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UNIT IV APPLIED NEUROBIOLOGY Sensory Reception Animals respond to the messages they receive from the world around them. Their reactions to the outside world depend on how the data collected from their surroundings are correctly coded into signals that can be received and processed by neurons in the brain. The sensory organs provide the only means of communication from the environment to the nervous system. Sensations arise when signals detected by sensory receptor cells are transmitted through the nervous system to the designated part of the brain. Various organs and cells are designated to receive specific stimuli. The major categories of sensory reception addressed here are chemoreception, mechanoreception, and photoreception. What are the general properties of sensory reception and how are these messages transmitted to the central nervous system? Animals require a constant detection of information from their surroundings. Such information is the animal’s link to the outside world. Sensory input is initially detected by sensory receptors. Some receptors are very complex, with many individual receptors along with other structures being organized into sensory organs such as the vertebrate eye. Sensory receptors are transducers; they convert stimuli into electric signals. In most cases, they do not directly generate action potentials. Instead, sensory receptors generate receptor potentials, which vary in intensity with the intensity of the stimulus. These changes in membrane potential are passed to adjacent sensory neurons, which may generate an action potential if the incoming stimuli are sufficient for the neuron to reach threshold (see section on Communication - the nervous system for further details about how this occurs). Increases in receptor potential intensity are translated into a higher frequency of action potentials in the sensory neurons. Sensory receptors are specialized to respond to only certain stimuli, which will activate the receptor with weak or moderate levels of intensity. The signal is then chemically amplified within the receptor cells. In order for the signal to be effective the intracellular chemical signal must cause membrane channels to open. This produces an electrical signal that will be transmitted to the central nervous system. How can sensory systems detect such a broad range of stimuli intensity? The sensitivity range of a sensory organ is much broader than the range of a single receptor cell. This is because individual afferent fibers of the sensory system cover different parts of the sensitivity spectrum. For example, only the most sensitive receptor cells will respond to a low level stimulus. As the stimulus intensity continues to increase, the receptors become fully activated (saturated), but a group of less sensitive receptor becomes stimulated. This recruitment of additional receptors continues as the stimulus intensity increases, until all receptors are fully saturated. This subdivision of the total range of response by receptor cells of different sensitivities is called range fractionation because individual receptors cover only a fraction of the total range of the sensory system. When all receptors are fully active, the system is not capable of detecting any further increase in stimulus intensity. Some sensory systems (receptors and their neurons) generate a rather constant "background" rate of action potentials. If stimulated further, the rate of action potential generation increases due to increase levels of depolarization of the neurons. Therefore, the system does not rely on a minimal level of sensory input in order to respond, which makes the system more sensitive. Chemoreception Chemoreception is the ability to perceive specific molecules in the air or in water. These molecules are important clues to the presence of specific objects in the environment. It is essential to many animals in finding food, locating a mate, and avoiding danger. Chemoreception is divided into two main categories: gustation (taste) and olfaction (smell). Gustatory receptors respond to dissolved molecules that come in contact with the receptors. Olfactory receptors respond to airborne molecules from sources a distance away. Differences in chemoreception in invertebrates and in vertebrates Vertebrates detect chemicals using general receptors and two types of specialized receptors, gustatory and olfactory. Many aquatic vertebrates have generalized chemical receptors scattered over their body surface. Vertebrates usually accomplish chemoreception by moving chemically rich air or water into a canal or sac that contains the chemical receptors. Chemoreception is much different in invertebrates than in vertebrates. For example, planarians find food by following chemical gradients in their surroundings. Their simple chemoreceptors are found in pits on their bodies, over which they move water with cilia. Insects have chemoreceptors in their body surface, mouthparts, antennae, forelegs, and, in some cases, the ovipositor. Moths, for example, smell with thousands of sensory hairs on their antennae. About 70 percent of the adult male receptors are made to respond to one molecule called bombkyol, a sex attractant released by females of the species. The molecules enter the tiny pores of the hair, or sensillum, where the olfactory receptors are found. Olfactory (smell) mechanisms The receptors for the olfactory nerves are located in the upper part of the nasal cavitity. The olfactory sense organ consists of hair-like cells at the end of a neuron and is simple compared to the complex visual and auditory organs. The olfactory receptors are very sensitive to stimuli; however, they also become very fatigued. This explains why odors seem to go away after being easily noticeable. Canals lined with sheets of receptors with the nasal cavity are called turbinates. Protruding from the end of the nerve are thin cilia that are covered by mucus. Molecules are absorbed into the mucous layer and passed to the cilia where the chemical is detected. Notice the chemicals must be dissolved in the mucus and absorbed in order for the olfactory receptors to react. This is a lot like the gustatory mechanisms. Gustatory (taste) mechanisms The receptors for the gustatory nerves are known as taste buds located on the tongue and the roof of the mouth. Sweet, sour, bitter, and salty are the four basic taste sensations resulting from stimulation of the taste buds and the stimulation of the olfactory receptor. This is why it is harder to taste when one has a cold. These four basic tastes may evolutionarily developed to show some basic food properties. Sweet taste signals foods high in calories, salty foods signal for food that helps maintain water balance, sour tastes may help to signal foods that could be dangerous if eaten in excess, and bitter taste sensations signal toxic foods. Taste is also referred to as contact chemoreception for obvious reasons. For example, insects have contact receptors called taste hairs or sensilla. At the tip of each sensillum is a tiny pore that allows molecules to reach the sensory cells. Each cell is sensitive to a different chemical. Sensilla can be located in a variety of locations on the body. Flies, for example, have sensilla on their tarsi (feet). Mechanoreception Mechanoreception is sensing physical contact on the surface of the skin or movement of the surrounding environment (such as sound waves in air or water). The simplest mechanoreceptors are nerve endings of skin’s connective tissue. The most complex example of mechanoreception occurs in the middle and inner ear of vertebrates. The hair cell is the basic unit of vertebrate mechanoreception. Structural mechanisms of the vertebrate ear Sound waves enter the external ear of a vertebrate aided by the pinna and the tragus. The entire external structure has a function similar to that of a funnel, amplifying and then concentrating sound waves. Vibrations from sound waves cause changes in air pressure, which travel from the external ear, down the auditory canal, and then move the eardrum (tympanum). This energy is then conducted through the malleus, incus, and stapes, the three small bones that constitute the rest of the middle ear. These three bones are key in the conversion from airborne vibrations to fluid movements. Beneath the stapes is a membrane called the oval window, which opens into the choclea of the spiral shaped, fluid filled inner ear. This entire process serves to amplify sound stimuli up to 22 times before it reaches the cochlea. How does the ear then change vibration waves to mechanical sound? The ear converts energy of sound into nerve impulses. This process begins at the tympanic membrane. The vibrations that move the eardrum, and then consequently the three additional bones of the middle ear, are transmitted to the oval window. These vibrations in turn move the fluid of the cochlea. The cochlea is divided into three longitudinal chambers. The two outer chambers are called the scala tympani, and the scala vestubuli, and they are both filled with a liquid perilymph that contains high sodium concentrations. The scala media is the compartment located between these outer two chambers. The scala media is filled with a fluid endolymph that had high concentrations of potassium. It also contains the organ of corti. The sound vibrations that pass by the oval window into the chochlear chambers and vibrate the tectorial and basilar membranes, eventually dissipate through the membrane of the round window. The floor of the chochlea contains the previously mentioned basilar membrane, and the scala media, containing the organ of corti is where these vibrations undergo the conversion to neuronal impulses. The organ of corti contain sensory hair cells, and the waves of fluid in the cochlea press the hair cells against an overhanging tectorial membrane, and then pull them away. These hair cells are just across synapses from sensory neurons, and this action provides a stimulus that opens sodium channels in the sensory cell membranes. This provides for an action potential in the environment of high potassium concentrations that the endolymph has. Auditory nerves located in a spiral ganglion carry the action potential to the brain. The frequency of impulses from action potentials relays information on sound to the brain. The louder a sound is the greater height or amplitude of the vibrations in the sound wave, the more movement of hair cells, and thus the more action potentials. Pitch can be distinguished through differences in sound wave frequencies. Different areas of the basilar membrane are sensitive to different pitches due to different levels of flexibility along the membrane. Higher frequencies stimulate the basilar membrane closest to the oval window, lower frequencies stimulate areas further along. These regions then stimulate neurons to send the sound signals to specific areas of the brain, and that leads to the perception of a certain pitch. How does the insect’s system of mechanoreception compare to that of the vertebrate’s? Most insects have ‘ears’ in their legs. A common structure consists of respiratory tracts called tracheae that lead to a membrane stretched over an internal air chamber. Similar to a mammal, sound waves stimulate the membrane to vibrate, but in the insect, this directly activates nerve impulses in attached receptor cells. These nerve impulses then travel to the central nervous system. Some insects also have a related tracheal system that directs information on air pressure changes, inside the insect, to the eardrum. If the right tympanum is stimulated, it will send the signal through the tracheae to the left tympanum. The delay in stimulus between the left and the right ear helps the insect locate the direction from which the sound came. Some insects such as the noctuid moths have ears specially adapted to avoid their predators; such as bats. The ear structure consists of a tympanic cavity, a membrane, and three neurons in a scolopida formation. The system is stimulated by the ultrasonic vibrations of bat cries. One specific neuron is sensitive to the low intensity vibrations picked up from distant predators, and a different neuron is sensitive to the strong vibrations of a nearby predator. When the neurons are stimulated they send an action potential along the tympanic nerve, and the moth can move according to which neurons have been stimulated. Some insects also use their sense of mechanoreception to attract mates. At dusk, their setae stand upright, and they vibrate in accordance to the sound waves sent out by the hum of the female. System of mechanoreception in a fish Many fishes and amphibians have a lateral line system enabling them to experience mechanoreception. Pores run up both sides of the fish, through which moving water enters the lateral line system. This leads to stimulation of neuromasts, the receptor cells of fishes. These neuromasts are located throughout the skin, in channels beneath the scales of the main body, and in the dermal bones of the head. These function like sensory hair cells, and vibrations in the water indicating nearby objects or organisms can be detected. Similar to in the vertebrate, their stimulation leads to an action potential. Eventually these nerve impulses travel to the brain through sensory neurons. Fish also have inner ears systems to extend their hearing to higher frequencies. Sound waves in the water surrounding the fish are conducted as vibrations through the skull. Then, they travel to chambers similar to those located in the cochlea of the vertebrate, and move small granules called otoliths. These granules then stimulate sensory hair cells. Most fish tissue has the same approximate density as water, so vibrations in the water travel right through a fish’s body. Any structures in the fish that have a significantly different density vibrate differently. The otolith provides this sensory detection in the inner ear of a fish. It’s membranes pass the signal on the neighboring sensory hair cells, and eventually trigger action potentials in the neurons of the auditory nerve. The gas bladders of some fish also provide an area of variable density. Vibrations pass through the gas bladder, and travel through a pathway of small bones called Weberian ossicles. These serve to connect the gas bladder directly with the inner ear of the fish. Photoreception Photoreception is the translation of photons of light into electrical and then neuronal signals. Structural mechanisms of the vertebrate eye In vertebrates such as humans, the surface of the eyeball is made up of the sclera, a white connective tissue, and under that a thin pigmented layer called the choroid. The sclera contains the cornea which is transparent, and is where light initially enters the eye, and the choroid contains the iris which contracts and expands to regulate the amount of light entering the hole in its center, known as the pupil. The rear internal surface of the eye is the retina, which contains the actual photoreception cells. Between the cornea and the rest of the eyeball is a clear protein lens. The rest of the eyeball consists of a mass of ‘jelly like’ vitreous humor, which functions as an additional liquid lens through which to focus light images. How does the vertebrate eye operate? Visual Perception in all animals is based on a conserved mechanism. Specific protein molecules make up an optical pathway in which light is directed towards a certain photoreceptive surface in which photoreceptors capture photons. Light initially enters the eye through the cornea. During this process, light rays are bent, and are then further refracted upon passage through the lens to form an inverted image on the retina. To focus on images, most vertebrates change the curve and thickness of the lens. This action is controlled through ciliary muscles surrounding the lens. They relax, and the lens flattens out when the organism is viewing a distant object, and they contract to provide a rounded lens through which to view closer images. Strong ocular muscles direct both left and right eyes so that images received by each eye travel to the same spots on the two retinas; producing binocular convergence. In the retina, there are two types of receptor cells, rods and cones. Rods are for dim light, and cones are for bright light and color. Rods and cones contain visual pigments made up of light absorbing retinal molecules. These are bound to proteins called opsins, which control which pigments are absorbed by each receptor cell. In the rods, this protein is called rhodopsin, and in bright light, the opsin and retina separate thus making the rods inactive. Rods are more sensitive to light than cones, which is why they work better in dim light. This sensitivity is due to the connections with neuronal cells that are significantly closer than the receptor cell/ neuronal cell connection in cones. This increased convergence leads to greater magnification of a weak stimuli. When only our rods are stimulated, such as in dim light, we only see in black and white. Additionally, because our rods are not part of the fovea, where images are best focused, we can see images better at night when we don’t look directly at them. In the human there are three kinds of cones; blue, green, and orange. Each type of cone has specific photopigment molecules, and each molecule experiences maximum absorption at a different wave length. All other colors are perceived by the stimulation of two or more cone types. In vertebrates such as human beings, there is a specialized portion of the retina called the fovea. This area provides for our high visual acuity. This region only contains cones, and this enables the human to see in great detail. This area of the eye is most efficiently taken advantage of during the day when the photoreceptor cells of the cones that dominate the fovea, are best able to absorb light. The light hitting the receptor cells, rods or cones, produces a charge gradient across the membrane, but this is not an action potential. These cells, however, synapse with neurons that then synapse with ganglion cells. These convey the image message as an action potential to the brain along optic nerves. The optic nerves from the right and left eyes meet at an optic chiasma in the brain. To demonstrate the blind spot, cover your left eye and look at the "O" below directly with your right eye. You should also be able to see the "+" even though you aren't looking directly at it. Now slowly move closer to the screen (or page), keeping you right eye focused on the "O". The image of the "+" should disappear, then reappear as you continue to move closer. This is because the image of the "+" moved across your blind spot as you moved closer.. 0 + Why do some animals see in black and white? Many animals are nocturnal, and have increased amounts of rods in their optical systems. The cones that control color vision, are really unnecessary or are needed in extremely small quantities. What kind of photoreception systems do insects have? Vertebrate and insect eyes have vastly different morphology and structure, although they operate under very similar photochemical systems. The compound eye of most insects has many facets. Behind the corneal lens of each facet, there are functional units called ommatidium. The receptor cells within the ommatidium each detect a very small fraction of the spectrum of light that the eye as a whole is exposed to; like the rods and cones of the vertebrate eye. In compound eyes, the photoreception cells are called retinular cells, and they surround a single eccentric cell. The receptor cells have a specific portion of membrane, designated as a rhabdomere, which has a high density of microvilli. Rhodopsin, a photoreceptive pigment molecule, is contained in this rhabdomere, and this protein absorbs the photons of light energy that enter the eye. This then provides for amplification of this light signal through a G-Protein directed reaction. Ion channels in the cells open, allowing calcium ions to enter the cell. This is the basis for a current traveling down the receptor cell axon, which crosses gap junctions and reaches the dendrite of the adjacent eccentric cell. This eccentric cell then depolarized and generates action potentials. These travel through the optic nerve to the Central Nervous System. Within each ommatiduim, different retinular cells are sensitive to different colors due to protein variations with in the rhodopsin. Most insects are equipped to see further along the short wavelength end of the color spectrum, towards ultra-violet, however, they don’t see into the reds, which make up the longer wavelengths that vertebrates can see. How do fish see? The optical system in fish is very similar to that of the land vertebrates, however, there are some important differences. The fish has a more spherical shaped lens than the land dwellers. Fish focus by changing the relative distance between the lens and the retina, where as other vertebrates change the curvature of their more flexible lens. Fish have choroids which contain a special structure, the tapetum lucidum, and this contains very reflective guanine crystals to aid in dim light vision. This is very important because of the lowered amount of light that penetrates the fish’s watery environment. Additionally, many deep-sea fish have only these and rods, for increased low light sensitivity. They even have epithelial layers for the specific purpose of protection from bright light. Fish with cones generally have four types, red, green, blue, and ultraviolet. Some only have two or three of these possibilities; fish with all four usually live close to the water’s surface, and may have further special adaptations. Some fish have upwardly directed eyes, especially those who are preyed upon by birds. Some deep sea fishes have tubular eyes, which help to concentrate the limited light that penetrates to great depths. The South American "four-eyed fish " swims along the surface, with it's eyes protruding partly out of the water. Each of its two eyes is split into an upper half for vision in the air and a lower half for underwater vision. Specific mechanisms of the conversion of light stimulation to neuronal impulses Visual pigment molecules are the specific structures that absorb photons of light. These pigment molecules are made up of an opsin such as rhodopsin, and an actual light absorbing component, which is usually retinal. When a photon of light hits this molecule, the normal cis-configuration of the retinal is isomerized into a trans-configuration. This in turn leads to a separation between the opsin and the retinal molecule, and eventually to changes in the opsin’s conformation too. When the light is absorbed by the retinal, proteins that are associated with the cell membrane are activated. This alters the cell's membrane potential, and can eventually lead to an action potential, which is carried to the brain via a sensory neuron. At a cell’s resting state, there is a certain concentration of each ion in and outside of the cell membrane. This provides for potential diffusions across the membrane. However, there are also charges on each of these ions, and there are polar gradients that do no necessarily correlate to the diffusion gradients. There is usually a stronger negative charge within the cell and a stronger positive charge outside of the cell. Positive ions are attracted to the cell membrane because of the negative interior, and vice versa. The only way that these ions can travel through the selectively permeable membrane, though, is through specific ion channels. Some of the channels are normally open, and stimulation of the cell closes them, and others are closed at resting state, and open in response to stimulation. Such a stimulus could be the absorption of a photon of light by retinal, and when this occurs, there are two possible results. The cell can become hyperpolarized, or depolarized. In retinal for example, sodium channels close in the presence of light, and potassium continues to move out of the cell. This makes the cell environment even more positive, and the inside more negative. This is hyperpolarization. A lessening in the charge of difference between the in and outside of the cell would conversely be depolarization. Each of these conditions leads to charges that travel across synapses to neuronal cells. This alters the firing rate of action potentials in the adjacent neurons. Thermoreception in snakes Temperature receptors in some snakes can be extremely sensitive. The infrared detectors in the facial pits of rattlesnakes are an excellent example. The sensory axons from the pit organs increase the rate of action potentials when the temperature inside the facial pit increases by 0.002 0 C. A rattlesnake can detect the body heat of a mouse standing 40cm away if the mouse’s body temperature is at least 10 0C above the surrounding air temperature. Because the snakes have a pit on each side of its head, they can tell the direction of the source of heat. Muscle Tissues Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten or remain the same. Though the term 'contraction' implies shortening, when referring to the muscular system it means muscle fibers generating tension with the help of motor neurons (the terms twitch tension, twitch force and fiber contraction are also used). Voluntary muscle contraction is controlled by the central nervous system. Voluntary muscle contraction occurs as a result of conscious effort originating in the brain. The brain sends signals, in the form of action potentials, through the nervous system to the motor neuron that innervates several muscle fibers. In the case of some reflexes, the signal to contract can originate in the spinal cord through a feedback loop with the grey matter. Involuntary muscles such as the heart or smooth muscles in the gut and vascular system contract as a result of non-conscious brain activity or stimuli proceeding in the body to the muscle itself. There are three general types of muscle tissues: Skeletal muscle responsible for movement Cardiac muscle responsible for pumping blood Smooth muscle responsible for sustained contractions in the blood vessels, gastrointestinal tract and other areas in the body Skeletal and cardiac muscles are called striated muscle because of their striped appearance under a microscope which is due to the highly organized alternating pattern of A band and I band. While nerve impulse profiles are, for the most part, always the same, skeletal muscles are able to produce varying levels of contractile force. This phenomenon can be best explained by Force Summation. Force Summation describes the addition of individual twitch contractions to increase the intensity of overall muscle contraction. This can be achieved in two ways: (1) by increasing the number and size of contractile units simultaneously, called multiple fiber summation, and (2) by increasing the frequency at which action potentials are sent to muscle fibers, called frequency summation. Multiple fiber summation – When a weak signal is sent by the CNS to contract a muscle, the smaller motor units, being more excitable than the larger ones, are stimulated first. As the strength of the signal increases, more motor units are excited in addition to larger ones, with the largest motor units having as much as 50 times the contractile strength as the smaller ones. As more and larger motor units are activated, the force of muscle contraction becomes progressively stronger. A concept known as the size principle allows for a gradation of muscle force during weak contraction to occur in small steps, which then become progressively larger when greater amounts of force are required. Frequency summation - For skeletal muscles, the force exerted by the muscle is controlled by varying the frequency at which action potentials are sent to muscle fibers. Action potentials do not arrive at muscles synchronously, and during a contraction some fraction of the fibers in the muscle will be firing at any given time. Typically when a human is exerting a muscle as hard as they are consciously able, roughly one-third of the fibers in that muscle will be firing at once, but various physiological and psychological factors (including Golgi tendon organs and Renshaw cells) can affect that. This 'low' level of contraction is a protective mechanism to prevent avulsion of the tendon - the force generated by a 95% contraction of all fibers is sufficient to damage the body. Skeletal muscle contractions Skeletal muscles contract according to the sliding filament model: 1. An action potential originating in the CNS reaches an alpha motor neuron, which then transmits an action potential down its own axon. 2. The action potential propagates by activating sodium dependent channels along the axon toward the synaptic cleft. Eventually, the action potential reaches the motor neuron terminal and causes a calcium ion influx through the calciumdependent channels. 3. The Ca2+ influx causes vesicles containing the neurotransmitter acetylcholine to fuse with the plasma membrane, releasing acetylcholine out into the extracellular space between the motor neuron terminal and the motor end plate of the skeletal muscle fiber. 4. The acetylcholine diffuses across the synapse and binds to and activates nicotinic acetylcholine receptors on the motor end plate of the muscle cell. Activation of the nicotinic receptor opens its intrinsic sodium/potassium channel, causing sodium to rush in and potassium to trickle out. Because the channel is more permeable to sodium, the muscle fiber membrane becomes more positively charged, triggering an action potential. 5. The action potential spreads through the muscle fiber's network of T-tubules, depolarizing the inner portion of the muscle fiber. 6. The depolarization activates L-type voltage-dependent calcium channels (dihydropyridine receptors) in the T tubule membrane, which are in close proximity to calcium-release channels (ryanodine receptors) in the adjacent sarcoplasmic reticulum. 7. Activated voltage-gated calcium channels physically interact with calcium-release channels to activate them, causing the sarcoplasmic reticulum to release calcium. 8. The calcium binds to the troponin C present on the actin-containing thin filaments of the myofibrils. The troponin then allosterically modulates the tropomyosin. Normally the tropomyosin sterically obstructs binding sites for myosin on the thin filament; once calcium binds to the troponin C and causes an allosteric change in the troponin protein, troponin T allows tropomyosin to move, unblocking the binding sites. 9. Myosin (which has ADP and inorganic phosphate bound to its nucleotide binding pocket and is in a ready state) binds to the newly uncovered binding sites on the thin filament (binding to the thin filament is very tightly coupled to the release of inorganic phosphate). Myosin is now bound to actin in the strong binding state. The release of ADP and inorganic phosphate are tightly coupled to the power stroke (actin acts as a cofactor in the release of inorganic phosphate, expediting the release). This will pull the Z-bands towards each other, thus shortening the sarcomere and the I-band. 10. ATP binds myosin, allowing it to release actin and be in the weak binding state (a lack of ATP makes this step impossible, resulting in the rigor state characteristic of rigor mortis). The myosin then hydrolyzes the ATP and uses the energy to move into the "cocked back" conformation. In general, evidence (predicted and in vivo) indicates that each skeletal muscle myosin head moves 10-12 nm each power stroke, however there is also evidence (in vitro) of variations (smaller and larger) that appear specific to the myosin isoform. 11. Steps 9 and 10 repeat as long as ATP is available and calcium is present on thin filament. 12. While the above steps are occurring, calcium is actively pumped back into the sarcoplasmic reticulum. When calcium is no longer present on the thin filament, the tropomyosin changes conformation back to its previous state so as to block the binding sites again. The myosin ceases binding to the thin filament, and the contractions cease. The calcium ions leave the troponin molecule in order to maintain the calcium ion concentration in the sarcoplasm. The active pumping of calcium ions into the sarcoplasmic reticulum creates a deficiency in the fluid around the myofibrils. This causes the removal of calcium ions from the troponin. Thus the tropomyosin-troponin complex again covers the binding sites on the actin filaments and contraction ceases. Classification of voluntary muscular contractions Voluntary muscular contractions can be classified according to either length changes or force levels. In spite of the fact that the muscle only actually shortens in concentric contractions, all are typically referred to as "contractions". In concentric contraction, the force generated is sufficient to overcome the resistance, and the muscle shortens as it contracts. This is what most people think of as a muscle contraction. In eccentric contraction, the force generated is insufficient to overcome the external load on the muscle and the muscle fibers lengthen as they contract. An eccentric contraction is used as a means of decelerating a body part or object, or lowering a load gently rather than letting it drop. In isometric contraction, the muscle remains the same length. An example would be holding an object up without moving it; the muscular force precisely matches the load, and no movement results. In isotonic contraction, the tension in the muscle remains constant despite a change in muscle length. This can occur only when a muscle's maximal force of contraction exceeds the total load on the muscle. In isovelocity contraction (sometimes called "isokinetic"), the muscle contraction velocity remains constant, while force is allowed to vary. True isovelocity contractions are rare in the body, and are primarily an analysis method used in experiments on isolated muscles which have been dissected out of the organism. Smooth muscle contraction The interaction of sliding actin and myosin filaments is similar in smooth muscle. There are differences in the proteins involved in contraction in vertebrate smooth muscle compared to cardiac and skeletal muscle. Smooth muscle does not contain troponin, but does contain the thin filament protein tropomyosin and other notable proteins-caldesmon and calponin. Contractions are initiated by the calcium activated phosphorylation of myosin rather than calcium binding to troponin. Contractions in vertebrate smooth muscle are initiated by agents that increase intracellular calcium. This is a process of depolarizing the sarcolemma and extracellular calcium entering through L type calcium channels, and intracellular calcium release predominately from the sarcoplasmic reticulum. Calcium release from the sarcoplasmic reticulum is from Ryanodine receptor channels (calcium sparks) by a redox process and Inositol triphosphate receptor channels by the second messenger inositol triphosphate. The intracellular calcium binds with calmodulin which then binds and activates myosin-light chain kinase. The calciumcalmodulin-myosin light chain kinase complex phosphorylates myosin, specifically on the 20 kilodalton (kDa) myosin light chains on amino acid residue-serine 19 to initiate contraction and activate the myosin ATPase. The phosphorylation of caldesmon and calponin by various kinases is suspected to play a role in smooth muscle contraction. Phosphorylation of the 20 kDa myosin light chains correlates well with the shortening velocity of smooth muscle. During this period there is a rapid burst of energy utilization as measured by oxygen consumption. Within a few minutes of initiation the calcium level markedly decrease, the 20 kDa myosin light chains phosphorylation decreases, and energy utilization decreases, however there is a sustained maintenance of force in tonic smooth muscle. During contraction of muscle, rapidly cycling crossbridges form between activated actin and phosphorylated myosin generating force. The maintenance of force is hypothesized to result from dephosphorylated "latch-bridges" that slowly cycle and maintain force. A number of kinases such as ROCK, Zip kinase, and Protein Kinase C are believed to participate in the sustained phase of contraction, and calcium flux may be significant. SOMESTHESIA: PERIPHERAL MECHANISMS The broadest definition of somesthesia is the awareness of having a body and the ability to sense the contact it has with its surroundings. Receptors are generally put into two broad classes: the exteroceptors, that sense stimuli from outside the body and signal what is happening in the outside world, and the enteroceptors, that receive stimuli from inside the body and tell us what is happening in the inside world. The broad class of exteroceptors includes, in addition to receptors in the skin, receptors for light in the eye, sound in the ear, and for chemical substances in the nasal mucosa and tongue. The Exteroceptors The skin serves many functions: as protection from injury and dehydration as a radiation surface and regulator in temperature maintenance in secretion of chemical substances, such as pheromones that function as attractants or repellents as camouflage due to coloration in some species in reception of mechanical, thermal and, to some extent, chemical stimulation From our present point of view, we may think of the skin as a sheet of sensory receptors held together and supported by a network of connective tissue and blood vessels. Figure 5-1 shows a cross section through a transitional region between glabrous and hairy skin. The outer layer or epidermis is composed of four to five layers of cells and connective tissue and is devoid of Fig. 5-1. A section through a trasitional region between glabrous and blood vessels. The hairy skin showing the locations and arrangements of various dermal and epidermis receives epidermal receptors (Warwick R and Williams PL [ed]: Gray's Anatomy, its nutrients from 35th ed. Philadelphia, WB Saunders, 1973). the dermis immediately beneath it. The dermis consists mainly of loose connective tissue. Nerve fibers course into the skin through the dermis, and many of them end at the dermal-epidermal border where many of the sensory receptor structures are located. Figure 5-1 shows several of the types of receptors that are typical of skin. Structure A is a typical hair follicle-note that all hairs are innervated and thus serve as sensory receptors. The nerve fibers associated with a hair enter the follicle and follow a wandering course up and down along the root sheath and also around it. This winding pattern of the nerve fiber may determine how the receptor responds to hair movement, but as yet we do not know how. In addition to hair follicles, there are many encapsulated nerve endings found at the dermalepidermal border. These are endings surrounded by specialized structures; a few of the types are shown in the figure (B-F). These structures vary somewhat in form so that it is not always clear in which class a particular structure belongs. The largest class of receptors is that with no specialized structure at all, the free nerve endings (G). Near their termination, the nerve fibers simply branch many times, and the many tiny terminal "twigs" lie in the dermis, near the border between the dermis and epidermis, or sometimes penetrate into the epidermis itself. Many attempts have been made to associate different receptor structures with particular sensations, but there appears to be no clear relationship between structure and sensation. One problem is that the sensations associated with skin are surprisingly complex. Nearly everyone allows that there are (1) mechanical sensations, (2) thermal sensations, and (3) nociceptive or pain sensations, but only some will divide mechanical sensations into touch, pressure, and pinch, whereas others maintain that the list should also include vibration, tickle, itch, and perhaps others. Clearly, we may have more describable sensations than we have receptor types to account for them. The problem is further compounded if we realize that we experience all of the normal skin sensations on the pinna or auricle, the external part of the ear, yet the pinna probably has only free nerve endings. Similarly, the cornea of the eye can sense temperature and pain, but has only free nerve endings. Although there is not a one-to-one relationship between receptor structure and sensation, that is not to say that there is no relationship at all. Free nerve endings are usually associated with the sensations of pain, temperature, and what many call crude touch, a sensation that requires firm pressure to elicit and is difficult to localize. The encapsulated endings are associated with light touch and pressure when they lie superficially within the skin and with deep pressure and tissue deformation when they lie deep within the tissue. Hair receptors, of course, can be associated with a class of sensations that accompany hair movement; these sensations have no special terminology. Mechanical sensations If recordings are made from the sensory nerve fibers innervating particular cutaneous receptors, the stimuli that best excite each type of receptor, the adequate stimuli, can be identified. Examples of recordings from four different primary afferent fibers serving four different kinds of receptors are shown in Figure 5-2. A monitor of the mechanical displacement of the structure is shown in trace 5-the probe indented the receptors in traces 1, 3 and 4, and pushed the hair laterally in trace 2. Traces 1 to 4 show the spike discharges recorded from the fibers, the primary afferent fibers. The bottom trace is a time scale, with each division representing 100 Fig. 5-2. Responses of cutaneous primary afferent msec. The discharge pattern of the fibers. A mechanical indentation or displacement was Pacinian corpuscle should already applied to four different types of receptors, the monitor of the movement being shown in trace 5 (numbered be familiar. The fiber discharges from the top down). The action potential responses of when the receptor is compressed two rapidly adapting fibers are shown in traces 1 and 2: and again when the receptor is They respond only at the onset or offset of the stimulus. restored to its resting state-the Responses of the two slowly adapting fibers are shown discharge is rapidly adapting or in traces 3 and 4: They discharge throughout the phasic. The same kind of discharge stimulus. A 100-msec time base is shown in trace 6. pattern is seen in recordings from afferent fibers associated with hairs when a hair (trace 2) is displaced. The hair receptors are all rapidly adapting, i.e., they are incapable of signaling sustained stimulation. On the other hand, the slowly adapting receptors, types I and II, can signal the presence of a sustained stimulus. They begin discharging with the indentation and continue to discharge until the stimulus is removed. The type I receptor is a receptor associated with a Merkel's disk, whereas the type II is associated with a Ruffini ending. A receptive field is the area of skin over which the application of a stimulus excites a primary afferent fiber. Receptive fields The area of skin over which the application of a stimulus excites a given primary afferent fiber is called the receptive field of that fiber. As far as we know, a primary afferent neuron only innervates one particular type of receptor, though it may innervate a number of individual receptors of that type. For example, a hair afferent neuron may innervate anywhere from a few to 100 hairs and a given hair may receive innervation from 2 to 20 different fibers. Thus, there is considerable overlap in the receptive fields of different fibers. The size of a receptive field varies over the body surface, with those located on the extremities being the smallest, of the order of a few square millimeters on the digits, growing in size along the leg or arm, and reaching a maximum size on the trunk. This arrangement might account, in part, for the observed distribution in two-point thresholds, a commonly used measure of touch sensitivity. Two-point thresholds can be tested by using an ordinary pair of dividers. When the closed dividers are touched to the skin, the perception is of being touched with only a single point. As the dividers are opened more and more on successive applications to the skin, a separation of the points is reached at which the perception is of being touched with two points. The separation at which this first happens is the two-point threshold. Temperature sensations Because of the high touch receptor density in some areas, touch sensitivity sometimes appears to be uniformly distributed. In contrast, temperature sensitivity is always punctate or localized to small spots on the skin. We speak of "warm spots" and "cold spots" on the skin that are areas sensitive to upward and downward changes in skin temperature, surrounded by areas of virtual insensitivity to changes in temperature. The low density of temperature-sensitive spots is indicated in Table 5-1. At no place is the density of temperature spots as high as is the lowest touch-spot density. Note also the low density of warm spots compared to cold spots. Table 5-1 Sensitive Spots Per Square Centimetera Touchb Pain Ball of thumb 120 60 Tip of nose 100 Forehead Chest Cold Warmth 44 13 1.0 50 184 8 0.6 29 196 9 0.3 Volar side of forearm 15 203 6 0.4 Back of hand 14 188 7 0.5 a Data from Woodworth RS, Schlosberg H: Experimental Psychology. New York, Holt, Rinehart and Winston, 1965. b Arranged in descending touch-spot density. Pain sensations The experience of pain is influenced by prior experience; by the meaning of the situation in which it occurs; by attention, anxiety and suggestion; and by the sensory adaptation level of the individual. Prior experience with a stimulus can cause that stimulus to be perceived as either more or less painful, depending upon the nature of the experience. Painful stimulation, repeated in a psychological trauma-producing situation, may tend to make similar stimulation in the future more painful, whereas painful stimulation, repeated in otherwise pleasant surroundings, may tend to make future stimulation less painful. Pricking pain is a short-duration pain; burning pain is a cutaneous pain that continues. All pain has two psychological aspects: one discriminative, that is, we can objectively gauge its intensity, location, and quality, and the other affective or emotional, pain causes suffering. It is important to distinguish the discriminative aspect from the affective aspect of pain. The importance of this distinction is highlighted by the fact that the two aspects can be dissociated by the proper clinical maneuvers, suggesting that different parts of the nervous system are involved. For example, separation of the prefrontal lobes from the rest of the cerebral cortex in the patient with intractable pain leaves the patient with his pain sensation intact, but the pain no longer bothers him. The suffering is eliminated even though the pain is not. The affective aspect of pain depends upon the integrity of cerebral cortical function; the discriminative aspect apparently does not. The Enteroceptors Joint sensations Though joints differ in the range and direction of their movement, most have an enclosed cavity filled with synovial fluid and are surrounded by cartilage. Free nerve endings are abundant in the articular cartilage and nearly everywhere around the joint. In addition, there are spray-like endings in the joint capsule and encapsulated corpuscles both on and in the capsule. Free nerve endings arise from both myelinated and unmyelinated fibers in the articular nerves, whereas spray-like endings and corpuscles arise from myelinated fibers only. Originally, it was thought that the sense of the position of the joint, that is, the angle between the bones of the joint, was signaled by the myelinated fibers of the articular nerve leaving that joint. Recent studies indicate that most of these fibers do not, in fact, signal the static position of the limb. This is because they fail to discharge at any position but the extremes of flexion and extension. In addition, anesthetizing the human knee joint does not diminish position sense for that joint. It appears that the most likely candidate for signaling joint angle would be the muscle spindle receptors or group Ia or II afferent fibers. Vision Most objects reflect light, and because light travels at high speed, it is possible to nearly instantly assess their shape, size, position, speed, and direction of movement. The light rays emanating from an object are gathered and focused onto an array of photoreceptors. Activities generated in the different photoreceptors by the light interact to produce a twodimensional representation of the object which is transmitted to the brain. The brain then reconstructs a three-dimensional representation using information received from the two eyes. The end-products of the activity of the visual system are sensations that represent the object and its surroundings. These sensations can be used to guide our immediate behavior, or they can be stored for future reference. Figure 7-1 shows a cross section through the human eye. It consists of two fluid-filled chambers separated by a transparent structure, the lens. Nearly the entire eye is covered with a tough, fibrous coating called the sclera that is modified anteriorly to form the transparent cornea. The human cornea is about 12 mm in diameter, about 0.5 mm thick in the center and 0.75 to 1 mm thick on the edge, and it is made of the Fig. 7-1. A section through the human eye illustrating the major same collagenous structures. (Walls GL: The Vertebrate Eye and its Adaptive connective tissue Radiations. New York, Hafner, 1967) substance as is the sclera, but the fibers of the cornea are oriented in parallel arrays that let light pass through with minimal scatter, whereas fibers of the sclera are random and light rays are scattered when passing through. The result is that light passes easily through the cornea, but not through the sclera. Lining the inside of the posterior twothirds of the sclera are two membranes: the choroid, a pigment layer containing the vascular supply for the eyeball as well as mechanisms for maintaining the integrity of the photoreceptors, and the retina that contains the photoreceptors and other neural elements essential to our visual process. Visual neurons in the retina The receptor cells and the bipolar cells of the retina respond to light with graded, electrotonic responses rather than all-or-nothing action potentials. The graded responses in the receptors are the result of the photochemical process, but those in the bipolar cells are synaptically driven. Furthermore, it may be surprising that the receptors respond to light with an hyperpolarizing receptor potential, that is accompanied by an increase in membrane resistance. Figure 7-17 shows a schematic diagram of a section of the retina with two receptors, one illuminated, the other unilluminated. The responses of the receptors, bipolar, ganglion, horizontal and amacrine cells are shown in circles representing each cell type. The time when a small spot of light was turned on is indicated by the upward deflection of the lower trace of each pair and the response of the cell by the upper trace. The hyperpolarizing responses of the illuminated receptor and its subjacent bipolar cell are illustrated as are the action potentials generated by the ganglion cell. It is now known that in the dark there is a constant inward Na+ current (dark current) flowing through the outer segment membrane and an outward current near the junction with the bipolar cell. This keeps the cell partly hypopolarized, and transmitter substance is continuously released onto the bipolar cell hypopolarizing it. The light flash decreases the dark current by the action of calcium to reduce membrane conductance, hyperpolarizes the cell relative to its dark state and decreases the amount of transmitter released onto the bipolar cell. If this scenario is correct, then adding excess magnesium to the bathing solution should cause bipolar and ganglion cells to behave as if their receptors were illuminated because excess magnesium blocks the release of transmitter substances at chemical synapses. A release of transmitter substance blocked by magnesium should be the same as one blocked by light, and it is. This scheme accounts mechanistically for the curious hyperpolarizing receptor potentials. Fig. 7-17. Synaptic organization of the vertebrate retina and responses of retinal neurons. The receptor on the left is illuminated, that on the right is not. The intracellularly recorded response from each cell is illustrated in the circle corresponding to its cell body (upper trace) along with a monitor of when the illumination was present over the left receptor. The responses were recorded in the retina of Necturus. (Dowling JE, Werblin FS: Vision Res Suppl 3:1-15, 1971) The response recorded from ganglion cells following light stimulation of the receptors is more conventional. Hypopolarizing synaptic potentials initiate trains of action potentials that propagate along the ganglion cell's axon. Ganglion cell responses are of three types: (1) they respond (either discharge or increase their rate of discharge) only when the light is turned on: (2) they respond only when the light is turned off; or (3) they discharge only at the beginning and end of a light period. These are called on-responses, off-responses and on-off-responses, respectively. The receptive fields of ganglion cells are usually circular areas of retina, as shown in Figure 7-18. Fig. 7-18. Receptive fields of two retinal ganglion cells. Fields are circuluar areas of the retina surrounded by an annulus of different properties. The cell in the upper part of the figure responds when the center is illuminated (on-center, a) and when the surround is darkened (off surround, b). The cell in the lower part of the figure responds when the center is darkened (off-center, d) and when the surround is illuminated (on-surround, e). Both cells give on- and off- responses when both center and surround are illuminated (c and f), but neither response is as strong as when only center or surround is illuminated. (Hubel DH: Sci Amer 209:54-62, 1963) When a ganglion cell fails to discharge at an on- or off-transient of the light, it is not because it is not being excited, but because it is being inhibited, as is indicated by the fact that illumination of both center and surround simultaneously produces both a reduced onresponse and a reduced off-response (c and e) compared to those produced by illuminating either center or surround alone. This effect is termed lateral inhibition or surround inhibition. Visual neurons outside the retina The axons of the ganglion cells form the optic nerves, which, after leaving the eyeball, proceed toward the brain until they come to the optic chiasm, where the optic nerves divide. Fibers from the nasal half of the retina cross to the opposite side of the brain; fibers from the temporal half go to the same side of the brain (Fig. 7-19). Past the chiasm, crossed fibers from the contralateral eye join the uncrossed fibers from the ipsilateral eye to form the optic tract. Fibers in the optic tract, which are still the axons of retinal ganglion cells, then proceed to the thalamus, where they end on cells of the lateral geniculate nucleus. The fibers of this nucleus project to neurons of the calcarine area of the occipital cortex. Fig. 7-19. The anatomic organization of the visual pathway from the retina to the visual cortex. Lesions of the visual pathway (a-g) produce defects in the visual fields as indicated at the right. (Homans A: Textbook of Surgery, 5th ed. Springfield, IL. C.C. Thomas, 1941) The retinal receptive fields of neurons in the occipital cortex are complicated. Some visual cortical neurons (non-oriented neurons) possess receptive fields not particularly different from those of geniculate neurons; they have circular receptive fields and respond equally to stimuli of all orientations. However, the receptive fields of most cortical neurons are not circular, most are arranged as parallel barlike excitatory and inhibitory areas with straight, rather than circular borders. Cortical cells with this characteristic receptive field are termed simple cells. In one sample of cortical neurons, two-thirds of the cells had simple receptive fields. These cells can have two inhibitory regions flanking an excitatory region, as in Figure 7-20; the reverse situation can occur; or there can be just two regions side by side, one excitatory, the other inhibitory. As a result the cells respond best to narrow bars of light oriented in a particular direction across the retina. Sample recordings are shown for three different orientations of such a bar in Figure 7-20. Rotation of the bar has two effects: (1) it reduces the excitation, because less of the excitatory area is illuminated and (2) it increases the inhibition, because more of the inhibitory area is illuminated. The result is that the cortical neuron responds less well when bars are not in their preferred orientation. Fig. 7-20. The receptive field on the retina (ellipse) of a simple cell in the visual cortex is shown at the left with a bar of light superimposed on it at various angles. The vertically striped portion of the receptive field is the excitatory area (excitatory receptive field), illumination of which excites the cell; the unhatched portion is the inhibitory area (inhibitory receptive field), illumination of which inhibits the cell. The bar of light is striped across its length. The responses of the cell to the three different orientations of the light are shown at the right. (Hubel DH: Sci Amer 209:54-62, 1963) Audition An object vibrating in air sets up motion of the molecules in the air around it so that when the object moves in the direction of an observer, it compresses the air and when it moves away, it produces a rarefaction. This sequence of compressions and rarefactions is transmitted in a straight line through the air at a characteristic speed. Sound waves, unlike light, cannot travel through a vacuum, but require some medium, gaseous, liquid or solid, each medium with a different speed of conduction. The ear is a structure specialized to receive these vibrations of the air, transduce them into nervous impulses, encoding important features, and transmit the impulses to the central nervous system; the result is what we call hearing. Highly sensitive mechanoreceptors in the ear are capable of sensing amplitudes of vibrations of the air as small as 10-8 centimeters (the diameter of a hydrogen ion is 2 x 10- 8 cm), yet the ear is structured in such a way that it can withstand sound so intense that it vibrates the whole body. The ear is normally considered to have three parts, an outer ear, a middle ear, and an inner ear, as illustrated in Figure 8-3. Fig. 8-3. The peripheral auditory apparatus with cochlea rotated slightly to show coils and auditory nerve. (Davis H, Silverman SR: Hearing and Deafness, 3rd ed. New York, Holt, Rinehart, Winston, 1970) Central auditory pathways Primary auditory fibers enter the brain stem and immediately make connections with secondary neurons in the cochlear nucleus, as illustrated in Figure 8-14. From here, the auditory information goes to a remarkable number of places in the central nervous system. Fibers arising from the cochlear nuclei ascend in both a crossed and an uncrossed projection, which either enters the lateral lemniscus directly or first relays in the nucleus of the trapezoid body or the superior olive before joining the lateral lemniscus. The lateral lemniscus contains both second and third-order neurons that project either directly or indirectly to the inferior colliculus, which is an obligatory relay for all auditory fibers. Cells of the inferior colliculus project to the medial geniculate nucleus bilaterally, and the medial geniculate nucleus projects to the primary auditory cerebral cortex, located on the superior and medial aspect of the temporal lobe, as indicated in Figure 8-15. The responses of neurons in the various nuclei of the central auditory system resemble those of primary auditory neurons in many ways, but they also differ in important ways. As shown in Figure 8-13, the cells of the trapezoid body (b), inferior colliculus (c), medial geniculate nucleus (d), and primary auditory cortex (e) respond to quite a wide range of sound frequencies and exhibit tuning curves reminiscent of those for auditory nerve fibers. The curves are narrower (i.e., the range of frequencies that causes the cell to discharge is smaller) for higher order neurons (indicated by numbers in Fig. 8-14) up to the level of the medial geniculate nucleus, and then they get wider again. This narrowing represents a sharpening of the cells' frequency discrimination abilities and probably results from a process like lateral inhibition, where cells with close best frequencies inhibit each other. Some investigators have concluded on the basis of this observation that frequency and intensity discriminations are accomplished at or before the medial geniculate level, because cortical neurons simply do not have fine discriminative behavior (i.e., they have wide tuning curves). This is probably true, at least in animals. Neurons in the auditory nerve change their frequency of discharge with changes in sound intensity. Sample intensity functions for these and other cells of the auditory system are illustrated in Figure 816. The relationship between intensity and discharge frequency is sigmoid for auditory nerve fibers and cells of the trapezoid body and the superior olive. These cells increase their frequency of discharge with increasing sound intensity, slowly at first and then more rapidly, to a certain intensity, at which the frequency reaches a maximum. At even greater intensities, there is no further increase in frequency. Cells of the medial geniculate nucleus and the auditory cortex do not increase their frequency of discharge with increasing intensity of sound. (This is the reason for claiming that intensity discriminations occur below this level.) Neurons at successively higher levels of the Fig. 8-14. Central auditory pathways. First, second, auditory system discharge fewer third, and fourth-order cells are indicated by the spikes in response to a standard numerals. tone. Below the level of the inferior colliculus, neurons give repetitive responses to maintained tone stimuli, but at and above the level of the colliculus, they more often give on-, off-, or on-off responses (these terms are used here in the same manner as for visual cells. In the auditory cortex, there are seldom continuous responses to sustained tones; most cells signal sound onset or offset or both. However, sounds that we hear are seldom pure tones (i.e., tones of a single frequency) as were those employed in the preceding experiments. More often, they are composites of sine waves of different frequencies and amplitudes. We know little about how the nervous system deals with such complex sounds, but a beginning has been made. In the cochlear and medial geniculate nuclei, the response to a tone is unaffected by a second tone Fig. 8-15. Diagram to indicate the location of the primary (of different frequency) auditory cortex on the superior lip of the temporal lobe. presented simultaneously at (Guyton A: Textbook of Physiology. Philadelphia, WB weak intensity. As the second Saunders, 1976) tone is increased in intensity, the response to the first tone is gradually suppressed until it finally fails completely. At this intensity, only responses to the second tone are seen if its frequency lies within the response range of the neuron. In the cerebral cortex, the same maneuver performed on a cell with high best frequency results in enhancement of the cell's response if the tones are harmonically related (i.e., if the ratio of their frequencies is 1:2, 1:3, 1:4) or if the difference in frequency is such that it results in 50 to 200 beats/sec. The greater the frequency of beats, the larger the discharge up to 100 beats/sec. Above 100, the response falls off again. It is tempting to speculate that cortical neurons are playing some role in decoding complex sounds or tone patterns, somehow using beats and harmonics. Fig. 8-16. Intensity functions for neurons in the cochlear nerve, trapezoid body, superior olivary complx, auditory cortex, and medial geniculate nucleus of the cat. Frequency of discharge of the neurons is plotted on the ordinate against sound intensity on the abscissa. (Katsuki Y: Neural mechanism of auditory sensation in cats. In Rosenblith WA [ed]: Sensory Communication. Cambridge MA, MIT Press, 1961) GUSTATORY AND OLFACTORY SENSES Taste The gustatory system is much simpler than the olfactory system. Four primary taste submodalities are generally recognized: sweet, sour, salty, and bitter. Different regions on the tongue exhibit different maximal sensitivities to the four taste submodalities (Figure 10-1 which also shows the pattern of innervation of the tongue). The tip of the tongue is the most sensitive to sweetness and saltiness. The sensation of sourness is experienced best on the lateral aspects of the tongue, and bitterness is experienced best and perhaps only on the back of the tongue. Next time you put some bitter substance such as tonic water (quinine) into your mouth, you can verify this for yourself. Fig. 10-1. The distribution of gustatory papillae, their innervation, and the regions of maximum sensitivity to different submodalities of taste on the human tongue. (Altner H: Physiology of taste. In Schmidt RF [ed]: Fundamentals of Sensory Physiology. New York, Springer-Verlag, 1978) Taste neurons normally respond to several different kinds of chemicals so that chorda tympani taste fibers typically respond to substances that are salty, bitter, sweet, and sour. That is, they appear to respond to stimuli of two or three or even four different taste submodalities. An example of the discharges evoked in a single taste fiber in the chorda tympani nerve by substances flowing over the tongue is shown in Figure 10-3. This particular nerve cell gives a brisk discharge when NaCl and saccharin flow over the tongue, but it is only minimally, if at all, excited by sucrose, HCl, or quinine. It is also not especially sensitive to changes in the temperature of the fluid bathing the tongue. Figure 10-3. Impulse discharges in a single chorda tympani nerve fiber of a rat. Responses elicited by application to the tongue of 0.1 M NaCl, 0.5 M sucrose, 0.01 N HCl, 0.02 M quinine hydrochloride, 0.02 M sodium saccharin, 40°C water and 20°C water. Spontaneous discharges are shown in the bottom trace. Between traces the tongue was rinsed with 25°C water. (Ogawa H, Sato M, Yamashita S: J. Physiol (Lond) 199:223-240, 1968) It appears that most taste receptors do not signal single submodalities uniquely, but the submodality, i.e., the quality of the taste, must be determined by the central nervous system from the discharge pattern across the ensemble of sensory nerve fibers. To see this, examine the histograms of Figure 10-4, which are plots of the number of spikes discharged by 28 different chorda tympani nerve fibers in the first five seconds after various solutions were allowed to flow over the tongue of a hamster. In Figure 10-4, the data plotted are from actual experiments, and they illustrate that taste nerve fibers respond better to one or two of the taste submodalities than to others. Few receptors signal a single submodality uniquely; therefore, submodality must be signaled in the form of the ensemble code. Figure 10-4. Response profiles of 28 hamster chorda tympani fibers. Stimuli were 0.1 M NaCl, 0.5 M sucrose, 0.01 N HCl, 0.02 M quinine hydrochloride, 20 C water and 40 C water. The response of a single fiber to each stimulus is found by reading up columns indicated by the letters on the abscissa. (OgawaH, Sato M, Yamashita J: J Physiol (Lond) 199:223-240, 1968) Taste intensity, on the other hand, seems to be signaled in terms of the total number of impulses discharged per second (i.e., the frequency of discharge) in the ensemble of primary taste fibers. Single cells increase their discharge frequencies with increasing concentration of taste substances, as illustrated in Figure 10-5. The graphs indicate the responses of three different chorda tympani fibers to increasing concentrations of taste stimuli. The number of impulses evoked in five sec is plotted against the concentration of the solution (on the abscissa). Fiber #1 was quite sensitive to NaCl, less so to sucrose. However, the discharge of the cell increased steadily as the concentration of either NaCl or sucrose was increased. Fiber #2 was more sensitive to sucrose than NaCl, but it still increased its discharge frequency when either substance was in higher concentration. Fiber #3 was sensitive to NaCl, quinine and HCl, and it showed the same sort of increased response to increasing concentration of any of the three substances. The total number of impulses per second increased in all the fibers, but their relative discharge for each substance was the same. Figure 10-5. Concentration-response magnitude relationships in three typical chorda tympani fibers of rats. Ordinate indicates the number of impulses discharged by the fiber in the first 5 sec after the substance was applied. Fiber #1 was predominantly sensitive to NaCl, fiber #2 was more sensitive to sucrose than NaCl, and fiber #3 was sensitive to NaCl, quinine, and HCl. (O Ogawa H, Sato M, Yamashita J: J Physiol (Lond) 199:223-240, 1968) In an attempt to correlate psychophysical data for taste intensity with neuron responses to stimulus concentration, subjective intensities for citric acid and sucrose were estimated by two human subjects for six different concentrations of each substance and responses of chorda tympani nerve fibers were recorded at the same six concentrations. The results of these two experiments are plotted together on the same log-log plot in Figure 10-6. The magnitudes of taste sensations are plotted as open circles; the magnitudes of neural responses are plotted as filled circles. The plot on the left is for citric acid, that on the right for sucrose. There is remarkable agreement between the psychophysical and neural data, both showing a power function relation between stimulus intensity and response magnitude. Figure 10-6. Dependence of subjective intensity of taste sensations (open circles) and of the frequency of discharge in fibers of the chorda tympani nerve (filled circles) upon the concentration of citric acid (red) and sucrose (green) solutions. Log-log plot. The slopes of the lines correspond to the exponents, k, of power functions with k=0.85 and 1.1. (Borg G, Diamant H, Strom L et al: J Physiol (Lond) 192:13-20, 1967) Smell The human can distinguish the odors of a vast number of different molecules and describes them as aromatic, fragrant, repulsive, ethereal, resinous, spicy, burned, putrid, and so forth. Whether any of these can be considered primary is a point of debate. Odorous substances have in common that they are either gases or volatile liquids. This is the form in which the odorant reaches the sensory epithelium, either through the nostrils with inspired air or by the back door through the mouth and throat. The receptor structures for olfaction are covered with mucus so that aqueous solubility is an asset to an odorant. Of all the chemical elements, only 16 seem to play any role in the production of odor sensation. These are hydrogen, carbon, silicon, nitrogen, phosphorus, arsenic, antimony, bismuth, oxygen, sulfur, selenium, tellurium, fluorine, chlorine, bromine, and iodine. Only the halogens and ozone, O3, are odorous as elements Smell anatomy The olfactory receptors are located in the posterior portion of the nasal cavity in a mucosal area that measures about 5 cm2. The location is shown in Figure 10-8, which is a sagittal section of the human nasal passages. The sensory epithelium sits at the top of the nasal cavity above the superior turbinate bones. It is yellow in color and has no synchronously beating cilia and therefore is distinguishable from the surrounding respiratory epithelia. Within this sensory region are found Bowman's glands that contain most of the yellow pigment and secrete much of the mucus that covers the sensory epithelium in a 10- to 40-m layer. The odorant must dissolve in this mucus layer in order to reach the olfactory receptors. Figure 10-8. Sagittal section of the human nasal passages, showing the nasal fossae, the location of the olfactory epithelium and olfactory bulb, and the direction of travel of inspired air (small arrows). (Douek E: The Sense of Smell and Its Abnormalities. Edinburgh, Livingstone, 1974) The olfactory epithelium contains the receptor cells, as shown in the diagram of Figure 10-9, as well as sustentacular and basal cells. The receptor cells are really bipolar nerve cells and therefore unlike the receptor cells of the eye, ear, and tongue which are specialized epithelial cells. The olfactory receptor cells have their nuclei in the lower 2/3 of the epithelium, but their apical ends project to the surface. The apical ends are slightly enlarged, and they possess numerous cilia that project 50 to 150 m out into the mucus. The location of the receptor sites for odorant molecules on the olfactory receptor cell is unknown. Many people believe they are on the cilia, but the existence of olfactory cells without cilia and the persistence of olfactory sensation after the cilia have been removed argue against this idea. The receptor cells are arranged in interconnected rings, one of which is illustrated in the figure. Gap junctions are thought to connect adjacent receptor cells both between spines and less frequently at their apical expansions. The centers of the rings are apparently filled with supporting cells. At its basal end, each receptor cell gives rise to an axon that forms a part of the olfactory nerve. Olfactory nerve fibers are unmyelinated and average about 0.2 m in diameter. In the rabbit, the olfactory epithelium contains about 100 million receptor cells, and thus there are about the same number of fibers in the olfactory nerve. In man, the olfactory nerve is short, merely perforating the cribriform plate into the brain cavity and terminating in the olfactory bulb. Olfactory nerve fibers converge onto mitral cells in the bulb, which send their axons (about 100,000 of them) in the olfactory tract to the piriform cortex, the periamygdaloid area, and the olfactory tubercle. The olfactory bulb contains interneurons, the granule cells that mediate a form of lateral inhibition between mitral cells; an active mitral cell inhibits (reduces) activity in its neighbors. There are also centrifugal fibers to the olfactory bulb that primarily mediate inhibition of mitral cell activity. The functions of this connection and of the lateral inhibition are not known. Unlike other sensory pathways to the cerebral cortex, the olfactory pathway does not relay in the thalamus as we have just seen. However, fibers do leave the olfactory cortical areas and relay in the thalamus on their way to the hypothalamus or other areas where they perhaps play a role in the regulation of the intake of food and other behaviors that depend upon olfactory information. Figure 10-9. The olfactory mucosa showing arrangement of receptor cells in interconnected rings, one of which is illustrated. Receptor cells are connected together by gap junctions both between spines and less frequently at their apical expansions (two shown) The centers of the rings are apparently filled with supporting cells. (Graziadei PPC: Z Zellforsch 118:449-466, 1971) Smell physiology The coding mechanism for olfactory quality (submodality) has been just as elusive as the identification of the qualities themselves. Microelectrode recordings from the olfactory epithelium yield two sorts of responses to olfactory stimulation. Both can be seen in Figure 10-10. First, there is a slow-wave potential reminiscent of the generator potentials of mechanoreceptors. However, this potential is much larger than generator potentials recorded extracellularly from single receptors elsewhere. It also does not have a fixed relationship to the time of spike initiation, as can be seen in the figure. This potential probably is the summation of the generator potentials of a number of nearby receptor cells and perhaps potentials generated by supporting cells. Second, there are the familiar spike discharges in the receptor cell axons or somata. It can be seen from this typical example that receptors are not highly specific in their responses to odorants. This particular cell responded to camphor, limonene, carbon disulfide, ethyl butyrate, and musk xylene, but it was insensitive to nitrobenzene, benzaldehyde, nbutanol and pyridine. In general, each olfactory receptor responds to a variety of odorants, suggesting a very complex ensemble code. Figure 10-10. Responses of a single cell in the olfactory epithelium to stimulation with camphor, limonene, carbon disulfide, ethyl butyrate, and musk xylene. (Gesteland RC, Lettvin JY, Pitts WH et al.: Odor specificities of frog's olfactory receptors. In Zotterman Y [ed]: Olfaction and Taste. New York, Macmillan, 1963) UNIT V BEHAVIOUR SCIENCE Refer 1. Guyton 2. Ganong Disorders associated with the nervous system Term Definition Cause Effect Bell's Palsy A form of Neuritis that involves paralysis of the facial nerve causing weakness of the muscles of one side of the face and an inability to close the eye. Unknown. Paralysis of the (Recovery may facial nerve; occur weakness of the spontaneously.) muscles of one side of the face; may result in inability to close the eye. (In some cases the patient's hearing may also be affected in such a way that sounds seem to him/her to be abnormally loud. Loss of taste sensation may also occur.) Cerebal Palsy A nonprogressive disorder of movement resulting from damage to the brain before, during, or immediately after birth. progressive Motor Neurone A degenerative disease Disease of the motor system occurring in middle Cerebal Palsy is attributed to damage to the brain, generally occuring before, during, or immediately after birth. It is often associated with other neurological and mental problems.There are many causes including birth injury, hypoxia, hypoglycaemia, jaundice and infection. The most common disability is a spastic paralysis. Sensation is often affected, leading to a lack of balance, and intelligence, posture and speech are frequently impaired. Contractures of the limbs may cause fixed abnormalities. Other associated features include epilepsy, visual impairment, squint, reduced hearing, and behavioural problems. Some forms of Motor Neurone Disease are inherited. Motor Neurone disease primarily affects the cells of the anterior horn of age and causing muscle weakness and wasting. the spinal cord, the motor nuclei in the brainstem, and the corticospinal fibres. Multiple Sclerosis A chronic disease of the nervous system that can affect young and middle-aged adults. The course of this illness usually involves recurrent relapses followed by remissions, but some patients experience a chronic progressive course. The myelin sheaths surrounding nerves in the brain and spinal cord are damaged, which affects the function of the nerves involved. A condition Myalgic by Encephalomyelitis characterized extreme disabling (ME) fatigue that has lasted for at least six months, is made worse by physical or mental exertion, does not resolve with bed rest, and cannot be attributed to other disorders. Unknown. The underlying cause of the nerve damage remains unknown. Often occurs as a sequel to such viral infections as glandular fever. Multiple Scerosis affects different parts of the brain and spinal cord, resulting in typically scattered symptoms. These can include: Unsteady gait and shaky movement of the limbs (ataxia); Rapid involuntary movements of the eyes (nystagmus); Defects in speech pronunciation (dysarthria); Spastic weakness and retrobulbar neuritis (= inflammation of the optic nerve). Extreme disabling fatigue that has lasted for at least six months, is made worse by physical or mental exertion, does not resolve with bed rest, and cannot be attributed to other disorders. The fatigue is accompanied by at least some of the following: Muscle pain or weakness; Poor co- Neuralgia Neuritis Parkinson's Disease ordination; Joint pain; Sore throat; Slight fever; Painful lymph nodes in the neck and armpits; Depression; Inability to concentrate; General malaise. Maybe due to A severe burning or previous attack of stabbing pain often shingles following the course (Postherpetic of a nerve. Neuralgia). A disease of the Inflammation of the peripheral nerves nerves, which may showing the be painful. pathological changes of inflammation. (This term may also be less precisely used to refer to any disease of the peripheral nerves, usually causing weakness and numbness.) Degenerative disease Associated with a Tremor, rigidity and process (associated deficiency of the poverty of with aging) that neurotransmitter spontaneous affects the basal dopamine. movements. ganglia of the brain. Also associated with The commonest aging. symptom is tremor, which often affects one hand, spreading first to the leg on the same side then to the other limbs. It is most profound in resting limbs, interfering with such actions as holding a cup. Sciatica A common condition arising from compression of, or damage to, a nerve or nerve root. Usually caused by degeneration of an intervertebral disc, which protrudes laterally to compress a lower lumbar or an upper sacral spinal nerve root.The onset may be sudden, brought on by an awkward lifting or twisting movement. The patient has an expressionless face, an unmodulated voice, an increasing tendency to stoop, and a shuffling walk. Pain felt down the back and outer side of the thigh, leg, and foot. The back is stiff and painful. There may be numbness and weakness in the leg.