Chair of the Department of Physiology at the University of California, San Francisco for many years, he received numerous teaching awards and enjoyed working with medical students. Dr Brooks is a member of the APS Renal Steering Section and the APS Committee of Committees.
Preface
From the Authors
Color Illustrations
New Boxed Clinical Cases
New End of Chapter Board Review Questions
New Media
CELLULAR & MOLECULAR BASIS OF MEDICAL PHYSIOLOGY
General Principles &
Energy Production in Medical Physiology
INTRODUCTION
GENERAL PRINCIPLES
THE BODY AS AN
ORGANIZED “SOLUTION”
UNITS FOR MEASURING
CONCENTRATION OF SOLUTES
Moles
Equivalents
WATER, ELECTROLYTES, & ACID/BASE
Their contribution to body weight percentage (based on a healthy young adult male; small variations exist with age and sex) emphasizes the dominance of body fluid composition.
DIFFUSION
The time required for equilibrium by diffusion is proportional to the square of the diffusion distance. The permeability of the boundaries across which diffusion occurs in the body varies, but diffusion is still an important force affecting the distribution of water and solutes.
OSMOSIS
The magnitude of the diffusion tendency from one region to another is directly proportional to the cross-sectional area over which diffusion occurs and the concentration gradient, or chemical gradient, which is the difference in concentration of the diffusing substance divided by it. by the thickness of the boundary (Ficks law of diffusion). Note that although a homogeneous solution contains osmotically active particles and can be said to have an osmotic pressure, it can only exert an osmotic pressure when it is in contact with another solution across a membrane permeable to the solvent, but not to the solute.
OSMOLAL CONCENTRATION OF PLASMA: TONICITY
NONIONIC DIFFUSION
DONNAN EFFECT
CLINICAL BOX 1–1
Chloride ions (Cl-) are present in higher concentrations in the ECF than in the cell interior, and they tend to diffuse along this concentration gradient into the cell. Therefore, no forces other than those represented by the chemical and electrical gradients need be invoked to explain the distribution of Cl– across the membrane.
GENESIS OF THE MEMBRANE POTENTIAL
However, the intracellular concentration of Na+ and K+ remains constant due to the action of Na,K ATPase, which actively transports Na+ out of the cell and K+ into the cell (against their electrochemical gradients).
ENERGY PRODUCTION
ENERGY TRANSFER
BIOLOGIC OXIDATIONS
In such dehydrogenation reactions, nicotinamide adenine dinucleotide (NAD+) and dihydronicotinamide adenine dinucleotide phosphate (NADP+) absorb hydrogen, forming dihydronicotinamide adenine dinucleotide (NADH) and dihydronicotinamide adenine dinucleotide phosphate (NADPH) (Figure 1-6). . Ninety percent of O2 consumption in the basal state is mitochondrial, and 80% of this is linked to ATP synthesis.
MOLECULAR BUILDING BLOCKS
NUCLEOSIDES, NUCLEOTIDES,
The double helix structure of DNA is compacted in the cell by association with histones, and further compacted into chromosomes. An indication of the complexity of DNA in the human haploid genome (the total genetic message) is its size; it consists of 3 x 109 base pairs that can code for approximately 30,000 genes.
CLINICAL BOX 1–2
Deoxyribonucleic acid (DNA) is found in bacteria, in the nuclei of eukaryotic cells, and in mitochondria. Gene mutations occur when the base sequence in DNA changes from its original sequence.
REPLICATION: MITOSIS & MEIOSIS
The proteins formed from the DNA blueprint include all enzymes, and these in turn regulate the cell's metabolism. A poly(A) tail of approximately 100 bases is added to the untranslated segment at the 3' end to help maintain the stability of the mRNA.
AMINO ACIDS & PROTEINS
AMINO ACIDS
THE AMINO ACID POOL
PROTEINS
The order of the amino acids in the peptide chains is called the primary structure of a protein. The tertiary structure of a protein is the arrangement of the twisted chains into layers, crystals or fibers.
PROTEIN SYNTHESIS
The chains are twisted and folded in complex ways, and the term secondary structure of a protein refers to the spatial arrangement produced by the twisting and folding. Many protein molecules are made of multiple proteins or subunits (eg hemoglobin) and the term quaternary structure is used to refer to the arrangement of the subunits into a functional structure.
POSTTRANSLATIONAL MODIFICATION
An anti-parallel β-sheet is formed when extended polypeptide chains are folded back and forth on each other and hydrogen bonding occurs between the peptide bonds of neighboring chains. SRPs are not the only signals that help direct proteins to their proper place in or out of the cell; other signal sequences, posttranslational modifications, or both (eg, glycosylation) may serve this function.
PROTEIN DEGRADATION
CATABOLISM OF AMINO ACIDS
UREA FORMATION
METABOLIC FUNCTIONS OF AMINO ACIDS
CARBOHYDRATES
In this way, and by converting lactate to glucose, nonglucose molecules can be converted to glucose (gluconeogenesis). Glucose can be converted to fat through acetyl-CoA, but because the conversion of pyruvate to acetyl-CoA, unlike most reactions in glycolysis, is irreversible, fats are not converted to glucose via this pathway.
CITRIC ACID CYCLE
Six ATPs are formed by oxidation via the flavoprotein cytochrome chain of the two NADHs formed when 2 moles of phosphoglyceraldehyde are converted to phosphoglycerate (Figure 1-22), six ATPs are formed from the two NADHs formed when 2 moles of pyruvate converted to acetyl-CoA, and 24 ATPs are formed during the subsequent two turns of the citric acid cycle. The amount of ATP generated depends on the amount of NADPH converted to NADH and then oxidized.
DIRECTIONAL-FLOW VALVES”
Of these, 18 are formed by oxidation of six NADHs, 4 by oxidation of two FADH2s, and 2 by oxidation at the substrate level when succinyl-CoA is converted to succinate. Thus, the net production of ATP per mole of blood glucose metabolized aerobically via the Embden-Meyerhof pathway and the citric acid cycle is the same.
GLYCOGEN SYNTHESIS & BREAKDOWN
During aerobic glycolysis, the net production of ATP is 19 times greater than the two ATPs formed under anaerobic conditions. The breakdown of glycogen into 1:4α linkage is catalyzed by phosphorylase, while another enzyme catalyzes the breakdown of glycogen into 1:6α linkage.
FACTORS DETERMINING THE PLASMA GLUCOSE LEVEL
METABOLISM OF HEXOSES OTHER THAN GLUCOSE
FATTY ACIDS & LIPIDS
FATTY ACID OXIDATION & SYNTHESIS
KETONE BODIES
Acetoacetate is also formed in the liver via the formation of 3-hydroxy-3-methyl-glutaryl-CoA, and this pathway is quantitatively more important than deacylation. Tissues other than the liver transfer CoA from succinyl-CoA to acetoacetate and metabolize the “active” acetoacetate to CO2 and H2O via the citric acid cycle.
CELLULAR LIPIDS
PLASMA LIPIDS & LIPID TRANSPORT
The enzyme catalyzes the breakdown of the triglyceride in the chylomicrons to FFA and glycerol, which then enter fat. Chylomicrons depleted of their triglycerides remain in the circulation as cholesterol-rich lipoproteins called chylomicron remnants, which are 30 to 80 nm in diameter.
CLINICAL BOX 1–3
IDL removes phospholipids and, through the action of the plasma enzyme lecithin-cholesterol acyltransferase (LCAT), collects cholesterol esters formed from cholesterol in HDL. The remaining IDL then loses more triglycerides and protein, possibly in the sinusoids of the liver, and becomes LDL.
FREE FATTY ACID METABOLISM
VLDLs are produced in the liver and transport triglycerides produced from fatty acids and carbohydrates in the liver to extrahepatic tissues. When their triglycerides are largely removed by the action of lipoprotein lipase, they become IDL.
CHOLESTEROL METABOLISM
ESSENTIAL FATTY ACIDS
Hydrogenation of fats in the body is known to occur, but synthesis of carbon chains through the arrangement of double bonds in essential fatty acids does not appear to occur.
EICOSANOIDS
CLINICAL BOX 1–4
CLINICAL BOX 1–5
Diseases in which they may be involved include asthma, psoriasis, respiratory distress syndrome in adults, allergic rhinitis, rheumatoid arthritis, Crohn's disease and ulcerative colitis.
CHAPTER SUMMARY
MULTIPLE-CHOICE QUESTIONS
When LDL enters cells by receptor-mediated endocytosis, which of the following does not occur?
CHAPTER RESOURCES
Overview of Cellular Physiology in
Medical Physiology
FUNCTIONAL MORPHOLOGY OF THE CELL
CELL MEMBRANES
In epithelial cells, the enzymes in the cell membrane at the mucosal surface differ from those in the FIGURE 2-2 Organization of the phospholipid bilayer and. Many are integral proteins, which span the membrane, but peripheral proteins are attached to the inside or outside (not shown) of the membrane.
MITOCHONDRIA
Beneath most cells is a thin, "soft" layer and a few fibrils that together make up the basement membrane or, more precisely, the basal lamina. The basal lamina, and the extracellular matrix in general, consists of many proteins that hold cells together, regulate their development, and determine their growth.
LYSOSOMES
Not surprisingly, these enzymes are all acid hydrolases, in that they function best at the acidic pH of the lysosomal compartment. This can be a safety feature for the cell; if the lysosome were to break open and release its contents, the enzymes would be inefficient at the near-neutral cytosolic pH (7.2), and thus unable to digest the cytosolic enzymes they encounter.
PEROXISOMES
This integral membrane protein uses ATP energy to move protons from the cytosol up their electrochemical gradient, keeping the lysosome relatively acidic, at pH 5.0.
CYTOSKELETON
CLINICAL BOX 2–1
It is the most abundant protein in mammalian cells, sometimes constituting up to 15% of the total protein in the cell. They reach the tips of the microvilli in the epithelial cells of the intestinal mucosa.
MOLECULAR MOTORS
CENTROSOMES
CILIA
CELL ADHESION MOLECULES
INTERCELLULAR CONNECTIONS
GAP JUNCTIONS
For example, X-linked Charcot-Marie-Tooth disease is a peripheral neuropathy associated with mutation of one specific connexin gene. Experiments in mice in which specific connexins are deleted by gene manipulation or replaced with different connexins confirm that the specific connexin subunits that make up connexons determine their permeability and selectivity.
NUCLEUS & RELATED STRUCTURES
ENDOPLASMIC RETICULUM
RIBOSOMES
GOLGI APPARATUS
Membranous vesicles containing newly synthesized proteins bud from the granular endoplasmic reticulum and fuse with the cisterna on the cis side of the apparatus. Conversely, vesicles are pinched off from the cell membrane by endocytosis and pass to endosomes.
QUALITY CONTROL
The proteins are then transferred via other vesicles to the intermediate cisternae and finally to the cisternae on the trans side, from which the vesicles are released into the cytoplasm. From the trans Golgi, vesicles move to lysosomes and to the cell exterior via constitutive and non-constitutive pathways that include exocytosis.
APOPTOSIS
Vesicular traffic in the Golgi and between other membrane compartments in the cell is regulated by a combination of common mechanisms along with specific mechanisms that determine where within the cell they will go. Another important feature is the presence of proteins called SNAREs (soluble N-ethylmaleimide-sensitive factor binding receptor).
TRANSPORT ACROSS CELL MEMBRANES
EXOCYTOSIS
ENDOCYTOSIS
CLINICAL BOX 2–2
From the early endosome, a new vesicle can bud and return to the cell membrane. However, removal of the cell membrane occurs by endocytosis, and such exocytosis-endocytosis coupling maintains the cell surface at its normal size.
RAFTS & CAVEOLAE
Alternatively, the early endosome becomes a late endosome and fuses with a lysosome (Figure 2–11), in which the contents are digested by lysosomal proteases. It is obvious that exocytosis adds to the total amount of membrane surrounding the cell, and if membranes were not removed elsewhere at an equivalent rate, the cell would enlarge.
COATS & VESICLE TRANSPORT
MEMBRANE PERMEABILITY &
MEMBRANE TRANSPORT PROTEINS
However, it can also be internal; intracellular Ca2+, cAMP, lipids, or one of the G proteins produced in cells can directly bind to channels and activate them. A typical example is glucose transport by the glucose transporter, which moves glucose down its concentration gradient from the ECF to the cytoplasm of the cell.
ION CHANNELS
Each of the subunits probably crosses the membrane twice, and the amino terminus and carboxyl terminus are located inside the cell. Renal ENaCs play an important role in the regulation of ECF volume by aldosterone.
Na, K ATPase
Another family of Na+ channels with a different structure has been found in the apical membranes of epithelial cells in the kidney, colon, lung and brain. Other Cl– channels have the same pentameric form as the acetylcholine receptor; examples include the γ-aminobutyric acid A (GABAA) and glycine receptors in the central nervous system (CNS).
REGULATION OF Na, K ATPase ACTIVITY
The epithelial sodium channels (ENaCs) consist of three subunits encoded by three different genes. The dimeric ClC channels are found in plants, bacteria and animals, and there are nine different ClC genes in humans.
SECONDARY ACTIVE TRANSPORT
The main gain for this energy consumption is the establishment of an electrochemical gradient in the cells.
TRANSPORT ACROSS EPITHELIA
THE CAPILLARY WALL
FILTRATION
ONCOTIC PRESSURE
TRANSCYTOSIS
INTERCELLULAR COMMUNICATION
RECEPTORS FOR
CHEMICAL MESSENGERS
MECHANISMS BY WHICH CHEMICAL MESSENGERS ACT
The resulting cell signaling pathway ensures amplification of the primary signal and distribution of the signal to appropriate targets within the cell. Some of the major ones important in mammalian cell signaling are summarized in Table 2-4.
STIMULATION OF TRANSCRIPTION
A series of enzymatic changes, protein-protein interactions, or other messenger changes can be activated in a cell in an orderly manner following receptor recognition of the primary messenger. Phosphorylation of the last MAP kinase in series allows it to migrate to the nucleus, where it phosphorylates a latent transcription factor.
INTRACELLULAR Ca 2+
A second route to gene transcription is the activation of cytoplasmic protein kinases that can move to the nucleus to phosphorylate a latent transcription factor for activation. A third common pathway is the activation of a latent transcription factor in the cytosol, which then migrates to the nucleus and alters transcription.
AS A SECOND MESSENGER
They contain a series of three kinases that coordinate stepwise phosphorylation to activate each protein in the series in the cytosol. This pathway is shared by a diverse set of transcription factors that include nuclear factor kappa B (NFκB; activated by tumor necrosis factor family receptor binding and others) and signal transducers of activated transcription (STAT; activated by cytokine receptor binding).
CALCIUM-BINDING PROTEINS
This pathway is a common endpoint of signals that pass through the mitogen-activated kinase (MAP) cascade. In all cases, the binding of an activated transcription factor to DNA increases (or in some cases decreases) the transcription of mRNAs encoded by the gene to which it binds.
It is unique in that amino acid residue 115 is trimethylated and is highly conserved as it is found in plants and animals. When calmodulin binds Ca2+, it can activate five different calmodulin-dependent kinases (CaMK; Table 2–4), among other proteins.
G PROTEINS
GTPase activity of the α subunit then converts GTP to GDP, and this leads to reassociation of the α with the βγ subunit and termination of effector activation. The GTPase activity of the α subunit can be accelerated by a family of regulators of G protein signaling (RGS).
G PROTEIN-COUPLED RECEPTORS
Heterotrimeric G proteins relay signals from over 1000 GPCRs, and their effectors in cells include ion channels and enzymes (Tables 2–5). Not all combinations occur in the cell, but over 20 different heterotrimeric G proteins have been well documented in cell signaling.
INOSITOL TRISPHOSPHATE
PLC isoforms can catalyze the hydrolysis of the membrane lipid phosphatidylinositol 4,5-diphosphate (PIP2) to form IP3 and diacylglycerol (DAG) (Figure 2-25). DAG is also another messenger; it stays in the cell membrane, where it activates one of several isoforms of protein kinase C.
CYCLIC AMP
PRODUCTION OF cAMP BY ADENLYL CYCLASE
GUANYLYL CYCLASE
GROWTH FACTORS
Phosphorylated STATs form homo- and heterodimers and translocate to the nucleus, where they act as transcription factors. Interestingly, the JAK–STAT pathway can also be activated by growth hormone and is another important direct pathway from the cell surface to the nucleus.
HOMEOSTASIS
The buffering properties of the body fluids and the adaptation of the kidneys and respiration to the presence of excess acid or alkali are examples of homeostatic. There are countless other examples, and much of physiology is concerned with regulatory mechanisms that ensure that the internal environment remains constant.
CLINICAL BOX 2–3
They do this in part by creating acidic (lysosomes) or oxidizing (peroxisomes) contents in relation to the cellular cytosol. Endocytosis is the formation of vesicles on the plasma membrane to take material from the extracellular space into the interior of the cell.
Immunity, Infection,
IMMUNE EFFECTOR CELLS
GRANULOCYTES
MAST CELLS
MONOCYTES
GRANULOCYTE & MACROPHAGE COLONY-STIMULATING FACTORS
LYMPHOCYTES
They calculated that in humans, lymphocytes per day enter the bloodstream only via the thoracic duct; however, this number includes cells that reenter the lymphatic vessels, thus crossing the thoracic duct several times. The effects of adrenocortical hormones on lymphatic organs, circulating lymphocytes, and granulocytes are discussed in Chapter 22.
CLINICAL BOX 3–1
IMMUNITY
OVERVIEW
CYTOKINES
Activation of lymphocytes; differentiation of B cells; stimulation of the production of acute-phase proteins. Interleukin-12 macrophages and B cells Stimulation of the production of interferon γ by type 1 (TH1) helper T cells and by natural killer cells; induction of type 1 (TH1) helper T cells.
THE COMPLEMENT SYSTEM
The chemokine receptors are G protein-coupled receptors that, among other things, cause the expansion of pseudopodia with migration of the cell to the source of the chemokine.
INNATE IMMUNITY
Activated cells produce their effects by releasing cytokines and, in some cases, complement and other systems. An important link in innate immunity in Drosophila is a receptor protein called toll, which binds fungal antigens and triggers the activation of genes encoding antifungal proteins.
ACQUIRED IMMUNITY
One of these, TLR4, binds bacterial lipopolysaccharide and a protein called CD14, and this triggers a cascade of intracellular events that activate the transcription of genes for various proteins involved in innate immune responses.
DEVELOPMENT OF THE IMMUNE SYSTEM
Most cytotoxic T cells display the glycoprotein CD8, and helper T cells display the glycoprotein CD4. Based on differences in their receptors and functions, cytotoxic T cells are divided into αβ and γδ types (see below).
MEMORY B CELLS & T CELLS
ANTIGEN RECOGNITION
ANTIGEN PRESENTATION
Thus, there are three main types of cytotoxic lymphocytes in the body: αβ T cells, γδ T cells, and NK cells. The class II MHC proteins (MHC-II proteins) are mainly concerned with peptide products of extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested in the late endosomes.
T CELL RECEPTORS
B CELLS
IMMUNOGLOBULINS
GENETIC BASIS OF DIVERSITY IN THE IMMUNE SYSTEM
In the gene family responsible for this region, there are several hundred different coding regions for segment V, about 20 for segment D and 4 for segment J. A similar variable recombination occurs in the coding regions responsible for the two variable segments (V and J ) in the light chain.
PLATELETS
Consequently, when the platelet count is low, less binds and more is available to stimulate platelet production. Conversely, when platelet counts are high, more are bound and less are available, resulting in a form of feedback regulation of platelet production.
INFLAMMATION &
When the platelet count is low, clot retraction is deficient and there is poor contraction of ruptured vessels. Purpura can also occur when the platelet count is normal, and in some of these cases the circulating platelets are abnormal (thrombasthenic purpura).
WOUND HEALING
Platelet production is regulated by the colony-stimulating factors that control the production of megakaryocytes, plus thrombopoietin, a circulating protein factor. The amino-terminal portion of the thrombopoietin molecule has the platelet-stimulating activity, while the carboxyl-terminal portion contains many carbohydrate residues and concerns the bioavailability of the molecule.
LOCAL INJURY
This factor, which facilitates megakaryocyte maturation, is produced constitutively by the liver and kidneys, and there are thrombopoietin receptors on platelets.
CLINICAL BOX 3–2
CLINICAL BOX 3–3
Evidence is accumulating that the transcription factor, nuclear factor-κB, plays a key role in the inflammatory response. NF-κB by increasing the production of IκBα, which is probably the main basis of their anti-inflammatory activity (see Chapter 22).
SYSTEMIC RESPONSE TO INJURY
NF-κB translocates to the nucleus, where it binds to the DNA of genes for many inflammatory mediators, resulting in their increased production and secretion. Wounds gain 20% of their ultimate strength within 3 weeks and gain more strength later, but never reach more than about 70% of normal skin strength.
PHYSIOLOGY OF NERVE & MUSCLE CELLS
Excitable Tissue: Nerve
CELLULAR ELEMENTS IN THE CNS
GLIAL CELLS
NEURONS
The myelin is then compacted when the extracellular parts of a membrane protein called protein zero (PO) attach to the extracellular parts of PO in the adjacent membrane. In the mammalian CNS, most neurons are myelinated, but the cells that form myelin are oligodendrocytes rather than Schwann cells (Figure 4–1).
AXONAL TRANSPORT
In the peripheral nervous system, myelin is formed when a Schwann cell wraps its membrane around an axon up to 100 times (Figure 4–1). In multiple sclerosis, a crippling autoimmune disease, patchy destruction of myelin occurs in the central nervous system (see Clinical Box 4–1). The loss of myelin is associated with slowed or blocked conduction in the demyelinated axons.
CLINICAL BOX 4–1
Various mutations in the gene for P0 cause peripheral neuropathy; 29 different mutations have been described that cause symptoms ranging from mild to severe. Synaptic vesicles are recycled into the membrane, but some used vesicles are carried back to the cell body and deposited in lysosomes.
EXCITATION & CONDUCTION
Some materials ultimately taken up by endocytosis, including nerve growth factor (NGF) and various viruses, are also transported back into the cell body. In them, single strands of mRNA transported from the cell body make contact with the appropriate ribosomes, and protein synthesis appears to create local protein domains.
RESTING MEMBRANE POTENTIAL
Membrane potential results from the separation of positive and negative charges across the cell membrane (Figure 4-5). FIGURE 4–5 This membrane potential results from the separation of positive and negative charges across the cell membrane.
IONIC FLUXES DURING THE ACTION POTENTIAL
An outward K+ concentration gradient results in a passive movement of K+ out of the cell when K+-selective channels are open. Similarly, an inward Na+ concentration gradient results in passive movement of Na+ into the cell when Na+-selective channels are open.
DISTRIBUTION OF ION CHANNELS IN MYELINATED NEURONS
Consequently, intracellular and extracellular K + concentrations are the main determinants of the resting membrane potential, which is therefore close to the equilibrium potential for K + . This is prevented by the Na+-K+ ATPase, which actively moves Na+ and K+ against their electrochemical gradient.
ALL-OR-NONE” LAW
The action potential does not occur if the stimulus is subthreshold in magnitude, and it occurs with constant amplitude and shape regardless of the strength of the stimulus if the stimulus is at or above threshold intensity. The action potential is therefore "all or none" in nature and is said to obey the all-or-none law.
ELECTROTONIC POTENTIALS, LOCAL RESPONSE, & FIRING LEVEL
Further increases in the intensity of a stimulus produce no increase or other change in the action potential as long as the other experimental conditions remain constant.
CHANGES IN EXCITABILITY DURING ELECTROTONIC POTENTIALS & THE
During the local response the threshold is lowered, but during the rising and much of the falling phases of the peak potential the neuron is insensitive to stimulation. These changes in threshold are correlated with the phases of the action potential in Figure 4–9.
ELECTROGENESIS OF THE ACTION POTENTIAL
This refractory period is divided into an absolute refractory period, corresponding to the period from the time when the firing level is reached until the repolarization is approx. one-third complete, and a relative refractory period lasting from this time to the onset of after-depolarization. During the absolute refractory period no stimulus, however strong, will excite the nerve, but during the relative refractory period stronger than normal stimuli can cause excitation.
SALTATORY CONDUCTION
During after-depolarization the threshold is lowered again, and during after-hyperpolarization it is increased. It is a fast process that allows myelinated axons to conduct up to 50 times faster than the fastest unmyelinated fibers.
ORTHODROMIC & ANTIDROMIC CONDUCTION
BIPHASIC ACTION POTENTIALS
PROPERTIES OF MIXED NERVES
NERVE FIBER TYPES & FUNCTION
Patterns of this type are sometimes seen in individuals who sleep with their arms under their heads for long periods of time, causing compression of the nerves in the arms. Due to the association of deep sleep with alcoholic intoxication, the syndrome is most common on weekends and holidays.
NEUROTROPHINS
By comparing the neurological deficits induced by careful dorsal root sectioning and other nerve cutting experiments with the histological changes in the nerves, the functions and histological features of each of the families of axons responsible for the different peaks of the compound action can be compared. potential has been identified. In addition to variations in conduction velocity and fiber diameter, the different classes of fibers in peripheral nerves differ in their sensitivity to hypoxia and anesthetics (Table 4-3).
TROPHIC SUPPORT OF NEURONS
In general, the larger the diameter of a particular nerve fiber, the higher its conduction velocity. Conversely, pressure on a nerve can cause loss of conduction in large-diameter motor, touch, and pressure fibers while pain sensation remains relatively intact.
RECEPTORS
ACTIONS
CLINICAL BOX 4–2
OTHER FACTORS AFFECTING NEURONAL GROWTH
Nicholls JG, Martin AR, Wallace BG: From neuron to brain: a cellular and molecular approach to nervous system function, 4th ed.
Excitable Tissue: Muscle
SKELETAL MUSCLE MORPHOLOGY
ORGANIZATION
The contractile mechanism in skeletal muscle is largely dependent on the proteins myosin-II, actin, tropomyosin and troponin.
STRIATIONS
The myosin molecules are arranged symmetrically on either side of the center of the sarcomere, and it is this arrangement that creates the ligand areas in the pseudo-H zone. The M line is the site of reversal of polarity of the myosin molecules in each of the thick filaments.
SARCOTUBULAR SYSTEM
Myosin contains heavy chains and light chains, and its heads are composed of the light chains and the amino termini of the heavy chains. Each of the three troponin subunits has a unique function: troponin T binds troponin components to tropomyosin; troponin I inhibits the interaction of myosin with actin; and troponin C contains binding sites for Ca2+, which helps initiate contraction.
DYSTROPHIN–GLYCOPROTEIN COMPLEX
Titin, the largest known protein (with a molecular mass of almost 3,000,000 Da), connects the Z lines to the M lines and provides a scaffold for the sarcomere. If the muscle is first stretched, there is relatively little resistance as the domains unfold, but with further stretch there is a rapid increase in resistance that protects the structure of the sarcomere.
ELECTRICAL PHENOMENA
Tropomyosin molecules are long filaments located in the groove between the two chains in the actin (Figure 5-3). Desmin adds structure to the Z-lines in part by tethering the Z-lines to the plasma membrane.
The thin filaments are polymers consisting of two actin chains that form a long double helix. Some additional structural proteins important in skeletal muscle function include actinin, titin, and desmin.
ELECTRICAL CHARACTERISTICS OF SKELETAL MUSCLE
At these points there are slender cross-links that keep the thick filaments in the proper array.
ION DISTRIBUTION & FLUXES
CONTRACTILE RESPONSES
Depolarization of the muscle fiber membrane usually begins at the motor end plate, a specialized structure below the motor nerve ending.
THE MUSCLE TWITCH
MOLECULAR BASIS OF CONTRACTION
CLINICAL BOX 5–1
ATP is hydrolyzed and inorganic phosphate (Pi) is released, causing a "refolding" of the myosin head and completing the cycle. It causes the release of Ca2+ from the terminal cisternae, the lateral sacs of the sarcoplasmic reticulum near the T system.
TYPES OF CONTRACTION
The process by which depolarization of the muscle fiber initiates contraction is called excitation-contraction coupling. Depolarization of the T-tubule membrane activates the sarcoplasmic reticulum via dihydropyridine receptors (DHPR), named after the drug dihydropyridine, which blocks them (Figure 5–8).
SUMMATION OF CONTRACTIONS
The frequency of stimulation at which the sum of contractions occurs is determined by the duration of twitching of the particular muscle being studied. For example, if the twitch duration is 10 ms, frequencies less than 1/10 ms (100/s) result in discrete responses that are terminated by complete relaxation, and frequencies greater than 100/s result in summation.
RELATION BETWEEN MUSCLE LENGTH &
TENSION & VELOCITY OF CONTRACTION
FIBER TYPES
ENERGY SOURCES & METABOLISM
PHOSPHORYLCREATINE
CARBOHYDRATE & LIPID BREAKDOWN
THE OXYGEN DEBT MECHANISM
RIGOR
HEAT PRODUCTION IN MUSCLE
PROPERTIES OF SKELETAL MUSCLES IN THE
INTACT ORGANISM
EFFECTS OF DENERVATION
THE MOTOR UNIT
Each spinal motor neuron innervates only one type of muscle fiber, so that all muscle fibers in a motor unit are of the same type. For example, in the leg muscles, the small, slow units are recruited first for standing.
ELECTROMYOGRAPHY
In muscles such as those of the hand and those involved in eye movement (ie, muscles involved in fine, graded, and precise movements), each motor unit innervates very few (on the order of three to in six) muscle fibers. Based on the type of muscle fiber they innervate, and thus on the duration of their contraction, motor units are divided into S (slow), FR (fast, fatigue-resistant) and FF. units (quick, tiresome).
THE STRENGTH OF SKELETAL MUSCLES
The differences between the types of muscle units are not inherent, but are determined, among other things, by their activity. This change is due to changes in the pattern of muscle activity; in stimulation experiments, changes in the expression of MHC genes and thus of MHC isoforms can be produced by changes in the pattern of electrical activity used to stimulate the muscles.
BODY MECHANICS
CARDIAC MUSCLE MORPHOLOGY
ELECTRICAL PROPERTIES
RESTING MEMBRANE
MECHANICAL PROPERTIES
CONTRACTILE RESPONSE
During phases 0 to 2 and about half of phase 3 (until the membrane potential reaches about –50 mV during repolarization), heart muscle cannot be re-excited; that is, it is in its absolute refractory period. Of course, tetanizing cardiac muscle for any length of time would have fatal consequences, and in this sense the fact that cardiac muscle cannot be tetanized is a safety feature.
ISOFORMS
CLINICAL BOX 5–2
CORRELATION BETWEEN MUSCLE FIBER LENGTH & TENSION
METABOLISM
SMOOTH MUSCLE MORPHOLOGY
TYPES
ELECTRICAL & MECHANICAL ACTIVITY
In particular, norepinephrine tends to persist in the muscle and cause the muscle to fire repeatedly after a single stimulus rather than a single action potential. Therefore, the contractile response produced is usually an irregular tetanus rather than a single jerk.
RELAXATION
When a single twitch response is obtained, it resembles the twitching contraction of skeletal muscle, except that its duration is 10 times longer.
CLINICAL BOX 5–3
NO produced in endothelial cells can freely diffuse into the smooth muscle for its effects. This molecule can activate cGMP-specific protein kinases that can affect ion channels, Ca2+ homeostasis, or phosphatases, or all of the above, leading to smooth muscle relaxation (see Chapters 7 and 33).
FUNCTION OF THE NERVE SUPPLY TO SMOOTH MUSCLE
PLASTICITY OF SMOOTH MUSCLE
After entering muscle, NO directly activates a soluble guanylate cyclase to produce another second messenger molecule, cyclic guanosine monophosphate (cGMP).
Synaptic & Junctional Transmission
SYNAPTIC TRANSMISSION
FUNCTIONAL ANATOMY
TYPES OF SYNAPSES
PRESYNAPTIC & POSTSYNAPTIC STRUCTURE & FUNCTION
Neuropeptides in large, dense-core vesicles must also be produced by the protein synthesis machinery in the cell body. However, small clear vesicles and small dense-core vesicles are recycled in the nerve terminal.
ELECTRICAL EVENTS IN POSTSYNAPTIC NEURONS
The vesicles and the proteins contained in their walls are synthesized in the neuronal cell body and transported along the axon to the ends by rapid axoplasmic transport. This orderly organization of the synapse depends in part on neurexins, proteins bound to the membrane of the presynaptic neuron, which bind neurexin receptors in the membrane of the postsynaptic neuron.
EXCITATORY & INHIBITORY POSTSYNAPTIC POTENTIALS
A single stimulus applied to the sensory nerves characteristically does not lead to the generation of a widespread action potential in the postsynaptic neuron. In the cytoplasm, it fuses with the early endosome and the cycle is ready to repeat.
CLINICAL BOX 6–1
The EPSP is produced by depolarization of the postsynaptic cell membrane immediately below the presynaptic terminal. When an inhibitory synaptic knob becomes active, the released transmitter causes the opening of Cl– channels in the area of the postsynaptic cell membrane below the knob.
TEMPORAL & SPATIAL SUMMATION
The fact that an IPSP is mediated by Cl– can be demonstrated by repeating the stimulus while changing the resting membrane potential of the postsynaptic cell. They can be produced, for example, by opening K+ channels, with movement of K+ out of the postsynaptic cell, or by closing Na+ or Ca2+ channels.
SLOW POSTSYNAPTIC POTENTIALS
GENERATION OF THE ACTION POTENTIAL IN THE
POSTSYNAPTIC NEURON
FUNCTION OF THE DENDRITES
ELECTRICAL TRANSMISSION
INHIBITION & FACILITATION AT SYNAPSES
DIRECT & INDIRECT INHIBITION
POSTSYNAPTIC INHIBITION IN THE SPINAL CORD
PRESYNAPTIC INHIBITION &
FACILITATION
ORGANIZATION OF INHIBITORY SYSTEMS
SUMMATION & OCCLUSION
NEUROMUSCULAR TRANSMISSION
NEUROMUSCULAR JUNCTION
ANATOMY
SEQUENCE OF EVENTS DURING TRANSMISSION
Binding of acetylcholine to these receptors increases the Na+ and K+ conductances of the membrane, and the resulting influx of Na+ produces a depolarizing potential, the endplate potential. Action potentials are generated on either side of the endplate and conducted away from the endplate in both directions along the muscle fiber.
END PLATE POTENTIAL
Acetylcholine is then removed from the synaptic cleft by acetylcholinesterase, which is present in high concentrations at the neuromuscular junction.
QUANTAL RELEASE OF TRANSMITTER
NERVE ENDINGS IN SMOOTH
JUNCTIONAL POTENTIALS
DENERVATION HYPERSENSITIVITY
CLINICAL BOX 6–2
CLINICAL BOX 6–3
Hypersensitivity of the postsynaptic structure to the transmitter previously secreted by the axon occurs mainly due to the synthesis or activation of more receptors. An IPSP is produced by a hyperpolarization of the postsynaptic cell; may be produced by a localized increase in Cl– transport.
Neurotransmitters &
Neuromodulators
CHEMICAL TRANSMISSION OF SYNAPTIC ACTIVITY
CHEMISTRY OF TRANSMITTERS
Figure 7-1 shows the biosynthesis of some common small molecule transmitters released by neurons in the central or peripheral nervous system. The individual receptors together with their ligands, are discussed in the following parts of this chapter.
REUPTAKE
The second family consists of at least three transporters that mediate glutamate uptake by neurons and two that transport glutamate into astrocytes. Like the family of neurotransmitter membrane transporters, they have 12 transmembrane domains but share little homology with other transporters.
SMALL-MOLECULE TRANSMITTERS
MONOAMINES Acetylcholine
Cholinesterases
Acetylcholine Receptors
CLINICAL BOX 7–1
Nicotinic cholinergic receptors in autonomic ganglia are heteromers that usually contain α3 subunits in combination with others, and nicotinic receptors in the brain are composed of many other subunits. Many of the nicotinic cholinergic receptors in the brain are located presynaptically on axon terminals that secrete glutamate and facilitate the release of this transmitter.
Serotonin
Some are located on structures other than neurons, and some appear to be free in the interstitial fluid, that is, they are perisynaptic in location. The nomenclature of these receptors is not standardized, but the receptor indicated M1 in Table 7-2 is abundant in the brain.
Serotonergic Receptors
5-HT3 receptors are present in the gastrointestinal tract and zona postrema and are associated with vomiting. 5-HT4 receptors are also present in the gastrointestinal tract, where they facilitate secretion and peristalsis, as well as in the brain.
Histamine
5-HT6 and 5-HT7 receptors in the brain are distributed throughout the limbic system, and the 5-HT6 receptors have a high affinity for antidepressant drugs.
CLINICAL BOX 7–2
CATECHOLAMINES
Norepinephrine & Epinephrine
Biosynthesis & Release of Catecholamines
CLINICAL BOX 7–3
The half-life of circulating dopamine β-hydroxylase is much longer than that of catecholamines, and circulating levels of this substance are influenced by genetic and other factors in addition to the level of sympathetic activity.
Catabolism of Catecholamines
Dopamine
The mesocortical system projects to the nucleus accumbens and limbic subcortical areas, and it is involved in reward behavior and addiction. PET scanning studies in normal humans show that there is a steady loss of dopamine receptors in the basal ganglia with age.
Dopamine Receptors
EXCITATORY & INHIBITORY AMINO ACIDS
Glutamate
Glutamate Receptors
CLINICAL BOX 7-4
They appear to be involved in the production of synaptic plasticity, particularly in the hippocampus and the cerebellum. Kainate receptors are located presynaptically on GABA-secreting nerve endings and postsynaptically at various localized sites in the brain.
GABA
They are both presynaptic and postsynaptic, and they are widely distributed in the brain. The concentration of NMDA receptors in the hippocampus is high, and blocking these receptors prevents long-term potentiation, a long-lasting facilitation of transmission in neural pathways after a short period of high-frequency stimulation.
GABA Receptors
This background stimulation reduces the "noise" caused by the random firing of billions of nerve units and greatly improves the signal-to-noise ratio in the brain. Peripheral-type benzodiazepine receptors are also present on astrocytes in the brain, and they are found in brain tumors.
Glycine
An observation of considerable interest is that there is a chronic, low-level stimulation of GABAA receptors in the CNS, which is promoted by GABA in the interstitial fluid. Metabolites of the steroid hormones progesterone and deoxycorticosterone bind to GABAA receptors and increase Cl– conductance.
Anesthesia
LARGE-MOLECULE TRANSMITTERS
NEUROPEPTIDES
Substance P & Other Tachykinins
Opioid Peptides
They are found in the substantia gelatinosa and have an analgesic effect when injected into the brain stem. They differ in physiological effects (Table 7-5), distribution in the brain and elsewhere, and affinity for different opioid peptides.
Other Polypeptides
Enkephalins are found on nerve endings in the gastrointestinal tract and in many different parts of the brain, and they appear to function as synaptic transmitters. Gastrin, neurotensin, galanin, and gastrin-releasing peptides are also found in the gastrointestinal tract and brain.
OTHER CHEMICAL TRANSMITTERS Purine & Pyrimidine Transmitters
It is also present together with substance P in the branches of primary afferent neurons that terminate near blood vessels. Neuropeptide Y-containing neurons have their cell bodies in the arcuate nuclei and project into the paraventricular nuclei.
Cannabinoids
In rats, and presumably in humans, CGRPβ is present in the gastrointestinal tract, while CGRPβ is found in primary afferent neurons, gustatory neurons that project impulses to the thalamus, and neurons in the medial forebrain bundle. In the thyroid gland, splicing produces the mRNA encoding calcitonin, while alternative splicing in the brain produces the mRNA encoding CGRPα.
Gases
Vasopressin and oxytocin are not only secreted as hormones, but are also present in neurons projecting to the brainstem and spinal cord. Neuropeptide Y is a polypeptide containing 36 amino acid residues that acts on at least two of the four known G protein-coupled receptors: Y1, Y2, Y4, and Y5.
Other Substances
Properties of Sensory Receptors
SENSE RECEPTORS
CLASSIFICATION OF SENSORY RECEPTORS
The term chemoreceptor is used to denote receptors that are stimulated by a change in the chemical composition of the environment in which they are located. These include taste and smell receptors and visceral receptors such as those sensitive to changes in plasma O2 levels, pH and osmolality.
SENSE ORGANS
However, the conscious component of proprioception ("body image") is actually synthesized from information coming not only from receptors in and around the joints, but also from touch and pressure receptors in the skin. Photoreceptors are those in the rods and cones of the retina that respond to light.
GENERATION OF IMPULSES IN CUTANEOUS RECEPTORS
PACINIAN CORPUSCLES
GENERATOR POTENTIALS
SOURCE OF THE GENERATOR POTENTIAL
When the first node of Ranvier is blocked by pressure or drugs, the generator potential is unaffected, but conducted impulses are abolished (Figure 8-2). These and other experiments have established that the generator potential is produced in the unmyelinated nerve terminal.
SENSORY CODING
The receptor therefore converts mechanical energy into an electrical response, the magnitude of which is proportional to the intensity of the stimulus. If the generator potential is large enough, the neuron will fire again as soon as it repolarizes, and it will continue to fire as long as the generator potential is large enough to bring the node's membrane potential to the firing level.
MODALITY
When the sensory nerve is severed and the unmyelinated terminal degenerates, a generator potential is not formed. The node thus converts the gradual response of the receptor into action potentials, the frequency of which is proportional to the magnitude of the stimuli applied.
LOCATION
In the cornea and adjacent sclera of the eye, the surface area provided by a single sensory unit is 50-200 mm2. One of the main mechanisms that allow localization of a stimulus site is lateral inhibition.
INTENSITY
Information from sensory neurons whose receptors are located at the peripheral edge of the stimulus is inhibited compared to information from the sensory neurons in the center of the stimulus. Thus, lateral inhibition increases the contrast between the center and periphery of a stimulated area and increases the brain's ability to localize a sensory input.
DURATION
In general, the areas provided by one unit overlap and overlap with areas provided by others.
SENSORY INFORMATION
LAW OF SPECIFIC NERVE ENERGIES
CLINICAL BOX 8–1
Action potentials in an afferent fiber from a mechanoreceptor of a single sensory unit increase in frequency as branches of the afferent neuron are stimulated by pressures of increasing magnitude. The general principle of specific nerve energies remains one of the cornerstones of sensory physiology.
LAW OF PROJECTION
This principle, first proclaimed by Müller in 1835, was given the rather cumbersome name of the law of specific nervous energies. Likewise, if a fine enough electrode could be placed in the appropriate fibers of the dorsal columns of the spinal cord, the thalamus, or the postcentral gyrus of the cerebral cortex, the sensation produced by stimulation would be touch.
RECRUITMENT OF SENSORY UNITS
Thus, when the nerve pathways of a particular sense are stimulated, the sensation produced is that for which the receptor is specialized, regardless of how or where along the pathway the activity is initiated. For example, if the sensory nerve of a Pacinian body in the hand is stimulated by pressure at the elbow or by irritation of a tumor in the brachial plexus, the sensation evoked is touch.
NEUROLOGICAL EXAM
CLINICAL BOX 8–2
CLINICAL BOX 8–3
In which of the following cases is the pacing rate not lin- . early related to the strength of the sensation felt?. The sensation evoked by impulses generated in a receptor depends in part on the specific part of the brain they ultimately activate.
Reflexes
MONOSYNAPTIC REFLEXES
THE STRETCH REFLEX
STRUCTURE OF MUSCLE SPINDLES
CLINICAL BOX 9–1
CENTRAL CONNECTIONS OF AFFERENT FIBERS
FUNCTION OF MUSCLE SPINDLES
EFFECTS OF γ -MOTOR NEURON DISCHARGE
CONTROL OF γ -MOTOR NEURON DISCHARGE
RECIPROCAL INNERVATION
CLINICAL BOX 9–2
INVERSE STRETCH REFLEX
MUSCLE TONE
POLYSYNAPTIC REFLEXES
THE WITHDRAWAL REFLEX
WITHDRAWAL REFLEX
CLINICAL BOX 9–3
This is difficult to demonstrate in normal animals, but is easily demonstrated in an animal in which the modulatory effects of impulses from the brain have been abolished by the anterior section of the spinal cord (spinal cord). This propagation of excitatory impulses up and down the spinal cord to more and more motor neurons is called stimulus radiation, and the increase in the number of active motor units is called motor unit recruitment.
IMPORTANCE OF THE WITHDRAWAL REFLEX
Strong stimuli in laboratory animals generate activity in the interneuron pool that spreads to all four limbs. For example, when a cat's hindlimb is pinched, the stimulated limb is retracted, the opposite hindlimb is extended, the ipsilateral forelimb is extended, and the contralateral forelimb is flexed.
FRACTIONATION & OCCLUSION
GENERAL PROPERTIES OF REFLEXES
ADEQUATE STIMULUS
FINAL COMMON PATH
All these pathways converge and determine the activity in the final common pathways.
CENTRAL EXCITATORY
CENTRAL &
PERIPHERAL NEUROPHYSIOLOGY
Pain & Temperature
NOCICEPTORS &
THERMORECEPTORS
Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissue that determines the reactions. CMR1, VR1 and VRL1 are members of the transient receptor potential (TRP) family of excitatory ion channels.
CLASSIFICATION OF PAIN
Cold metal objects are cooler to the touch than wooden objects of the same temperature, because metal conducts heat away from the skin faster and thus cools the subcutaneous tissues more. However, due to the different properties of VR1 and VRL-1 receptors, it is likely that there are also many different C nociceptor fiber systems.
CLINICAL BOX 10–1
VR1 has a PIP2 binding site and when the amount of bound PIP2 decreases, the sensitivity of the receptors increases. Apart from the fact that activation of the cool receptor causes an influx of Ca2+, little is known about the ionic basis of the initial depolarization they produce.
DEEP PAIN
Figure 10-1 shows how chemicals released at the site of injury can further activate nociceptors leading to inflammatory pain. Prostaglandin E2 (a cyclooxygenase metabolite of arachidonic acid) is released from damaged cells and causes hyperalgesia.
VISCERAL PAIN
CLINICAL BOX 10–2
There are no proprioceptors in the viscera and few temperature and touch receptors. Their cell bodies are located in the dorsal roots and the homologous cranial nerve ganglia.
REFERRED PAIN
The receptors for pain and the other sensory modalities in the viscera are similar to those in the skin, but there are distinct differences in their distribution. The receptors in the walls of the hollow intestines are particularly sensitive to distension of these organs.
CLINICAL BOX 10–3
Specifically, there are visceral afferents in the facial, glossopharyngeal, and vagus nerves; in the thoracic and upper lumbar spinal roots; and in the sacral roots (Figure 10–2). Such distension can be experimentally created in the digestive tract by inflating a swallowed balloon attached to a tube.
Somatosensory Pathways
DORSAL HORN
DORSAL COLUMN PATHWAY
SOMATOTOPIC ORGANIZATION
Stimulation of different parts of the postcentral gyrus causes anticipated sensations in the appropriate parts of the body. The representation of body parts is not as complete or detailed as it is in the postcentral gyrus.
VENTROLATERAL
SII is located in the superior wall of the Sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The conscious awareness of the positions of the various body parts in space is partly dependent on impulses from senses in and around the joints.
SPINOTHALAMIC TRACT
Not only is there a detailed localization of the fibers from different parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportional to the use of that part. Research with microelectrodes indicates that many of the neurons in the sensory cortex respond to certain movements, and not just to touch or static position.
CORTICAL PLASTICITY
In contrast, the pathway involving synapses in the brainstem reticular formation and centrolateral thalamic nucleus projects to the frontal lobe, limbic system, and insula. In the central nervous system (CNS), visceral sensation travels along the same pathways as somatic sensation in the spinothalamic tracts and thalamic radiation, and the cortical receptive areas for visceral sensation are intermingled with the somatic receptive areas.
EFFECTS OF CNS LESIONS
This is the pathway responsible for the discriminative aspect of pain and is also called the neospinothalamic tract. This pathway mediates the motivational-affective component of pain and is called the paleospinothalamic tract.
CLINICAL BOX 11–1
The information carried in the lemnisal system is concerned with the detailed localization, spatial shape and temporal pattern of tactile stimuli. The information carried in the spinothalamic channels, on the other hand, is concerned with poorly localized, gross tactile sensations.
MODULATION OF PAIN TRANSMISSION
An increase in the touch threshold and a decrease in the number of touch points on the skin are also observed after disruption of the spinothalamic tract, but the touch deficit is mild and the localization of touch remains normal. Diseases of the dorsal columns produce ataxia due to disruption of proprioceptive input to the cerebellum.
STRESS-INDUCED ANALGESIA
A good part of the proprioceptive input goes to the cerebellum, but some passes through the medial lemniscus and thalamic radiations to the cortex.
MORPHINE & ENKEPHALINS
CLINICAL BOX 11–2
Acupuncture at the site of pain appears to work primarily in the same way as touching or vibrating (gate control mechanism).
ACETYLCHOLINE
These observations make it clear that a nicotinic cholinergic mechanism is involved in the regulation of pain, although its exact role has yet to be determined.
CANNABINOIDS
CLINICAL BOX 11–3
A 50-year-old woman undergoes a neurologic examination that shows loss of pain and temperature sensitivity, vibratory sensation, and proprioception in both feet. Baron R, Maier C: Phantom limb pain: Are cutaneous nociceptors and spinothalamic neurons involved in the signaling and maintenance of spontaneous and touch-evoked pain.
Vision
ANATOMIC CONSIDERATIONS
The space between the lens and the retina is mostly filled with a clear gelatinous material called the vitreous (vitreous humor). It is normally reabsorbed through a network of trabeculae in Schlemm's canal, a venous channel at the junction between the iris and the cornea (angle of the anterior chamber).
RETINA
Aqueous humor, a clear fluid that nourishes the cornea and lens, is produced in the ciliary body by diffusion and active transport from plasma.
CLINICAL BOX 12–1
The arteries, arterioles and veins in the superficial layers of the retina near its vitreous surface can be seen through the ophthalmoscope. Because it is the one place in the body where arterioles are readily visible, ophthalmoscopic examination is of great value in the diagnosis and evaluation of diabetes mellitus, hypertension, and other diseases affecting blood vessels.
NEURAL PATHWAYS
When attention is drawn or focused on an object, the eyes usually move so that light rays coming from the object fall on the fovea. Retinal vessels are supplied by bipolar and ganglion cells, but the receptors are mainly fed from the capillary plexus in the choroid.
CLINICAL BOX 12–2
Cone regeneration is a more diffuse process and appears to occur at multiple locations in the outer segments. In the extrafoveal parts of the retina, rods predominate (Figure 12-7), and there is a good deal of convergence.
PROTECTION
There are twice as many fibers in the geniculocarcinal tracts as in the optic nerves, and in the visual cortex the number of neurons responsible for vision is 1000 times greater than the number of fibers in the optic nerves. One of the most important features of the vision system is its ability to operate in a wide range of light intensities.
THE IMAGE-FORMING MECHANISM
Another factor in responding to fluctuations in intensity is the presence of two types of receptors. Thus, there are two kinds of input to the central nervous system (CNS) from the eye: input from the rods and input from the cones.
PRINCIPLES OF OPTICS
The main focus is on a line passing through the center of curvature of the lens, the principal axis. The refractive power of a lens is usually measured in diopters, where the number of diopters is the reciprocal of the main focal length in meters.
COMMON DEFECTS OF THE IMAGE-FORMING MECHANISM
In the eye, light actually refracts at the front surface of the cornea and at the front and back surfaces of the lens. The connections of the retinal receptors are such that from birth every inverted image on the retina is viewed right up and projected into the visual field on the side opposite the stimulated area of the retina.
