flux.
Glial cells provide vital support for neurons
Glial cells have a significant role in neuron function because they provide physical support to neurons, maintain the chemical environment of neurons, and provide immunological function. The four principal types include the oligodendroglia, Schwann cells, astrocytes, and microglia. Schwann cells and oligodendroglia, described earlier, produce the myelin sheath on axons of the peripheral nervous system (PNS) nerves and central nervous system (CNS) nerves, respectively. Schwann cells and oligodendroglia differ in several ways in addition to their location in the nervous system. Schwann cells are dedicated to a single neuron, and these PNS axons, when damaged, are prompted to regenerate axons because of Schwann cell response. First, the Schwann cells release growth factors, and second, they provide a pathway for the regrowth of the axon toward the target tissue. Oligodendroglia, in contrast, send out multiple paddle-shaped “arms,” which wrap many different axons to produce segments of the myelin sheath. In addition, they do not provide nerve growth factors when an axon is damaged, nor do they provide a path for growth.
Two other significant types of glial cells are the astrocytes and microglia. Astrocytes are large, star-shaped cells having numerous extensions. They intertwine with neurons and provide structural support; in addition, they help to maintain the ionic environment around neurons and modulate the chemical environment as well by taking up excess neurochemicals that might otherwise damage cells. Because astrocytes have a close relationship with both blood vessels and neurons, it is likely that they may aid the movement of necessary materials from the blood to nerve cells. Microglia are far smaller than astrocytes and act as scavengers that collect at sites of neuron damage to remove the dying cells. In addition to this phagocytosis, microglia are the primary source of immune response in the CNS and are responsible for the inflammation reaction that occurs following brain damage.
The nerve cells in the nervous system, called neurons, are surrounded by a cell membrane and filled with cytoplasm and the organelles needed for optimal functioning. Among the most important organelles are the mitochondria, which provide the energy for the metabolic work of the cell. The principal external features of a neuron reflect the special function of transmitting electrochemical messages over long distances. These cells have a soma, treelike dendrites, and a single axon extending from the soma that carries the electrical signal all the way to the axon terminals. The enlarged endings of the terminals contain vesicles filled with neurotransmitter molecules that are released into the synapse between the cells when the action potential arrives.
The dendrites of a neuron are covered with minute spines that increase the receiving surface area of the cell. Thousands of receptors that respond to neurotransmitters released by other neurons are found on the dendrites, dendritic spines, and soma of the cell. The axon hillock, which is located at the juncture of soma and axon, is responsible for summation (or integration) of the multiple signals to generate an action potential. Conduction of the action potential along the axon is enhanced by the insulating property of the myelin created by nearby glial cells.
The nucleus of the cell is located in the soma, and protein synthesis occurs there. The transcription of the genetic code for a specific protein by mRNA occurs within the nucleus, and the translation of the “recipe,” carried by the mRNA, occurs on the ribosomes in the cytoplasm. The ribosomes are ultimately responsible for linking the appropriate amino acids together to create the protein. Which genes are activated depends on various transcription factors that are activated by changes in synaptic activity.
The newly manufactured proteins are moved by axoplasmic transport within the cell to where they are needed. Packets of protein are moved by motor proteins that slide along the neuron’s microtubules (part of the cytoskeleton) to the terminals (anterograde transport). In a similar manner, protein waste and cell debris is transported from the terminals back to the soma (retrograde transport) for recycling.
The cell membrane is a phospholipid bilayer that prevents most materials from passing through, unless the material is lipid soluble. Special transporters into the cell carry other essential materials, such as glucose, amino acids, and neurotransmitters. Ion channels also penetrate the membrane and selectively allow ions such as Na+, K+, Cl-, and Ca2+ to move across the membrane. In addition to transporters and ion channels, proteins associated with the membrane include receptors and enzymes.
The second type of cell in the nervous system is the glial cell. The four types described in this section are the Schwann cells and oligodendroglia, which are responsible for producing the myelin sheath on peripheral and central nervous system neurons, respectively, and the astrocytes and microglia. Astrocytes regulate the extracellular environment of the neurons and provide physical support and nutritional assistance. Microglia acting as phagocytes remove cellular debris and provide immune function.