Week 7- Fundamentals of the Nervous System and Nervous Tissue PDF

Fundamentals of the Nervous System and Nervous Tissue The learning outcome: • To understand how the nervous system receives, integrates, and responds to information • To explain how Neuroglia support and maintains neurons • Discuss how the Neurons are the structural units of the nervous system • T...

Fundamentals of the Nervous System and Nervous Tissue The learning outcome: • To understand how the nervous system receives, integrates, and responds to information • To explain how Neuroglia support and maintains neurons • Discuss how the Neurons are the structural units of the nervous system • The Classification of Neurons • The resting membrane potential depends on differences in ion concentration and permeability • Graded potentials are brief, short-distance signals within a neuron • Action potentials are brief, long-distance signals within a neuron and the Synapses transmit signals between neurons • Postsynaptic potentials excite or inhibit the receiving neuron • Neurons act together, making complex behaviors possible • Developmental Aspects of Neurons The nervous system Is the master controlling and communicating system of the body. Every thought, action, and emotion reflects its activity. Its cells communicate by electrical and chemical signals, which are rapid and specific, and usually cause almost immediate responses. • The nervous system consists mostly of nervous tissue, which is highly cellular. For example, less than 20% of the CNS is extracellular space, which means that the cells are densely packed and tightly intertwined. • Although it is very complex, nervous tissue is made up of just two principal types of cells: 1. Supporting cells called neuroglia (or glial cells), small cells that surround and wrap the more delicate neurons 2. Neurons, nerve cells that are excitable (respond to stimuli by changing their membrane potential) and transmit electrical signals List the basic functions of the nervous system The nervous system has three overlapping functions: • Sensory input: The nervous system uses its millions of sensory receptors to monitor changes occurring both inside and outside the body. The gathered information is called sensory input. • Integration: The nervous system processes and interprets sensory in put and decides what should be done at each moment, a process called integration. • Motor out put: The nervous system activates effector organs-the muscles and glands-to cause a response, called motor output. List the basic functions of the nervous system Example: a thirsty person seeing and then lifting a glass of water The structural and functional divisions of the nervous system The structural and functional divisions of the nervous system It is divided into two principal parts: • The Central Nervous System (CNS) consists of the brain and spinal cord, which occupy the dorsal body cavity. The CNS is the integrating and control center of the nervous system. It interprets sensory input and dictates motor output based on reflexes, current conditions, and past experience. • The Peripheral Nervous System (PNS) is the part of the nervous system outside the CNS. The PNS consists mainly of nerves (bundles of axons) that extend from the brain and spinal cord, and ganglia (collections of neuron cell bodies). Spinal nerves carry impulses to and from the spinal cord, and cranial nerves carry impulses to and from the brain. The structural and functional divisions of the nervous system The PNS has two functional subdivisions: • The Sensory, or Afferent, division "carrying toward" consists of nerve fibers (axons) that convey impulses to the central nervous system from sensory receptors located throughout the body. • The Motor, or Efferent , division "carrying away“ of the PNS transmits impulses from the CNS to effector organs, which are the muscles and glands. These impulses activate muscles to contract and glands to secrete. In other words, they effect (bring about) a motor response. The structural and functional divisions of the nervous system The Sensory (Afferent) Division: • Somatic sensory fibers convey impulses from the skin, skeletal muscles, and joints • Visceral sensory fibers transmit impulses from the visceral organs (organs within the ventral body cavity) The Motor (Efferent) Division: • The somatic nervous system is composed of somatic motor nerve fibers that conduct impulses from the CNS to skeletal muscles. It is often referred to as the voluntary nervous system because it allows us to consciously control our skeletal muscles. • The autonomic nervous system (ANS) consists of visceral motor nerve fibers that regulate the activity of smooth muscles, cardiac muscle, and glands. Autonomic means "a law unto itself," and because we generally cannot control such activities as the pumping of our heart or the movement of food through our digestive tract, the ANS is also called the involuntary nervous system. The ANS has two functional subdivisions, the sympathetic division and the parasympathetic division. Neuroglia support and maintain neurons • There are six types of neuroglia-four in the CNS and two in the PNS Neuroglia in the CNS: • Neuroglia in the CNS outnumber neurons and include Astrocytes, Microglial cells, Ependymal cells, and Oligodendrocyles. • Like neurons, most neuroglia have branching processes (extensions) and a central cell body. They can be distinguished, however, by their much smaller size and their darker-staining nuclei. Astrocytes • Shaped like delicate branching sea anemones, astrocytes “star cells" are the most abundant and versatile glial cells. • Their numerous radiating processes cling to neurons and their synaptic endings, and cover nearby capillaries. • They support and brace the neurons and anchor them to their nutrient supply lines. • Astrocytes play a role in making exchanges between capillaries and neurons, helping determine capillary permeability. • They guide the migration of young neurons and formation of synapses (junctions) between neurons. • Astrocytes also control the chemical environment around neurons, where their most important job is "mopping up" leaked potassium ions and recapturing and recycling released neurotransmitters. • Astrocytes have been shown to respond to nearby nerve impulses and released neurotransmitters. • Connected by gap junctions, astrocytes signal each other with slow-paced intracellular calcium pulses (calcium waves), and by releasing extracellular chemical messengers. • They also influence neuronal functioning and therefore participate in information processing in the brain. Microglial cells • Are small and ovoid with relatively long "thorny" processes • Their processes touch nearby neurons, monitoring their health, and when they sense that certain neurons are injured or in other trouble, the microglial cells migrate toward them. • Where invading microorganisms or dead neurons are present, the microglial cells transform into a special type of macrophage that phagocytizes the microorganisms or neuronal debris. • This protective role is important because cells of the immune system have limited access to the CNS. Ependymal cells • "Wrapping Garment" range in shape from squamous to columnar, and many are ciliated • They line the central cavities of the brain and the spinal cord, and form a fairly permeable barrier between the cerebrospinal fluid that fills those cavities and the tissue fluid bathing the cells of the CNS. • The beating of their cilia helps to circulate the cerebrospinal fluid that cushions the brain and spinal cord. Oligodendrocytes • The oligodendrocytes have fewer processes (oligo = few; dendr = branch) than astrocytes. • Oligodendrocytes line up along the thicker nerve fibers in the CNS and wrap their processes tightly around the fibers, producing an insulating covering called a Myelin sheath Neuroglia in the PNS • The two kinds of PNS neuroglia-Satellite Cells and Schwann Cells, differ mainly in location. • Satellite cells surround neuron cell bodies located in the peripheral nervous system and are thought to have many of the same functions in the PNS as astrocytes do in the CNS. Their name comes from a fancied resemblance to the moons (satellites) around a planet. • Schwann cells (also called Neurolemmocytes) surround all nerve fibers in the PNS and form myelin sheaths around the thicker nerve fibers. In this way, they are functionally similar to oligodendrocytes. Schwann cells are vital to regeneration of damaged peripheral nerve fibers. Neurons are the structural units of the nervous system Neurons: also called nerve cells, are the structural units of the nervous system. There are billions of these (typically) large, highly specialized cells that conduct messages in the form of nerve impulses from one part of the body to another. Besides their Excitability, they have three other special characteristics: 1. Neurons have extreme longevity. Given good nutrition, they can function optimally for a lifetime. 2. Neurons are amitotic. As neurons assume their roles as communicating links of the nervous system, they lose their ability to divide. We pay a high price for this feature because neurons cannot be replaced if destroyed. There are exceptions to this rule. For example, olfactory epithelium and some hippocampal regions of the brain contain stem cells that can produce new neurons throughout life. 3. Neurons have an exceptionally high metabolic rate and require continuous and abundant supplies of oxygen and glucose. They cannot survive for more than a few minutes without oxygen. Neuron Cell Body • The neuron cell body consists of a spherical nucleus (with a conspicuous nucleolus) surrounded by cytoplasm. Also called the Perikaryon Or Soma. Most neuron cell bodies are located in the CNS, and protected by the bones of the skull and vertebral column. Clusters of cell bodies in the CNS are called Nuclei, and those in the PNS are called Ganglia • In most neurons, the plasma membrane of the cell body acts as part of the receptive region that receives information from other neurons. • The cell body is the major biosynthetic center and ,metabolic center of a neuron. In addition to abundant mitochondria, it contains many structures you are already familiar with, including: 1. Protein- and membrane-making machinery: Neuron cell bodies (not axons) have the organelles needed to synthesize proteins-rough endoplasmic reticulum (ER), free ribosomes, and Golgi apparatus. The rough ER, also called the chromatophilic substance or Nissl bodies stains darkly with basic dyes. 2. Cytoskeletal elements: Microtubules and neurofibrils, which are bundles of intermediate filaments (neurofilaments), maintain cell shape and integrity. They form a network throughout the cell body and its processes. 3. Pigment inclusions: Pigments found inside neuron cell bodies include black melanin, a red iron-containing pigment, and a golden-brown pigment called Lipofuscin. Lipofuscin, a harmless by-product of lysosomal activity, is sometimes called the "aging pigment" because it accumulates in neurons of elderly. Neuron Processes • Armlike processes extend from the cell body of all neurons. The brain and spinal cord (CNS) contain both neuron cell bodies and their processes. The PNS consists chiefly of neuron processes (whose cell bodies are in the CNS). • The two types of neuron processes, Dendrites and Axons differ in the structure and function of their plasma membranes. Many sensory neurons and some tiny CNS neurons differ from the "typical" pattern is presented here. Dendrites • Dendrites of motor neurons are short, tapering, diffusely branching extensions. • Typically, motor neurons have hundreds of twiglike dendrites clustering close to the cell body. • Virtually all organelles present in the cell body also occur in dendrites. • Dendrites, the main receptive or input regions, provide an enormous surface area for receiving signals from other neurons. • In many brain areas, the finer dendrites are highly specialized for collecting information. • They bristle with dendritic spines-thorny appendages with bulbous or spiky ends-which represent points of close contact (synapses) with other neurons. • Dendrites convey incoming messages toward the cell body. These electrical signals are usually not action potentials (nerve impulses) but are short-distance signals called Graded Potentials. The Axon: Structure • A neuron never has more than a single. The axon arises from a cone-shaped area of the cell body called the Axon Hillock. • The Initial Segment of the axon narrows to form a slender process that is uniform in diameter for the rest of its length. • In some neurons, the axon is very short or absent, but in others it accounts for nearly the entire length of the neuron. For example, axons of the motor neurons controlling the skeletal muscles of your big toe extend a meter or more (3-4 feet) from the lumbar region of the spine to the foot, making them among the longest cells in the body. • Any long axon is also called a Nerve Fiber. Bundles of axons are called Tracts in the CNS and Nerves in the PNS. • Although only one axon arises from the cell body, the axon may have occasional branches along its length. These branches, called axon collaterals, extend from the axon at more or less right angles. • An axon usually branches profusely at its end (terminus): 10,000 or more terminal branches (also called terminal arborizations) per neuron is not unusual. The knoblike distal endings of the terminal branches are called axon terminals. The Axon: Functional Characteristics • The axon is the Conducting Region of the neuron. It generates nerve impulses and transmits them, typically away from the cell body, along the plasma membrane, or Axolemma. • In motor neurons, the nerve impulse is generated at the Initial Segment of the axon (The Trigger Zone) and conducted along the axon to the axon terminals, which are the secretory region of the neuron. • When the impulse reaches the axon terminals, it causes Neurotransmitters-signaling chemicals-to be released into the extracellular space. • The neurotransmitters either Excite or Inhibit neurons (or muscle or gland cells) with which the axon is in close contact. • Each neuron receives signals from and sends signals to scores of other neurons, carrying on "conversations" with many different neurons at the same time. • An axon contains the same cytoplasmic organelles found in the dendrites and cell body with two important exceptions-it lacks rough endoplasmic reticulum and a Golgi apparatus, the structures involved with protein synthesis and packaging. • Consequently, an axon depends on (1) its cell body to renew the necessary proteins and membrane components, and (2) efficient transport mechanisms to distribute them. • Axons quickly decay if cut or severely damaged. Axonal Transport • Because axons are often very long, the task of moving molecules along their length might appear difficult. However, through the cooperative efforts of motor proteins and cytoskeletal elements (mostly microtubules), substances travel continuously along the axon in both directions: 1. Anterograde Movement: is movement away from the cell body. Substances moved in this direction include mitochondria, cytoskeletal elements, membrane components (vesicles) used to renew the axon plasma membrane, and enzymes needed to synthesize certain neurotransmitters. (Some neurotransmitters are synthesized in the cell body, packaged into vesicles, and then transported to the axon terminals.) 2. Retrograde Movement: is movement toward the cell body. Substances moved in this direction are mostly organelles returning to the cell body to be degraded or recycled. Retrograde transport is also an important means of intracellular communication. It allows the cell body to be advised of conditions at the axon terminals. It also delivers vesicles to the cell body containing signal molecules (such as nerve growth factor, which activates certain nuclear genes promoting growth). • A single basic bidirectional transport mechanism is responsible for axonal transport. It uses different ATP-dependent "motor" proteins (Kinesin or Dynein), depending on the direction of transport. These proteins propel cellular components along the microtubules like trains along tracks at speeds up to 40 cm per day. Myelin Sheath • Many nerve fibers, particularly those that are long or large in diameter, are covered with a whitish, fatty (protein-lipoid), segmented myelin sheath. • Myelin protects and electrically insulates fibers, and it increases the transmission speed of nerve impulses. • Myelinated fibers conduct nerve impulses rapidly, whereas nonmyelinated fibers conduct impulses more slowly. *** Note that myelin sheaths are associated only with axons. Dendrites are always nonmyelinated. Myelination in the PNS • Myelin sheaths in the PNS are formed by Schwann cells, which indent to receive an axon and then wrap themselves around it in a jelly roll fashion. • Initially the wrapping is loose, but the Schwann cell cytoplasm is gradually squeezed from between the membrane layers. • When the wrapping process is complete, many concentric layers of Schwann cell plasma membrane enclose the axon, much like gauze wrapped around an injured finger. This tight coil of wrapped membranes is the myelin sheath, and its thickness depends on the number of spirals. • The nucleus and most of the cytoplasm of the Schwann cell end up as a bulge just external to the myelin sheath. This portion is called the Outer Collar of Perinuclear Cytoplasm (The Neurilemma). • Plasma membranes of myelinating cells contain much less protein than those of most body cells. Channel and carrier proteins are notably absent, making myelin sheaths exceptionally good electrical insulators. • Another unique characteristic of these membranes is the presence of specific protein molecules that interlock to form a sort of Molecular Velcro® between adjacent myelin membranes. • Adjacent Schwann cells do not touch one another, so there are gaps in the sheath. These myelin sheath gaps, or Nodes Of Ranvier, occur at regular intervals along a myelinated axon. Axon Collaterals can emerge at these gaps. Myelinaion in the PNS • Sometimes Schwann cells surround peripheral nerve fibers but the coiling process does not occur. In such instances, a single Schwann cell can partially enclose 15 or more axons, each of which occupies a separate recess in the Schwann cell surface. • Nerve fibers associated with Schwann cells in this manner are said to be Nonmyelinated and are typically thin fibers. • Unlike a Schwann cell, which forms only one segment of a myelin sheath, an Oligodendrocyte has multiple flat processes that can coil around as many as 60 axons at the same time. • As in the PNS, myelin sheath gaps separate adjacent sections of an axon's myelin sheath. However, CNS myelin sheaths lack an outer collar of perinuclear cytoplasm because cell extensions do the coiling and the squeezed-out cytoplasm is forced back toward the centrally located nucleus instead of peripherally. • As in the PNS, the smallest-diameter axons are nonmyelinated. These nonmyelinated axons are covered by the long extensions of adjacent glial cells. Myelinaion in the PNS • Sometimes Schwann cells surround peripheral nerve fibers but the coiling process does not occur. In such instances, a single Schwann cell can partially enclose 15 or more axons, each of which occupies a separate recess in the Schwann cell surface. • Nerve fibers associated with Schwann cells in this manner are said to be Nonmyelinated and are typically thin fibers. Myelinaion in the PNS Classification of Neurons • Neurons are classified both structurally and functionally. Neurons are grouped structurally according to the number of processes extending from their cell body: • Multipolar neurons (polar = end, pole) have three or more processes-one axon and the rest dendrites. They are the most common neuron type in humans, with more than 99% of neurons in this class. Multi polar neurons are the major neuron type in the CNS. • Bipolar neurons have two processes-an axon and a dendrite that extend from opposite sides of the cell body. These rare neurons are found in some of the special sense organs such as in the retina of the eye and in the olfactory mucosa . • Unipolar neurons have a single short process that emerges from the cell body and divides T-like into proximal and distal branches. The more distal peripheral process is often associated with a sensory receptor. The central process enters the CNS. Unipolar neurons are more accurately called pseudounipolar neurons because they originate as bipolar neurons. During early embryonic development, the two processes converge and partially fuse to form the short single process that issues from the cell body. Unipolar neurons are found chiefly in ganglia in the PNS, where they function as sensory neurons. Classification of Neurons Functional Classification • This scheme groups neurons according to the direction in which the nerve impulse travels relative to the central nervous system: • Sensory, or afferent, neurons transmit impulses from sensory receptors in the skin or internal organs toward or into the central nervous system. Except for certain neurons found in some special sense organs, virtually all sensory neurons are Unipolar, and their cell bodies are located in sensory ganglia outside the CNS. Only the most distal parts of these unipolar neurons act as the receptive region, and the peripheral processes are often very long. For example, fibers carrying sensory impulses from the skin of your big toe travel for more than a meter before they reach their cell bodies in a ganglion close to the spinal cord. In some sensory neurons, the receptive endings function directly as sensory receptors. In other sensory neurons, receptive endings are associated with larger sensory receptors that include other cell types. • Motor, or efferent, neurons carry impulses away from the CNS to the effector organs (muscles and glands) of the body. Motor neurons are Multi Polar. Except for some neurons of the autonomic nervous system, their cell bodies are located in the CNS. • Interneurons, or association neurons, lie between motor and sensory neurons in neural pathways and shuttle signals through CNS pathways where integration occurs. Most interneurons are confined within the CNS. They make up over 99% of the neurons of the body, including most of those in the CNS. Almost all interneurons are Multi Polar, but there is considerable diversity in size and fiber-branching patterns. The resting membrane potential depends on differences in ion concentration and permeability • Like all cells, neurons have a resting membrane potential. However, unlike most other cells, neurons can rapidly change their membrane potential. This ability underlies the function of neurons throughout the nervous system. • Any situation in which there are separated electrical charges of opposite sign has the potential to do work. We call this potential energy. • In the body, electrical currents reflect the flow of ions across cellular membranes. (Unlike the electrons flowing along your house wiring, there are no free electrons "running around" in a living system.) Recall that there is a slight difference in the numbers of positive and negative ions on the two sides of cellular plasma membranes (a charge separation), so there is a potential across those membranes. The plasma membranes provide the resistance to current flow. Role of Membrane Ion Channels • Recall that plasma membranes are peppered with a variety of membrane proteins that act as ion channels. • Each of these channels is selective as to the type of ion (or ions) it allows to pass. For example, a potassium ion channel allows only potassium ions to pass. • Membrane channels are large proteins, often with several subunits. Some channels, leakage or nongated channels, are always open. • Other channels are gated: Part of the protein forms a molecular "gate" that changes shape to open and close the channel in response to specific signals. Three main types of gated channels: 1. Chemically gated channels, also known as ligand-gated channels, open when the appropriate chemical (in this case a neurotransmitter) binds. 2. Voltage-gated channels open and close in response to changes in the membrane potential. 3. Mechanically gated channels open in response to physical deformation of the receptor (as in sensory receptors for touch and pressure). Electrochemical gradient • When gated ion channels open, ions diffuse quickly across the membrane. The direction an ion moves (into or out of the cell) is determined by the Electrochemical gradient. • The electrochemical gradient has two components: 1- The concentration gradient: Ions move along chemical concentration gradients from an area of their higher concentration to an area of lower concentration. 2- The electrical gradient: Ions move toward an area of opposite electrical charge. • The two gradients do not necessarily work together to drive an ion in the same direction. Often, the two gradients oppose each other, each trying to drive ions in the opposite direction. Whichever gradient is the strongest "wins" and drives the net flow of ions in its direction. Generating the Resting Membrane Potential • A voltmeter is used to measure the potential difference between two points. When one microelectrode of the voltmeter is inserted into a neuron and the other is in the extracellular fluid, it records a voltage across the membrane of approximately - 70 mV . The minus sign indicates that the cytoplasmic side (inside) of the membrane is negatively charged relative to the outside. • This potential difference in a resting neuron (Vr) is called the resting membrane potential, and the membrane is said to be polarized. • The value of the resting membrane potential varies (from -40 mV to -90 mV) in different types of neurons. • The resting potential exists only across the membrane; the solutions inside and outside the cell are electrically neutral. • Two factors generate the resting membrane potential: differences in the ionic composition of the intracellular and extracellular fluids, and differences in the plasma membrane's permeability to those ions. Measuring membrane potential in neurons Resting Membrane Potential Generating a resting membrane potential depends on: (1) differences in K+ and Na+ concentrations inside and outside cells (2) differences in permeability of the plasma membrane to these ions Differences in Ionic Composition and in Plasma Membrane Permeability • First, let's compare the ionic makeup of the intracellular and extracellular fluids: The cell cytosol contains a lower concentration of Na+ and a higher concentration of K+ than the extracellular fluid. Negatively charged (anionic) proteins help to balance the positive charges of intracellular cations (primarily K+). In the extracellular fluid, the positive charges of Na+ and other cations are balanced chiefly by chloride ions (Cl-). Although there are many other solutes (glucose, urea, and other ions) in both fluids, potassium (K+) plays the most important role in generating the membrane potential. • The differential permeability of the membrane to various ions: At rest the membrane is impermeable to the large anionic cytoplasmic proteins, very slightly permeable to sodium, approximately 25 times more permeable to potassium than to sodium, and quite permeable to chloride ions. These resting permeabilities reflect the properties of the leakage ion channels in the membrane. Potassium ions diffuse out of the cell along their concentration gradient much more easily than sodium ions can enter the cell along theirs. K+ flowing out of the cell causes the cell to become more negative inside. Na+ trickling into the cell makes the cell just slightly more positive than it would be if only K+ flowed. Therefore, at resting membrane potential, the negative interior of the cell is due to a much greater ability for K+ to diffuse out of the cell than for Na+ to diffuse into the cell. Because some K + is always leaking out of the cell and some Na+ is always leaking in, you might think that the concentration gradients would eventually "run down," resulting in equal concentrations of Na+ and K+ inside and outside the cell. This does not happen because the ATP-driven sodium-potassium pump first ejects three Na+ from the cell and then transports two K+ back into the cell. • In other words, the sodium-potassium pump (Na+ -K+ ATPase) stabilizes the resting membrane potential by maintaining the concentration gradients for sodium and potassium Changing the Resting Membrane Potential • Neurons use changes in their membrane potential as signals to receive, integrate, and send information. • A change in membrane potential can be produced by (1) anything that alters ion concentrations on the two sides of the membrane, or (2) anything that changes membrane permeability to any ion. However, only permeability changes (changes in the number of open channels) are important for transferring information. • Changes in membrane potential can produce two types of signals: • Graded potentials-usually incoming signals operating over short distances that have variable (graded) strength • Action potentials-long-distance signals of axons that always have the same strength. • The terms Depolarization and Hyperpolarization describe changes in membrane potential relative to resting membrane potential. • Depolarization is a decrease in membrane potential: The inside of the membrane becomes less negative (moves closer to zero) than the resting potential. For instance, a change in resting potential from -70 mV to 65mv is a depolarization. Depolarization also includes events in which the membrane potential reverses and moves above zero to become positive. • Hyperpolarization is an increase in membrane potential: The inside of the membrane becomes more negative (moves farther from zero) than the resting potential. For example, a change from -70 mV to -75 mV is hyperpolarization . As we will describe shortly, depolarization increases the probability of producing nerve impulses, whereas hyperpolarization reduces this probability . Changing the Resting Membrane Potential Graded potentials are brief, short-distance signals within a neuron • Graded potentials are short-lived, localized changes in membrane potential, usually In Dendrites or The Cell Body. They can be either Depolarizations or Hyperpolarizations. • These changes cause current flows that decrease in magnitude with distance. Graded potentials are called "graded" because their magnitude varies directly with stimulus strength. The stronger the stimulus, the more the voltage changes and the farther the current flows. • Graded potentials are triggered by some change (a stimulus) in the neuron's environment that opens gated ion channels. Graded potentials are given different names, depending on where they occur and the functions they perform. • A receptor potential or a generator potential is produced when a sensory receptor is excited by its stimulus (e.g., light, pressure, chemicals). • A postsynaptic potential is produced when the stimulus is a neurotransmitter released by another neuron. Here, the neurotransmitter is released into a fluid-filled gap called a synapse and influences the neuron beyond the synapse. The spread and decay of a graded potential. • Fluids inside and outside cells are fairly good conductors, and current, carried by ions, flows through these fluids whenever voltage changes. • Suppose a stimulus depolarizes a small area of a neuron's plasma membrane. Current (ions) flows on both sides of the membrane between the depolarized (active) membrane area and the adjacent polarized (resting) areas. • Positive ions migrate toward more negative areas (the direction of cation movement is the direction of current flow), and negative ions simultaneously move toward more positive areas. • Positive ions (mostly K+) inside the cell move away from the depolarized area and accumulate on the neighboring membrane areas, where they neutralize negative ions. • Meanwhile, positive ions (mostly Na+) on the outside of the membrane move toward the depolarized region, which is momentarily less positive. As these positive ions move, their "places" on the membrane become occupied by negative ions (such as Cl- and HC03 - ), sort of like ionic musical chairs. Graded potentials are brief, short-distance signals within a neuron • In this way, at regions next to the depolarized region, the inside becomes less negative and the outside becomes less positive. The depolarization spreads as the neighboring membrane patch is, in turn, depolarized. • The current dies out within a few millimeters of its origin and is said to be Decremental. • Because the current dissipates quickly declines with increasing distance from the site of initial depolarization, graded potentials can act as signals only over very short distances such as in the dendrites and cell body. • Nonetheless, they are essential in initiating action potentials, the longdistance signals of axons. Graded Potential Vs Action Potential Action potentials are brief, long-distance signals within a neuron • The principal way neurons send signals over long distances is by generating and propagating (transmitting) action potentials. • Only cells with excitable membranes-neurons and muscle cells-can generate action potentials. • An action potential (AP) is a brief reversal of membrane potential with a total amplitude (change in voltage) of about 100 mV (from - 70 mV to +30 mV). • Depolarization is followed by repolarization and often a short period of hyperpolarization. The whole event is over in a few milliseconds. Unlike graded potentials, action potentials do not decay with distance. • In a neuron, an AP is also called a Nerve Impulse, and is typically generated only in axons. The stimulus changes the permeability of the neuron's membrane by opening specific voltage-gated channels on the axon. • These voltage-gated channels are generally found only on axons, where they are critical for AP formation. No voltage-gated channels means no AP. • Voltage-gated channels open and close in response to changes in the membrane potential. They are initially activated by local currents (graded potentials) that spread toward the axon along the dendritic and cell body membranes. • In many neurons, the transition from local graded potential to long-distance action potential takes place at the Initial Segment Of The Axon. In sensory neurons, the action potential is generated by the peripheral (axonal) process just proximal to the receptor region. The action potential (AP) Is a brief change in membrane potential in a patch of membrane that is depolarized by local currents. The Key players The events: Each step corresponds to one part of the AP graph. Generating an Action Potential 1) Resting state: All voltage-gated Na+ and K+ channels are closed. Only the leakage channels are open, maintaining resting membrane potential. Each Na+ channel has two gates: a voltage-sensitive activation gate that is closed at rest and responds to depolarization by opening, and an inactivation gate that blocks the channel once it is open. Thus, depolarization opens and then inactivates sodium channels. Both gates must be open for Na+ to enter, but the closing of either gate effectively closes the channel. In contrast, each voltage-gated potassium channel has a single voltage sensitive gate that is closed in the resting state and opens slowly in response to depolarization. 2) Depolarization: Voltage-gated Na+ channels open. As local currents depolarize the axon membrane, the voltage gated sodium channels open and Na+ rushes into the cell. This influx of positive charge depolarizes that local patch of membrane further, opening more Na+ channels so the cell interior becomes progressively Jess negative. When depolarization reaches a critical level called threshold (often between -55 and - 50 mV), depolarization becomes selfgenerating, urged on by positive feedback. As more Na+ enters, the membrane depolarizes further and opens still more channels until all Na+ channels are open. At this point, Na+ permeability is about 1000 times greater than in a resting neuron. As a result, the membrane potential becomes less and less negative and then overshoots to about + 30 m V as Na+ rushes in along its electrochemical gradient. This rapid depolarization and polarity reversal produces the sharp upward spike of the action potential. This explosive positive feedback cycle is responsible for the rising (depolarizing) phase of an action potential-it puts the "action" in the action potential. Generating an Action Potential 3) Repolarization: Na+ channels are inactivating, and voltage-gated K+ channels open. The explosively rising phase of the action potential persists for only about 1 ms. It is self-limiting because the inactivation gates of the Na+ channels begin to close at this point. As a result, the membrane permeability to Na+ declines to resting levels, and the net influx of Na+ stops completely. Consequently, the AP spike stops rising. As Na+ entry declines, the slow voltage-gated K+ channels open and K + rushes out of the cell, following its electrochemical gradient. This restores the internal negativity of the resting neuron, an event called repolarization. Both the abrupt decline in Na+ permeability and the increased permeability to K+ contribute to repolarization. 4) Hyperpolarization: Some K+ channels remain open, and Na+ channels reset. The period of increased K+ permeability typically lasts longer than needed to restore the resting state. As a result of the excessive K+ efflux before the potassium channels close, a hyperpolarization is seen on the AP curve as a slight dip following the spike. At the end of this phase, the Na+ channels have reset to their original position by changing shape to reopen their inactivation gates and close their activation gates. Threshold and the All-or-None Phenomenon • Not all local depolarization events produce APs. The depolarization must reach threshold values if an axon is to "fire." • Threshold is typically reached when the membrane has been depolarized by 15 to 20 mV from the resting value. This depolarization status represents an unstable equilibrium state. If one more Na+ enters, further depolarization occurs, opening more Na+ channels and allowing more Na+ to enter. If, on the other hand, one more K+ leaves, the membrane potential is driven away from threshold, Na+ channels close, and K+ continues to diffuse outward until the potential returns to its resting value. • Recall that local depolarization's are graded potentials and their magnitude increases when stimuli become more intense. Brief weak stimuli (subthreshold stimuli) produce subthreshold depolarizations that are not translated into nerve impulses. On the other hand, stronger threshold stimuli produce depolarizing currents that push the membrane potential toward and beyond the threshold voltage. • As a result, Na+ permeability rises to such an extent that entering sodium ions "swamp" (exceed) the outward movement of K+, establishing the positive feedback cycle and generating an AP. The critical factor here is the total amount of current that flows through the membrane during a stimulus (electrical charge x time). Strong stimuli depolarize the membrane to threshold quickly. • Weaker stimuli must be applied for longer periods to provide the crucial amount of current flow. Very weak stimuli do not trigger an AP because the local current flows they produce are so slight that they dissipate long before threshold is reached. Propagation of an Action Potential • An AP must be propagated along the axon's entire length. The AP is generated by the influx of Na+ through a given area of the membrane. This influx establishes local currents that depolarize adjacent membrane areas in the forward direction (away from the origin of the nerve impulse), which opens voltage-gated channels and triggers an action potential there. • This process repeats down the length of the axon so that an AP is self-propagating and continues along the axon at a constant velocity-something like falling dominos. • Following depolarization, each segment of axon membrane repolarizes, restoring the resting membrane potential in that region. Because these electrical changes also set up local currents, the repolarization wave chases the depolarization wave down the length of the axon. • Although the phrase conduction of a nerve impulse is commonly used, nerve impulses are not really conducted in the same way that an insulated wire conducts current. In fact, neurons are fairly poor conductors, and local current flows decline with distance because the charges leak through the membrane. • The expression propagation of a nerve impulse is more accurate, because the AP is regenerated anew by the voltage-gated channels at each membrane patch, and every subsequent AP is identical to the one that was generated initially. Without voltage-gated channels, propagation cannot occur. Propagation of an action potential (AP): Recordings at three successive times as an AP propagates along an axon (from left to right). The arrows show the direction of local current flow generated by the movement of positive ions. This current brings the resting membrane at the leading edge of the AP to threshold, propagating the AP forward. Coding for Stimulus Intensity How can the CNS determine whether a particular stimulus is intense or weak? • Strong stimuli generate nerve impulses more often in a given time interval than do weak stimuli. • Stimulus intensity is coded for by the number of impulses per second-that is, by the frequency of action potentials-rather than by increases in the strength (amplitude) of the individual Aps. Refractory Periods • When a patch of neuron membrane is generating an AP and its voltage-gated sodium channels are open, the neuron cannot respond to another stimulus, no matter how strong. Called the Absolute Refractory Period, this period begins with the opening of the Na+ channels and ends when the Na+ channels begin to reset to their original resting state. The absolute refractory period: • Ensures that each AP is a separate, all-or-none event • Enforces one-way transmission of the AP. Because the area where the AP originated has just generated an AP, the Na+ channels in that area are inactivated and no new AP is generated there. *** For this reason, the AP propagates away from its point of origin. In the body, APs are initiated at one end of the axon and conducted away from that point toward the other end. (lf an axon is stimulated by an electrode at a location that is not at either end of the axon, the AP will move away from the point of stimulus in both directions along the axon.) Refractory Periods The relative refractory period follows the absolute refractory period: • During the relative refractory period, most Na+ channels have returned to their resting state, some K+ channels are still open, and repolarization is occurring. • The axon's threshold for AP generation is substantially elevated, so a stimulus that would normally generate an AP is no longer sufficient. **An exceptionally strong stimulus can reopen the Na+ channels that have already returned to their resting state and generate another AP. • Strong stimuli trigger more frequent APs by intruding into the relative refractory period. It might help you to remember the difference between the absolute and relative refractory periods if you know that the word "refractory" means stubborn or unmanageable. Refractory Periods Absolute and Relative refractory periods in an AP. Conduction Velocity • Nerve fibers that transmit impulses most rapidly (100 m/s or more) are found in neural pathways where speed is essential, such as those that mediate postural reflexes. Axons that conduct impulses more slowly typically serve internal organs (the gut, glands, blood vessels), where slower responses are not a handicap. The rate of impulse propagation depends largely on two factors: • Axon diameter. As a rule, the larger the axon's diameter, the faster it conducts impulses. Larger axons conduct more rapidly because they offer less resistance to the flow of local currents, bringing adjacent areas of the membrane to threshold more quickly. • Degree of myelination: The presence of a myelin sheath dramatically increases the speed of propagation. The conduction velocity increases with the degree of myelination. Lightly myelinated fibers conduct more slowly than heavily myelinated fibers. Action potentials can be propagated in one of two ways, depending on whether myelin is present or absent from the axon • Continuous Conduction: Action potential propagation in nonmyelinated axons occurs by continuous conduction because the voltage-gated channels in the membrane are immediately adjacent to each other. Continuous conduction is relatively slow. • Saltatory Conduction: When an AP is generated in a myelinated fiber, the local depolarizing current does not dissipate through the adjacent membrane regions, which are nonexcitable. Instead, the current is maintained and moves rapidly to the next myelin sheath gap, a distance of approximately 1mm, where it triggers another AP. Consequently, APs are triggered only at the gaps. This type of conduction is called saltatory conduction (to leap) because the electrical signal appears to jump from gap to gap along the axon. Saltatory conduction is about 30 times faster than continuous conduction. Action Potential propagation in Nonmyelinated and Myelinated axons Nerve fibers may be classified according to diameter, degree of myelination, and conduction speed. • Group A fibers are mostly Somatic Sensory And Motor Fibers serving the skin, skeletal muscles, and joints. They have the largest diameter, thick myelin sheaths, and conduct impulses at speeds up to 150 m/s (over 300 miles per hour). • Group B fibers are lightly myelinated fibers of intermediate diameter. They transmit impulses at an average rate of 15 m/s (about 30 mi/h). • Group C fibers have the smallest diameter. They are nonmyelinated, so they are incapable of saltatory conduction and conduct impulses at a leisurely pace- 1m/s (2 mi/h) or less. ***The B and C fiber groups include Autonomic Nervous System Motor Fibers serving the visceral organs; visceral sensory fibers; and the smaller Somatic Sensory Fibers that transmit sensory impulses from the skin (such as pain and small touch fibers). Synapses transmit signals between neurons • The operation of the nervous system depends on the flow of information through chains of neurons functionally connected by synapses • A synapse "to clasp or join," is a junction that mediates information transfer from one neuron to the next or from a neuron to an effector cell- it's where the action is. • The neuron conducting impulses toward the synapse is the presynaptic neuron, and the neuron transmitting the electrical signal away from the synapse is the postsynaptic neuron. • At a given synapse, the presynaptic neuron sends the information, and the postsynaptic neuron receives the information. • Most neurons function as both presynaptic and postsynaptic neurons. Neurons have anywhere from 1000 to 10,000 axon terminals making synapses and are stimulated by an equal number of other neurons. • Outside the central nervous system, the postsynaptic cell may be either another neuron or an effector cell (a muscle cell or gland cell). Synapses • Synapses between the axon endings of one neuron and the dendrites of other neurons are Axodendritic synapses. • Those between axon endings of one neuron and the cell body (soma) of another neuron are Axosomatic synapses. • Less common (and far less understood) are synapses between axons (axoaxonal), between dendrites (dendrodendritic), or between cell bodies and dendrites (somatodendritic). • There are two types of synapses: Electrical and Chemical. Electrical Synapses • Electrical synapses are much less common than chemical synapses. They consist of Gap Junctions like those found between certain other body cells. Their channel proteins (Connexons) connect the cytoplasm of adjacent neurons and allow ions and small molecules to flow directly from one neuron to the next. • These neurons are electrically coupled, and transmission across these synapses is very rapid. Depending on the nature of the synapse, communication may be unidirectional or bidirectional. • Electrical synapses between neurons provide a simple means of synchronizing the activity of all interconnected neurons. • In adults, electrical synapses are found in regions of the brain responsible for certain stereotyped movements, such as the normal jerky movements of the eyes. • They also occur in axoaxonal synapses in the hippocampus, a brain region involved in emotions and memory. • Electrical synapses are far more abundant in embryonic nervous tissue, where they permit exchange of guiding cues during early neuronal development so that neurons can connect properly with one another. • As the nervous system develops, chemical synapses replace some electrical synapses and become the vast majority of all synapses. For this reason, we will focus on chemical synapses from now on. Chemical Synapses They are the most common type of synapse and are specialized to allow the release and reception of chemical messengers known as neurotransmitters. A typical chemical synapse is made up of two parts: • A knoblike axon terminal of the presynaptic neuron, which contains many tiny, membrane-bound sacs called synaptic vesicles, each containing thousands of neurotransmitter molecules • A neurotransmitter receptor region on the postsynaptic neuron's membrane, usually located on a dendrite or the cell body Although close to each other, presynaptic and postsynaptic membranes are separated by the synaptic cleft, a fluid-filled space approximately 30 to 50 nm (about one-millionth of an inch) wide. 1) Action potential arrives at axon terminal. Neurotransmission begins with the arrival of an AP at the presynaptic axon terminal. 2) Voltage-gated Ca2+ channels open and ca2+ enters the axon terminal. Depolarization of the membrane by the action potential opens not only Na+ channels but voltage gated Ca2+ channels as well. During the brief time the Ca2+ channels are open, Ca2+ floods down its electrochemical gradient from the extracellular fluid into the terminal. 3) Ca2+ entry causes synaptic vesicles to release neurotransmitter by exocytosis. The surge of Ca2+ into the axon terminal acts as an intracellular messenger. A Ca2+ -sensing protein (synaptotag,nin) on the vesicle binds Ca2+ and interacts with the SNARE proteins that control membrane fusion. As a result, synaptic vesicles fuse with the axon membrane and empty their contents by exocytosis into the synaptic cleft. Ca2+ is then quickly removed from the terminal-either taken up into the mitochondria or ejected from the neuron by an active Ca2+ pump 4) Neurotransmitter diffuses across the synaptic cleft and binds to specific receptors on the postsynaptic membrane. 5) Binding of neurotransmitter opens ion channels, creating graded potentials. When a neurotransmitter binds to the receptor protein, this receptor changes its shape. This change in turn opens ion channels and creates graded potentials. Postsynaptic membranes often contain receptor proteins and ion channels packaged together as chemically gated ion channels. Depending on the receptor protein to which the neurotransmitter binds and the type of channel the receptor controls, the Postsynaptic Neuron may be either Excited or Inhibited. 6) Neurotransmitter effects are terminated. Binding of a neurotransmitter to its receptor is reversible. As long as it is bound to a postsynaptic receptor, a neurotransmitter continues to affect membrane permeability and block reception of additional signals from presynaptic neurons. For this reason, some means of "wiping the postsynaptic slate clean" is necessary. The effects of neurotransmitters generally last a few milliseconds before being terminated in one of three ways, depending on the particular neurotransmitter: • Reuptake by astrocytes or the presynaptic terminal, where the neurotransmitter is stored or destroyed by enzymes (as with the neurotransmitter norepinephrine) • Degradation by enzymes associated with the postsynaptic membrane or present in the synaptic cleft (as with acetylcholine) • Diffusion away from the synapse **Synaptic Delay: It reflects the time required for neurotransmitter to be released, diffuse across the synaptic cleft, and bind to receptors. Typically, this synaptic delay lasts 0.3-5.0 ms, making transmission across the chemical synapse the rate-limiting (slowest) step of neural transmission. Synaptic delay helps explain why transmission along neural pathways involving only two or three neurons occurs rapidly, but transmission along multisynaptic pathways typical of higher mental functioning occurs much more slowly. However, in practical terms these differences are not noticeable. Postsynaptic potentials excite or inhibit the receiving neuron • Many receptors on postsynaptic membranes at chemical synapses are specialized to open ion channels, in this way converting chemical signals to electrical signals. • Unlike the voltage-gated ion channels responsible for APs, these chemically gated channels are relatively insensitive to changes in membrane potential. • Channel opening at postsynaptic membranes cannot become self-amplifying or self-generating. Instead, neurotransmitter receptors mediate graded potentials-local changes in membrane potential that are graded (vary in strength) based on the amount of neurotransmitter released and how long it remains in the area. • Chemical synapses are either excitatory or inhibitory, depending on how they affect the membrane potential of the postsynaptic neuron. Excitatory Synapses and EPSPs • Neurotransmitter binding depolarizes the postsynaptic membrane. Chemically gated ion channels open on postsynaptic membranes (those of dendrites and neuronal cell bodies). Each channel allows Na+ and K+ to diffuse simultaneously through the membrane but in opposite directions • Remember that the electrochemical gradient for sodium is much steeper than that for potassium. As a result, Na+ influx is greater than K+ efflux, and net depolarization occurs. • If enough neurotransmitter binds, depolarization of the postsynaptic membrane can reach above an axon's threshold (about -50 mV) for firing an AP. • The postsynaptic membranes generally do not generate APs. The dramatic polarity reversal seen in axons never occurs in membranes containing only chemically gated channels because the opposite movements of K and Na prevent excessive positive charge from accumulating inside the cell. • APs, depolarizing graded potentials called excitatory postsynaptic potentials (EPSPs) occur at excitatory postsynaptic membranes • The only function of EPSPs is to help trigger an AP distally at the initial segment of the postsynaptic neuron's axon. Inhibitory Synapses and IPSPs • As the name suggests, binding of neurotransmitters at inhibitory synapses reduces a postsynaptic neuron's ability to generate an AP. • Most inhibitory neurotransmitters hyperpolarize the postsynaptic membrane by making the membrane more permeable to K + or Cl- . Sodium ion permeability is not affected. • If K+ channels open, K + moves out of the cell. If Cl- channels open, Cl- moves in. • In either case, the charge on the inner face of the membrane becomes more negative. As the membrane potential increases and is driven farther from the axon's threshold, the postsynaptic neuron becomes Less and Less likely to "fire," and larger depolarizing currents are required to induce an AP. • Hyperpolarizing changes in potential are called inhibitory postsynaptic potentials (IPSPs). Integration and Modification of Synaptic Events Inhibitory synapses occur most often on the cell body and Excitatory synapses occur most often on the dendrites Summation by t he Postsynaptic Neuron • A single EPSP cannot induce an AP in the postsynaptic neuron. But if thousands of excitatory axon terminals fire on the same postsynaptic membrane, or if a small number of terminals deliver impulses rapidly, the probability of reaching threshold soars. Otherwise, nerve impulses would never result. EPSPs and IPSPs can add together, or summate, to influence the activity of a postsynaptic neuron • Most neurons receive both excitatory and inhibitory inputs from thousands of other neurons. How is all this conflicting information sorted out? Each neuron's initial segment keeps a running account of all the signals it receives. Not only do EPSPs summate and IPSPs summate, but also EPSPs summate with IPSPs. Summation by the Postsynaptic Neuron In other words, the axon's initial segment functions as a neural integrator, and the potential there at any time reflects the sum of all incoming neural information: • If the stimulatory effects of EPSPs dominate the membrane potential enough to reach threshold, the neuron will fire. • If summation yields only subthreshold depolarization, the neuron is facilitated. It does not fire an action potential but is more easily excited by successive depolarization events because it is already near threshold. • If summation yields hyperpolarization, the neuron cannot generate an AP. Because EPSPs and IPSPs are graded potentials that decay the farther they spread, the most effective synapses are those closest to the axon's initial segment. Specifically, inhibitory synapses are most effective when located between the site of excitatory inputs and the site of action potential generation (the axon's initial segment). • Synaptic Potentiation Repeated or continuous use of a synapse (even for short periods) enhances the presynaptic neuron's ability to excite the postsynaptic neuron, producing larger-than-expected EPSPs. This phenomenon is synaptic potentiation . The presynaptic terminals at such synapses contain relatively high Ca2 + concentrations, a condition that triggers the release of more neurotransmitter, which in turn produces larger EPSPs. Synaptic potentiation also brings about Ca2+ influx into the postsynaptic neuron via dendritic spines. As Ca2 + floods into the cell, it activates certain kinase enzymes that promote changes resulting in more effective responses to subsequent stimuli. Synaptic potentiation can be viewed as a learning process that increases the efficiency of neurotransmission along a particular pathway. Indeed, the hippocampus of the brain, which plays a special role in memory and learning, exhibits an important type of synaptic plasticity called Long-term potentiation (LTP). • Presynaptic Inhibition Events at the presynaptic membrane can also influence postsynaptic activity. Presynaptic inhibition occurs when the release of excitatory neurotransmitter by one neuron is inhibited by the activity of another neuron via an axoaxonal synapse. More than one mechanism is involved, but the end result is that less neurotransmitter is released and bound, forming smaller EPSPs. In contrast to postsynaptic inhibition by IPSPs, which decreases the excitability of the postsynaptic neuron, presynaptic inhibition decreases the excitatory stimulation of the postsynaptic neuron. In this way, presynaptic inhibition temporarily turns off specific synapse