Spinal Control of Movement PDF

CHAPTER THIRTEEN Spinal Control of Movement INTRODUCTION THE SOMATIC MOTOR SYST...

CHAPTER THIRTEEN Spinal Control of Movement INTRODUCTION THE SOMATIC MOTOR SYSTEM THE LOWER MOTOR NEURON The Segmental Organization of Lower Motor Neurons Alpha Motor Neurons Graded Control of Muscle Contraction by Alpha Motor Neurons Inputs to Alpha Motor Neurons Types of Motor Units Neuromuscular Matchmaking BOX 13.1 OF SPECIAL INTEREST: ALS: Glutamate, Genes, and Gehrig EXCITATION–CONTRACTION COUPLING BOX 13.2 OF SPECIAL INTEREST: Myasthenia Gravis Muscle Fiber Structure The Molecular Basis of Muscle Contraction BOX 13.3 OF SPECIAL INTEREST: Duchenne Muscular Dystrophy Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. SPINAL CONTROL OF MOTOR UNITS Proprioception from Muscle Spindles The Stretch Reflex BOX 13.4 PATH OF DISCOVERY: Nerve Regeneration Does Not Ensure Full Recovery, by Timothy C. Cope Gamma Motor Neurons Proprioception from Golgi Tendon Organs Proprioception from the Joints Spinal Interneurons Inhibitory Input Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  Excitatory Input The Generation of Spinal Motor Programs for Walking CONCLUDING REMARKS Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  INTRODUCTION We are now ready to turn our attention to the system that actually gives rise to behavior. The motor system consists of all our muscles and the neurons that control them. The importance of the motor system was summarized by the pioneering English neurophysiologist Charles Sherrington in the Linacre lecture of 1924: “To move things is all that mankind can do... for such the sole executant is muscle, whether in whispering a syllable or in felling a forest.” A moment’s thought will convince you that the motor system is also incredibly complex. Behavior requires the coordinated action of various combinations of almost 700 muscles in a changing and often unpredictable environment. Have you heard the expression “running around like a chicken with its head cut off”? It comes from the observation that some complex patterns of behavior (running around a barnyard, at least briefly) can be generated without the participation of the brain. There is a considerable amount of circuitry within the spinal cord for the coordinated control of movements, particularly stereotyped (repetitive) ones such as those associated with locomotion. This point was established early in this century by Sherrington and his English contemporary Thomas Graham Brown, who showed that rhythmic movements could be elicited in the hind legs of cats and dogs long after their spinal cords had been severed from the rest of the central nervous system. Today’s view is that the spinal cord contains certain motor programs for the generation of coordinated movements, and that these programs are accessed, executed, and modified by descending commands from the brain. Thus, motor control can be divided into two parts: (1) the spinal cord’s command and control of coordinated muscle contraction, and (2) the brain’s command and control of the motor programs in the spinal cord. In this chapter, we will explore the peripheral somatic motor system: the joints, skeletal muscles, and spinal motor neurons and interneurons, and how they communicate with each other. In Chapter 14, we will take a look at how the brain influences the activity of the spinal cord. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  THE SOMATIC MOTOR SYSTEM Based on their appearance under the microscope, the muscles in the body can be described according to two broad categories: striated and smooth. But they are also distinct in other ways. Smooth muscle lines the digestive tract, arteries, and related structures and is innervated by nerve fibers from the autonomic nervous system (see Chapter 15). Smooth muscle plays a role in peristalsis (the movement of material through the intestines) and the control of blood pressure and blood flow. There are two types of striated muscle: cardiac and skeletal. Cardiac muscle is heart muscle, which contracts rhythmically even in the absence of any innervation. Innervation of the heart from the autonomic nervous system (ANS) functions to accelerate or slow down the heart rate. (Recall Otto Loewi’s experiment in Chapter 5.) Skeletal muscle constitutes the bulk of the muscle mass of the body and functions to move bones around joints, to move the eyes within the head, to inhale and exhale, to control facial expression, and to produce speech. Each skeletal muscle is enclosed in a connective tissue sheath that, at the ends of the muscle, forms the tendons. Within each muscle are hundreds of muscle fibers, the cells of skeletal muscle, and each fiber is innervated by a single axon branch from the central nervous system (CNS) (Figure 13.1). Because skeletal muscle is derived embryologically from 33 paired somites (see Chapter 7), these muscles and the parts of the nervous system that control them are collectively called the somatic motor system. We focus our attention on this system here because it is under voluntary control and it generates behavior. (The visceral motor system of the ANS will be discussed in Chapter 15.) Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.1 The structure of skeletal muscle. Each muscle fiber is innervated by a single axon. Consider the elbow joint (Figure 13.2). This joint is formed where the humerus, the upper arm bone, is bound by fibrous ligaments to the radius and ulna, the bones of the lower arm. The joint functions like a hinge on a pocket knife. Movement in the Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. direction that closes the knife is called flexion, and movement in the direction that opens the knife is called extension. Note that muscles only pull on a joint; they cannot push. The major muscle that causes flexion is the brachialis, whose tendons insert into the humerus at one end and into the ulna at the other. Two other muscles cause flexion at this joint, the biceps brachii and the coracobrachialis (which lies under the biceps). Together, these muscles are called flexors of the elbow joint, and, because the three muscles all work together, they are called synergists of one another. The two synergistic muscles that cause extension of the elbow joint are the triceps brachii and the anconeus; these two muscles are called extensors. Because the flexors and extensors pull on the joint in opposite directions, they are called Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  antagonists to one another. The relationships between these muscles and bones, and the forces and movements they generate, are shown schematically in Figure 13.3. Even the simple flexion of the elbow joint requires the coordinated contraction of the synergistic flexor muscles and the relaxation of the antagonistic extensor muscles. Relaxing the antagonists allows movements to be faster and more efficient because the muscles are not working against one another. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.2 Major muscles of the elbow joint. The biceps and triceps are antagonistic muscles. Contraction of the biceps causes flexion of the elbow, and contraction of the triceps causes extension. Description Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.3 How contracting muscles flex or extend a joint. Contractions of the flexors pull the right end of the bone upward (flexion). Contraction of the extensor pulls the left end of the bone upward, causing the right end to pivot downward (extension). Flexor #1 and flexor #2 are synergists. Flexors #1 and #2 are antagonist Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. muscles of the extensor. Other terms to note about somatic musculature refer to the location of the joints they act on. The muscles that are responsible for movements of the trunk are called axial muscles; those that move the shoulder, elbow, pelvis, and knee are called proximal (or girdle) muscles; and those that move the hands, feet, and digits (fingers and toes) are called distal muscles. The axial musculature is very important for maintaining posture, the proximal musculature is critical for locomotion, and the distal musculature, particularly of the hands, is specialized for the manipulation of objects. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  THE LOWER MOTOR NEURON The somatic musculature is innervated by the somatic motor neurons in the ventral horn of the spinal cord (Figure 13.4). These cells are sometimes called lower motor neurons to distinguish them from the higher order upper motor neurons of the brain that supply input to the spinal cord. Remember, only the lower motor neurons directly command muscle contraction. Sherrington called these neurons the final common pathway for the control of behavior. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.4 Muscle innervation by lower motor neurons. The ventral horn of the spinal cord contains motor neurons that innervate skeletal muscle fibers. Description Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  The Segmental Organization of Lower Motor Neurons The axons of lower motor neurons bundle together to form ventral roots; each ventral root joins with a dorsal root to form a spinal nerve that exits the cord through the notches between vertebrae. Recall from Chapter 12 that there are as many spinal nerves as there are notches between vertebrae; in humans, this adds up to 30 on each side. Because they contain sensory and motor fibers, they are called mixed spinal nerves. The motor neurons that provide fibers to one spinal nerve are said to belong to a spinal segment, named for the vertebra where the nerve originates. The segments are cervical (C) 1–8, thoracic (T) 1–12, lumbar (L) 1–5, and sacral (S) 1–5 (see Figure 12.11). Skeletal muscles are not distributed evenly throughout the body, nor are lower motor neurons distributed evenly within the spinal cord. For example, innervation of the more than 50 muscles of the arm originates entirely from spinal segments C3–Tl. Thus, in this region of the spinal cord, the dorsal and ventral horns appear swollen to accommodate the large number of spinal interneurons and motor neurons that control the arm musculature (Figure 13.5). Similarly, spinal segments Ll–S3 have swollen dorsal and ventral horns because this is where the neurons controlling the leg musculature reside. Thus, we can see that the motor neurons that innervate distal and proximal musculature are found mainly in the cervical and lumbar–sacral segments of the spinal cord, whereas those innervating axial musculature are found at all levels. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.5 The distribution of motor neurons in the spinal cord. The cervical enlargement of the spinal cord contains the motor neurons that innervate the arm muscles. The lumbar enlargement contains the neurons that innervate the muscles of the leg. Description Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  The lower motor neurons are also distributed within the ventral horn at each spinal segment in a predictable way, depending on their function. The cells innervating the axial muscles are medial to those innervating the distal muscles, and the cells innervating flexors are dorsal to those innervating extensors (Figure 13.6). Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.6 The distribution of lower motor neurons in the ventral horn. Motor neurons controlling flexors lie dorsal to those controlling extensors. Motor neurons controlling axial muscles lie medial to those controlling distal muscles. Description Alpha Motor Neurons There are two categories of lower motor neurons of the spinal cord: alpha motor neurons and gamma motor neurons (the latter are discussed later in the chapter). Alpha motor neurons directly trigger the generation of force by muscles. One alpha motor neuron and all the muscle fibers it innervates collectively make up the elementary component of motor control; Sherrington called it the motor unit. Muscle contraction results from the individual and combined actions of motor units. The collection of alpha motor neurons that innervates a single muscle (e.g., the biceps brachii) is called a motor neuron pool (Figure 13.7). Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.7 A motor unit and motor neuron pool. (a) A motor unit is an alpha motor neuron and all the muscle fibers it innervates. (b) A motor neuron pool is all the alpha motor neurons that innervate one muscle. Description Graded Control of Muscle Contraction by Alpha Motor Neurons. It is important to exert just the right amount of force during movements: Too much, and you’ll crush the egg you just picked up, while also wasting metabolic energy. Too little, and you may lose the swim race. Most of the movements we make, such as walking, talking, and writing, require only weak muscle contractions. Now and then we need to jog, hop, or lift a pile of books, and stronger contractions are necessary. We reserve the maximal contraction force of our muscles for rare events, such as competitive sprinting or scrambling up a tree to escape a charging bear. The nervous system uses several mechanisms to control the force of muscle contraction in a finely graded fashion. The first way the CNS controls muscle contraction is by varying the firing rate of motor neurons. An alpha motor neuron communicates with a muscle fiber by releasing the neurotransmitter acetylcholine (ACh) at the neuromuscular junction, the specialized synapse between a nerve and a skeletal muscle (see Chapter 5). Because of the high reliability of neuromuscular transmission, the ACh released in response to one presynaptic action potential causes an excitatory postsynaptic potential (EPSP) in the muscle fiber (sometimes also called an end-plate potential) large enough to trigger one postsynaptic action potential. By mechanisms we will discuss in a moment, a postsynaptic action potential causes a twitch—a rapid sequence of contraction and relaxation—in the muscle fiber. A sustained contraction requires a continual barrage of action potentials. High-frequency presynaptic activity causes temporal summation of the postsynaptic responses, as it does for other types of synaptic transmission. Twitch summation increases the tension in the muscle fibers and smoothes the contraction (Figure 13.8). The rate of firing of motor units is therefore one important way the CNS grades muscle contraction. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.8 From muscle twitch to sustained contraction. (a) A single action potential in an alpha motor neuron causes the muscle fiber to twitch. (b) The summation of twitches causes a sustained contraction as the number and frequency of incoming action potentials increase. Description A second way the CNS grades muscle contraction is by recruiting additional synergistic motor units. The extra tension provided by the recruitment of an active motor unit depends on how many muscle fibers are in that unit. In the antigravity muscles of the leg (muscles that oppose the force of gravity when standing upright), each motor unit tends to be quite large, with an innervation ratio of over 1000 muscle fibers per single alpha motor neuron. In contrast, the smaller muscles that control the movement of the fingers and the rotation of the eyes are characterized by much smaller innervation ratios, as few as three muscle fibers per alpha motor neuron. In general, muscles with a large number of small motor units can be more finely controlled by the CNS. Most muscles have a range of motor unit sizes, and these motor units are usually recruited in the order of smallest first, largest last. This orderly recruitment explains why finer control is possible when muscles are under light loads than when they are under greater loads. Small motor units have small alpha motor neurons, and large motor units have large alpha motor neurons. Thus, one way orderly recruitment occurs is that small neurons, as a consequence of the geometry and physiology of their soma and dendrites, are more easily excited by signals descending from the brain. The idea that the orderly recruitment of motor neurons is due to variations in alpha motor neuron size is called the size principle, first proposed in the late 1950s by Harvard University neurophysiologist Elwood Henneman. Inputs to Alpha Motor Neurons. Alpha motor neurons excite skeletal muscles. Therefore, to understand the control of muscles, we must understand what regulates motor neurons. Lower motor neurons are controlled by synaptic inputs in the ventral horn. There are only three major sources of input to an alpha motor neuron, as Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. shown in Figure 13.9. The first source is dorsal root ganglion cells with axons that innervate a specialized sensory apparatus embedded within the muscle known as a muscle spindle. As we shall see, this input provides feedback about muscle length. The second source of input to an alpha motor neuron derives from upper motor neurons in the motor cortex and brain stem. This input is important for the initiation and control of voluntary movement and will be discussed in more detail in Chapter 14. The third and largest input to an alpha motor neuron derives from interneurons in the spinal cord. This input may be excitatory or inhibitory and is part of the circuitry that generates the spinal motor programs. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.9 An alpha motor neuron and its three sources of input. Description Types of Motor Units Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. If you have ever eaten different parts of chicken, you know that not all muscle is the same; the leg has dark meat and the breast and wing have white meat. The different appearance, and taste, of the various muscles are due to the biochemistry of the constituent muscle fibers. The red (dark) muscle fibers are characterized by a large number of mitochondria and enzymes specialized for oxidative energy metabolism. These, sometimes called slow (S) fibers, are relatively slow to contract but can sustain contraction for a long time without fatigue. They are typically found in the antigravity muscles of the leg and torso and in the flight muscles of birds that fly (as opposed to domesticated chickens). In contrast, the pale (white) muscle fibers contain fewer mitochondria and rely mainly on anaerobic (without oxygen) metabolism. These fibers, sometimes called fast (F) fibers, contract rapidly and Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  powerfully, but they also fatigue more quickly than slow fibers. They are typical of muscles involved in escape reflexes; for example, the jumping muscles of frogs and rabbits. In humans, the arm muscles contain a large number of white fibers. Fast fibers can be further divided into two subtypes: Fatigue-resistant (FR) fibers generate moderately strong and fast contractions and are relatively resistant to fatigue; fast fatigable (FF) fibers generate the strongest, fastest contractions but are quickly exhausted when stimulated at high frequency for long periods. Even though all three types of muscle fibers can (and usually do) coexist in a given muscle, each motor unit contains muscle fibers of only a single type. Thus, there is one type of slow motor unit that contains only slowly fatiguing red fibers, and there are two types of fast motor units, each containing either FR or FF white fibers (Figure 13.10). Just as the muscle fibers of the three types of units differ, so do many of the properties of alpha motor neurons. For example, the motor neurons of the FF units are generally the biggest and have the largest diameter, fastest conducting axons; FR units have motor neurons and axons intermediate in size; and slow units have small-diameter, slowly conducting axons. The firing properties of the three types of motor neuron also differ. Fast (FF) motor neurons tend to generate occasional high-frequency bursts of action potentials (30–60 impulses per second), whereas slow motor neurons are characterized by relatively steady, low-frequency activity (10–20 impulses per second). Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.10 Three types of motor units and their contractile properties. (a) A single action potential triggers contraction strengths of different force and time-course in each of the three types of motor units. (b) Repeated trains of action potentials at 40 Hz over many minutes lead to different rates of fatigue in the three types of motor units. (Source: Adapted from Burke et al., 1973.) Description Neuromuscular Matchmaking. The precise matching of particular motor neurons to particular muscle fibers raises an interesting question. Since we’ve been talking about chickens, let’s pose the question this way: Which came first, the muscle fiber or the motor neuron? Perhaps during early embryonic development, there is a Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  matching of the appropriate axons with the appropriate muscle fibers. Alternatively, we could imagine that the properties of the muscle are determined solely by the type of innervation it gets. If it receives a synaptic contact from a fast motor neuron, it becomes a fast fiber and vice versa for slow units. John Eccles and his colleagues, working at the Australian National University, addressed this question with an experiment in which the normal innervation of a fast muscle was removed and replaced with a nerve that normally innervated a slow muscle (Figure 13.11). This procedure resulted in the muscle’s acquiring slow properties, including not only the type of contraction (slow, fatigue-resistant) but also a switch in much of its underlying biochemistry. This change is referred to as a switch of muscle phenotype—its physical characteristics—because the types of proteins expressed by the muscle were altered by the new innervation. Work by Terje Lømo and his colleagues in Norway suggests that this switch in muscle phenotype can be induced simply by changing the activity in the motor neuron from a fast pattern (occasional bursts at 30–60 spikes per second) to a slow pattern (steady activity at 10–20 spikes per second). These findings are particularly interesting because they raise the possibility that neurons switch phenotype as a consequence of synaptic activity (experience), and that this may be a basis for learning and memory (see Chapters 24 and 25). Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.11 A crossed-innervation experiment. Forcing slow motor neurons to innervate a fast muscle causes the muscle to switch to assume slow properties. Description Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  Besides the alterations imposed by patterns of motor neuron activity, simply varying the absolute amount of activity can also change muscle fibers. A long-term consequence of increased activity (especially due to isometric exercise) is hypertrophy, or exaggerated growth, of the muscle fibers as seen in bodybuilders. Conversely, prolonged inactivity leads to atrophy, or degeneration, of muscle fibers, which can happen when joints are immobilized in a cast following an injury. Clearly, there is an intimate relationship between the lower motor neuron and the muscle fibers it innervates (Box 13.1). BOX 13.1 OF SPECIAL INTEREST ALS: Glutamate, Genes, and Gehrig Amyotrophic lateral sclerosis (ALS) is a particularly cruel disease that was first described in 1869 by the French neurologist Jean-Martin Charcot. The initial signs of the disease are muscle weakness and atrophy. Usually over the course of 1–5 years, all voluntary movement is lost; walking, speaking, swallowing, and breathing gradually deteriorate. Death is usually caused by failure of the respiratory muscles. Because the disease often has no effect on sensations, intellect, or cognitive function, patients are left to watch their bodies slowly waste away, keenly aware of what is happening. The disease is relatively rare, afflicting one out of approximately every 20,000 individuals. Still, an estimated 30,000 Americans are currently diagnosed with ALS. Its most famous victim was Lou Gehrig, a star baseball player with the New York Yankees, who died of ALS in 1936. In the United States, ALS is often called Lou Gehrig’s disease. Muscle weakness and paralysis are characteristics of motor unit damage. Indeed, the main pathology associated with ALS is the degeneration of the large alpha motor neurons. The large neurons of the motor cortex that innervate alpha motor neurons are also affected, but, curiously, other neurons in the CNS are generally spared. The selective damage to motor neurons explains the selective loss of motor functions in ALS patients. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. There appear to be many causes of ALS, most of them still unknown. One suspected cause is excitotoxicity. As we learned in Chapter 6, overstimulation by the excitatory neurotransmitter glutamate and closely related amino acids can cause the death of otherwise normal neurons (see Box 6.4). Many ALS patients have elevated levels of glutamate in their cerebrospinal fluid. Excitotoxicity has been implicated in the unusually high incidence of ALS on the island of Guam that occurred before World War II. It has been suggested that one environmental cause in Guam may have been the ingestion of cycad nuts, which contain an excitotoxic amino acid. In addition, research indicates that a glutamate transporter may be defective in ALS, thereby prolonging the exposure of active neurons to extracellular glutamate. Thus, the first drug approved by the U.S. Food and Drug Administration for the treatment of ALS was riluzole, a blocker of glutamate release. The drug treatment can slow the disease by only a few months, however, and unfortunately, the long-term outcome is the same. Only 10% of ALS cases are obviously inherited, and screens for defective genes have pointed to several mutations that can lead to ALS. The first mutation, discovered in 1993, leads to defects in the enzyme superoxide dismutase. A toxic by-product of cellular metabolism is the negatively charged Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  molecule O2–, called the superoxide radical. Superoxide radicals are extremely reactive and can inflict irreversible cellular damage. Superoxide dismutase is a key enzyme that causes superoxide radicals to lose their extra electrons, converting them back to oxygen. Thus, the loss of superoxide dismutase would lead to a buildup of superoxide radicals and cellular damage, particularly in cells that are metabolically very active. The death of motor neurons seems to depend on the actions of glial cells that surround them. More recent research has identified mutations of about 15 more genes that can cause inherited forms of ALS. They affect a surprisingly wide variety of basic cellular processes. Some mutations cause defects in proteins that normally bind and regulate RNA during transcription. Others affect proteins involved in the trafficking of vesicles, protein secretion, cell division, ATP production, or the dynamics of the cytoskeleton. Genome-wide association studies, which examine a large number of gene variations to reveal which are associated with a disease, suggest that the coincidence of two mutations of distinctly different genes can also cause ALS. The picture that is emerging is that ALS can have many distinct causes; it is really a group of diseases that happen to share similar clinical characteristics. There is still much to be learned about selective motor neuron loss in ALS. What we know so far has led to new ideas for possible treatments, including the use of neuronal stem cells to replace lost neurons and glia, and genetics-based strategies to suppress the effects of mutations. Translating these ideas into effective treatments for ALS patients is an exciting but still distant possibility. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  EXCITATION–CONTRACTION COUPLING Muscle contraction is initiated by the release of acetylcholine (ACh) from the axon terminals of alpha motor neurons, as we said. ACh produces a large EPSP in the postsynaptic membrane due to the activation of nicotinic ACh receptors. Because the membrane of the muscle cell contains voltage-gated sodium channels, this EPSP is sufficient to evoke an action potential in the muscle fiber (but see Box 13.2). By the process of excitation–contraction coupling, this action potential (the excitation) triggers the release of Ca2+ from an organelle inside the muscle fiber, which leads to contraction of the fiber. Relaxation occurs when the Ca2+ levels are lowered by reuptake into the organelle. To understand this process, we must take a closer look at the muscle fiber. BOX 13.2 OF SPECIAL INTEREST Myasthenia Gravis The neuromuscular junction is an exceptionally reliable synapse. A presynaptic action potential causes the contents of hundreds of synaptic vesicles to be released into the synaptic cleft. The liberated ACh molecules act at densely packed nicotinic receptors in the postsynaptic membrane, and the resulting EPSP is many times larger than what is necessary to trigger an action potential, and twitch, in the muscle fiber—normally, that is. In a clinical condition called myasthenia gravis, the ACh released is far less effective, and neuromuscular transmission often fails. The name is derived from the Greek for “severe muscle weakness.” The disorder is characterized by weakness and fatigability of voluntary muscles, typically including the muscles of facial expression, and it can be fatal if respiration is compromised. The disease Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. strikes roughly one in 10,000 people of all ages and ethnic groups. An unusual feature of myasthenia gravis is that the severity of the muscle weakness fluctuates, even over the course of a single day. Myasthenia gravis is an autoimmune disease. In 1973, Jim Patrick and Jon Lindstrom, working at the Salk Institute in California, discovered that rabbits injected with purified nicotinic ACh receptors generated antibodies to their own ACh receptors and contracted a rabbit version of myasthenia gravis. For reasons we don’t understand, the immune systems of most myasthenia-afflicted humans generate antibodies against their own nicotinic ACh receptors. The antibodies bind to the receptors, interfering with the normal actions of ACh at the neuromuscular junctions. In addition, the binding of antibodies to the receptors leads to secondary, degenerative changes in the structure of the neuromuscular junctions that also make transmission much less efficient. An effective treatment for myasthenia gravis is the administration of drugs that inhibit the enzyme acetylcholinesterase (AChE). Recall from Chapters 5 and 6 that AChE breaks down ACh in the synaptic cleft. In low doses, AChE inhibitors can strengthen neuromuscular transmission by prolonging the life of released ACh. But the drugs are imperfect and the therapeutic window is narrow. As we saw in Box 5.5, too much ACh in the cleft leads to desensitization of the receptors and a block of neuromuscular Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  transmission. Different muscles may respond differently to the same drug dose. The increased levels of ACh can also affect the ANS, leading to side effects such as nausea, vomiting, abdominal cramps, diarrhea, and bronchial secretions. Another common treatment for myasthenia gravis involves suppression of the immune system, either with drugs or by surgical removal of the thymus gland. With careful and continual medical treatment, the long-term prognosis is good and life expectancy is normal for patients with this disease of the neuromuscular junction. Muscle Fiber Structure The structure of a muscle fiber is shown in Figure 13.12. Muscle fibers are formed early in fetal development by the fusion of muscle precursor cells, or myoblasts, which are derived from the mesoderm (see Chapter 7). This fusion leaves each cell with more than one cell nucleus, so individual muscle cells are said to be multinucleated. The fusion elongates the cells (hence the name fiber), and fibers can range from 1 to 500 mm in length. Muscle fibers are enclosed by an excitable cell membrane called the sarcolemma. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.12 The structure of a muscle fiber. T tubules conduct electrical activity from the surface membrane into the depths of the muscle fiber. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  Description Within the muscle fiber are a number of cylindrical structures called myofibrils, which contract in response to an action potential sweeping down the sarcolemma. Myofibrils are surrounded by the sarcoplasmic reticulum (SR), an extensive intracellular sac that stores Ca2+ (similar in appearance to the smooth endoplasmic reticulum of neurons; see Chapter 2). Action potentials sweeping along the sarcolemma gain access to the sarcoplasmic reticulum deep inside the fiber by way of a network of tunnels called T tubules (T for transverse). These are like inside-out axons; the interior of each T tubule is continuous with the extracellular fluid. Where the T tubule comes in close apposition to the SR, there is a specialized coupling of the proteins in the two membranes. A voltage-sensitive cluster of four calcium channels, called a tetrad, in the T tubule membrane is linked to a calcium release channel in the SR. As illustrated in Figure 13.13, the arrival of an action potential in the T tubule membrane causes a conformational change in the voltage- sensitive tetrad of channels, which opens the calcium release channel in the SR membrane. Some Ca2+ flows through the tetrad channels, and even more Ca2+ flows through the calcium-release channel, and the resulting increase in free Ca2+ within the cytosol causes the myofibril to contract. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.13 The release of Ca2+ from the sarcoplasmic reticulum. Depolarization of the T tubule membrane causes conformational changes in proteins that are linked to calcium channels in the SR, releasing stored Ca2+ into the cytosol of the muscle fiber. Description The Molecular Basis of Muscle Contraction A closer look at the myofibril reveals how Ca2+ triggers contraction (Figure 13.14). The myofibril is divided into segments by disks called Z lines (named for their appearance when viewed from the side). A segment composed of two Z lines and the myofibril in between is called a sarcomere. Anchored to each side of the Z lines is a series of bristles called thin filaments. The thin filaments from adjacent Z lines face one another but do not come in contact. Between and among the two sets of thin filaments are a series of fibers called thick filaments. Muscle contraction occurs when the thin filaments slide along the thick filaments, bringing adjacent Z lines toward one another. In other words, the sarcomere becomes shorter in length. This sliding-filament model of sarcomere shortening is shown in Figure 13.15. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.14 The myofibril: a closer look. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  FIGURE 13.15 The sliding-filament model of muscle contraction. Myofibrils shorten when the thin filaments slide toward one another on the thick filaments. Description The sliding of the filaments with respect to one another occurs because of the interaction between the major thick filament protein, myosin, and the major thin filament protein, actin. The exposed “heads” of the myosin molecules bind actin molecules and then undergo a conformational change that causes them to pivot (Figure 13.16). This pivoting causes the thick filament to move with respect to the thin filament. Adenosine triphosphate (ATP) then binds to the myosin heads and the heads disengage and “uncock” so that the process can repeat itself. Repeating this cycle enables the myosin heads to “walk” along the actin filament. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. FIGURE 13.16 The molecular basis of muscle contraction. The binding of Ca2+ to troponin shifts tropomyosin and allows the myosin heads to bind to the actin filament. Then the myosin heads pivot, causing the filaments to slide with respect to one another. Description When the muscle is at rest, myosin cannot interact with actin because the myosin attachment sites on the actin molecule are covered by a complex of two proteins: Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  tropomyosin and troponin. Ca2+ initiates muscle contraction by binding to troponin and causing tropomyosin to shift its position, thereby exposing the sites where myosin binds to actin. Contraction continues as long as Ca2+ and ATP are available; relaxation occurs when the Ca2+ is sequestered by the SR. The reuptake of Ca2+ by the SR depends on the action of a calcium pump and hence also requires ATP. We can summarize the steps of excitation–contraction coupling as follows: Excitation 1. An action potential occurs in an alpha motor neuron axon. 2. ACh is released by the axon terminal of the alpha motor neuron at the neuromuscular junction. 3. Nicotinic receptor channels in the sarcolemma open, and the postsynaptic sarcolemma depolarizes (EPSP). 4. Voltage-gated sodium channels in the sarcolemma open and an action potential is generated in the muscle fiber, which sweeps down the sarcolemma and into the T tubules. 5. Depolarization of the T tubules causes Ca2+ release from the SR. Contraction 1. Ca2+ binds to troponin. 2. Tropomyosin shifts position and myosin binding sites on actin are exposed. 3. Myosin heads bind actin. 4. Myosin heads pivot. 5. An ATP binds to each myosin head and it disengages from actin. 6. The cycle continues as long as Ca2+ and ATP are present. Relaxation 1. As EPSPs end, the sarcolemma and T tubules return to their resting potentials. 2. Ca2+ is sequestered by the SR by an ATP-driven pump. Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. 3. Myosin binding sites on actin are covered by tropomyosin. You can now understand why death causes stiffening of the muscles, a condition known as rigor mortis. Starving the muscle cells of ATP prevents the detachment of the myosin heads and leaves the myosin attachment sites on the actin filaments exposed for binding. The end result is the formation of permanent attachments between the thick and thin filaments. Since the proposal of the sliding-filament model in 1954 by English physiologists Hugh Huxley, Andrew Huxley, and their colleagues, there has been a tremendous amount of progress in identifying the detailed molecular mechanisms of excitation– contraction coupling in muscle. This progress has resulted from a multidisciplinary Bear, Mark, et al. Neuroscience: Exploring the Brain, Enhanced Edition : Exploring the Brain, Enhanced Edition, Jones & Bartlett Learning, LLC, 2020. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/berkeley-ebooks/detail.action?docID=6175387. Created from berkeley-ebooks on 2024-09-09 09:34:35.  approach to the problem, with critical contributions made by the use of electron microscopy as well as biochemical, biophysical, and genetic methods. The application of molecular genetic techniques also has added important new information to our understanding of muscle function, in both health and disease (Box 13.3). BOX 13.3 OF SPECIAL INTEREST Duchenne Muscular Dystrophy Muscular dystrophy is a group of inherited disorders, all of which are characterized by progressive weakness and deterioration of muscle. The most common type, Duchenne muscular dystrophy, afflicts about one in 3500 boys before adolescence. The disease is first detected as a weakness of the legs and usually puts its victims in wheelchairs by the time they reach age 12. The disease continues to progress, and afflicted males typically do not survive past the age of 30. The characteristic hereditary pattern of this disease, which afflicts only males but is passed on from their mothers, led to a search for a defective gene on the X chromosome. Major breakthroughs came in the late 1980s when the defective region of the X chromosome was identified. Researchers discovered that this region contains the gene that codes for a cytoskeletal protein dystrophin. The dystrophin gene is enormous—2.6 million base pairs—and its size makes it unusually vulnerable to mutations. Boys with Duchenne muscular dystrophy have an entirely dysfunctional dystrophin gene: They cannot produce the mRNA encoding dystrophin. A milder form of the disease, called Becker muscular dystrophy, is associated with an altered mRNA encoding a portion of the dystrophin protein. Dystrophin is a large protein that helps to link the muscle cytoskeleton, lying just under the sarcolemma, to the extracellular matrix. The protein also seems to be important for helping muscle deal with oxidative stress. Dystrophin must not be strictly required for muscle contraction because movements in afflicted boys appear to be normal during their first few years of life. The absence of dystrophin may lead to secondary changes in the contractile apparatus, eventually resulting in muscle degeneration. It is interesting to note that dystrophin is also concentrated in axon terminals in the brain, where it might Copyright © 2020. Jones & Bartlett Learning, LLC. All rights reserved. contribute to excitation-secretion coupling. Intensive efforts are underway to find a strategy for treating, or even curing, Duchenne muscular dystrophy with some form of gene therapy. One long-standing idea is to introduce an artificial gene that essentially repairs the patient’s defective dystrophin gene or mimics a normal dystrophin gene. A big challenge, as with most attempts at gene therapy, has been to get the artificial gene into dystrophic muscle cells safely and effectively. Specially engineered forms of viruses that carry the gene, infect muscle cells, and induce the cells to express dystrophin are often used. Another approach is to transplant stem cells—immature cells that can grow and differentiate into mature, normal muscle cells that express dystrophin—into dystrophic muscles. Stem cell therapy has been very promising when tested in mouse models of muscula