Overview Organization: Central Nervous System (CNS) Peripheral Nervous System (PNS) innervate Divisions: a. Afferent

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1 Overview Organization: Central Nervous System (CNS) Brain and spinal cord receives and processes information. Peripheral Nervous System (PNS) Nerve cells that link CNS with organs throughout the body. Neurons that transmit messages to an organ or carry information from a sensory organ are said to innervate that organ. Divisions: a. Afferent Provides information about the somatic senses (the body in general as we are aware of it) including information from the skin, muscles and joints; special senses (vision, hearing, equilibrium, taste and smell), and visceral senses (information from the internal organs). b. Efferent Sends out commands to effector organs (muscles and glands). Subdivisions: 1. Somatic Nervous System Include nerve cells that innervate skeletal muscle. 2. Autonomic Nervous System Nerve cells that control smooth muscle and glands which are not under voluntary control. Enteric Nervous System Network of nerves in gastrointestinal tract that can function independently of the rest of the nervous system but which is under the influence of the autonomic nervous system. Cells of the Nervous System Two kinds of cells: 1. Neuron or nerve cell is the functional unit. These cells are excitable cells capable of conducting electrochemical signals along their membranes. 2. Glial cells provide structural and metabolic support for neurons. These cells constitute about 90% of the cells in the nervous system.

2 Neurons Consist of: Cell body (soma) - Contains the nucleus and most of the cell's organelles. Dendrites - Processes that branch off the cell body and receive input from other neurons at specialized junctions called synapses. The cell body also receives this input. Axons (nerve fiber) - Processes that send information. Typically each neuron has only one axon coming off the cell body but the axon may have branches called collaterals. Axons transmit information over long distances in the form of action potentials. The axon comes off the cell body at the axon hillock and transmits an action potential to the axon terminal where the neuron synapses with another neuron or effector organ. Locations of Ion Channels Leak channels are non-gated channels found throughout the neuron. They are always open and contribute to the resting membrane potential. Ligand-gated channels are found on dendrites and the cell body and open or close in response to the presence of neurotransmitters (ligands). Voltage-gated channels open or close in response to changes in membrane potential. Many of these are voltage-gated Na + and K + channels that are important for the initiation and propagation of action potentials along the axon. Voltage-gated Ca 2+ channels are found at axon terminals where the opening of these channels permit Ca 2+ to enter and trigger the release of neurotransmitter. Classification of Neurons Structural Classification Bipolar A neuron that has two processes, one axon and one dendrite. Seen in special sensory neurons for olfaction and vision. Most sensory neurons are a subclass of bipolar neurons called pseudo-unipolar. This is a neuron with one process coming off the cell body. However, this process results from the fusion of an axon and a dendrite modified to transmit action potentials. Multipolar This neuron is the most common. The multipolar neuron has multiple processes with one being an

3 axon and the rest dendrites. Functional Classification Afferent Neuron Neurons that transmit sensory information from the outside (sensory receptors) or inside (visceral receptors) the body to the CNS. Interneurons Neurons located entirely in the CNS that process sensory information; send out commands to effector organs; and perform complex integrative and analytical functions. Most neurons (99%) of the nervous system are interneurons. Efferent Neuron Neurons that transmit information or commands from the CNS to effector organs.

4 Glial Cells Glial cells include astrocytes, ependymal cells, microglia, oligodendrocytes (in the CNS) and Schwann cells (in the PNS). Oligodendrocytes and Schwann cells increase the rapidity and efficiency of nerve transmission by forming an insulating wrap of myelin around the axons of neurons. Myelin consists of concentric layers of cell membranes wrapped around axons. Myelin forms a barrier that prevents the leakage of ions except at gaps between consecutive oligodendrocytes and Schwann cells called nodes of Ranvier. The nodes of Ranvier contain voltage-gated sodium and potassium channels that function in the transmission of action potentials. Electrical Concepts Electrical potentials (E) result from the separation of opposite charges (measured in millivolts). The actual movement of charges is called current (measured in microamperes). Resistance (R ) is a measure of hindrance to the movement of charged particles. Charge flow through extra and intracellular fluid with ease but the lipid bilayer of cell membranes create a barrier to the movement of charge. Conductance is a measure of the ability of charges to move across a membrane and is inversely related to resistance: g = 1/R Ohm's Law describes the relationship between potential difference, current and resistance and is expressed in the equation I = E/R where I = current, E = potential difference and R = resistance. Resting Membrane Potential Animation showing creation of resting membrane potential

5 A nerve cell at rest (not undergoing an electrochemical change across its membrane) has a resting membrane potential of approximately - 70 mv across its membrane. (This actually varies among different cells but unless otherwise indicated we will assume this to be the value.) This is because across the cell membrane of the neuron the intracellular surface of the membrane is -70 mv more negative than the extracellular surface. The resting membrane potential results from the concentration gradients of ions across the cell membrane and the presence of ion channels in the plasma membrane. The Na + /K + pump pumps 3 Na + out of the cell for every 2 K + it pumps in creating concentration gradients for Na + and K + across the cell membrane. Na + is more concentrated on the outside, and K + is more concentrated on the inside. Also present in the cell membrane are ion channels for Na + and K + as well as for Cl - and Ca ++. The resting membrane potential depends on the permeability of the cell membrane for these ions, particularly Na + and K +. The permeability of these ions depends upon the presence of the ion channels and whether or not they are open. Equilibrium potential for K + If the cell were only permeable to K +, K + would leave the cell and go down its concentration gradient. As the positively charged K + leaves the cell, a negative membrane potential develops. This results in two forces acting upon K +, the chemical force (concentration gradient) pushing K + out, and an electrical force (negative membrane potential) pulling the K + in. The two forces together constitute an electrochemical force and balance one another when the membrane potential is -94 mv. Hence, the equilibrium potential for K + is -94 mv, or, E k+ = -94 mv. Equilibrium potential for Na +

6 If the cell is only permeable to Na + this ion will move across the membrane down its concentration gradient. This creates a positive membrane potential that will balance the chemical force when the membrane potential is +60 mv. Hence, E Na+ = 60 mv. Resting Membrane Potential of Neurons The Nernst-Goldman Equation Simulator

7 The real cell has similar concentration gradients of Na + and K + across the membrane. However, when the membrane is resting, K + is about 25 times more permeable than Na +. Both K + and Na + will move down their concentration gradients but in opposite directions. This movement of K + out of the cell, and Na + into the cell, continues until the number of positive charges exiting the cell equals the number of positive charges entering. At this point the resting membrane potential is reached at - 70 mv. The final resting membrane potential reflects a balance between the electrochemical forces associated with each ion. When the cell is "at rest", the cell is more permeable to K + than to Na + and because of this, the electrochemical force of K + has a greater influence over the membrane potential than the electrochemical force of Na +. The resting potential of -70 mv is a lot closer to E K+ than to E Na+. The resting membrane potential needs to be maintained by the Na + /K + pump that is constantly pumping Na + out and K + in. This is because over time Na + would continually leak in and K + would leak out and the concentration gradients would diminish. The Na + /K + pump keeps the membrane potential as a steady state. Because more Na + (3) are pumped out than K + (2) are pumped in, the Na + /K + pump is electrogenic, but this makes only a small contribution to the final resting potential. The general rule is that a cell's membrane potential is a weighted sum of the equilibrium potentials of all permeant ions. The weighting (amount of influence) given to each ion is proportional to that ion's permeability. The more permeable the ion, the closer the resting potential will match that of the ion. Another important concept to understand is that at the steady state of the resting membrane potential, the ions are not at their equilibrium potentials and there is an electrochemical force acting on the ions to bring them to equilibrium. The net electrochemical force driving the ions is proportional to the difference between the membrane potential and the equilibrium potential for that ion. Hence, at a resting membrane potential of -70 mv K + is -24 mv (-94 mv - (-70) mv = -24 mv) away from its equilibrium potential and Na + is 130 mv (60 mv - (- 70) mv = 130 mv) from its equilibrium potential. In other words, the electrochemical force acting upon Na + to move it into the cell is greater than that acting upon K + to move it out of the cell. Changes in Membrane Potential The resting membrane potential is due to the difference in the permeability of the cell membrane to Na + and K + as determined by leak channels for these respective ions. Changes in the membrane potential from the resting level result from gated ion channels. Gated ion channels are channels that open in response to some stimulus as indicated below: 1. Electrical changes - Voltage-gated channels. 2. Chemical messengers - Ligand-gated channels. 3. Physical alteration - Mechanically-gated channels The typical nerve cell has a resting potential of -70 mv. At this resting level the membrane is polarized because the inside surface of the membrane is negative with respect to the outside. If the potential becomes more negative (e.g. -90 mv) the membrane is said to be hyperpolarized. When the membrane becomes less negative (e.g. -50 mv) the membrane is said to be depolarized. After the membrane is depolarized, when it returns to its resting level it is repolarized.

8 Electrical Signaling Through Changes in the Membrane Potential Animation of Action Potential from Harvard Neurons communicate through two kinds of changes in membrane potential: 1. Graded Potentials A graded potential is a small change in the potential that is proportional (graded) to the strength of the stimulus causing the change. The stimulus may be a neurotransmitter or a sensory stimulus. Graded potentials may be either depolarization or hyperpolarizations. Graded potentials are significant because they either bring the membrane potential closer to or further from the potential that triggers an action potential. The potential that triggers an action potential is the threshold. If the graded potential brings the potential closer to threshold it is excitatory. If it brings it further from threshold it is inhibitory. A graded potential can only travel a short distance because the change in voltage spreads by the passive movement of ions in a process called electrotonic conduction. As the current moves further from the site of stimulation, the membrane potential decreases because the ions diffuse and the ions pass through channels in the membrane. Therefore, the change in membrane potential that is due to electrotonic conduction is decremental (decreasing). The graded potentials produced in neurons may add up spatially or temporally: In spatial summation the graded potentials produced at different locations of the cell membrane add together. This addition is particularly effective if the graded potentials are produced about the same time. It is important to remember that the graded potentials can be inhibitory (hyperpolarizing) as well

9 as excitatory (depolarizing) and can therefore cancel each other out. In temporal summation the stimuli producing the graded potential at the same location come together so rapidly the postsynaptic membrane does not have time to repolarize before the next stimulus is received. The greater the overlap in time, the greater the temporal summation. 2. Action Potentials During an action potential a rapid depolarization occurs that actually causes a reversal in the polarity of the membrane (-70 mv to 30 mv). This reversal is brief and the negative potential is rapidly restored. Once the action potential begins it becomes self propagating and can travel over a long distance along the length of an axon without any decrease in strength. (See table 7.2 for comparisons between graded and action potentials.) Ionic Basis Action Potential Animation There are three distinct phases in an action potential that depends upon the electrochemical gradients of Na + and K + and changes in the permeability of the membrane to these ions.

10 1. Depolarization. A sudden increase in the permeability of the membrane to Na + causes Na + ions to rush into the cell. The permeability of Na + is now greater than that of K + and the membrane potential swings toward the equilibrium potential for Na + (+60 mv). The membrane potential goes from -70 mv to 30 mv. 2. Repolarization. Within 1 msec Na + permeability decreases rapidly and the K + permeability increases. This causes a net outflow of positive charge as K + moves down its electrochemical gradient and the membrane potential becomes negative again returning to -70 mv. 3. After-Hyperpolarization. The potassium permeability remains high for 5-15 msec. This causes the membrane to overshoot the resting membrane potential and hyperpolarize as the increase in K + permeability causes the membrane potential to approach the equilibrium potential of K + (-94 mv). The changes in permeability that occur are due to voltage-gated ion channels. Voltage-Gated Ion Channels Voltage-gated Na + and K + channels are located primarily in the plasma membrane of the axon hillock and axon. A model is used to explain how these channels work. The model for the Na + channel states that there are two kinds of gates in the Na + channels: 1. Activation gate - opens to allow ions to pass through. 2. Inactivation gate - closes to block the passage of ions. If we take the voltage-gated channel for Na + the model will work this way during an action potential: Go to: Voltage-gated channels and the action potential

11 a. During the resting membrane potential the activation gate is closed while the inactivation gate is open. b. During the depolarization phase, the activation gate opens with both gates open Na + rushes down its concentration gradient and enters the cell. c. When repolarization begins (approximately 1 msec after the activation gate opens) the inactivation gate closes and stops the inrush of Na +. d. When repolarization ends and the membrane returns to resting potential the activation gate closes and the inactivation gate opens. The channel has now returned to its original position before depolarization. The activation of the voltage-gated Na + channels is a regenerating phenomenon because when activated the change in potential activates other channels in a positive feedback loop. This is because when one channel opens and Na + rushes in, this depolarizes the membrane and activates other Na + channels. These channels in turn activate more channels, and so forth. The potassium channels contribute to the repolarizing phase of the action potential by opening slowly and closing slowly. The model for the voltage-gated K + channel describes only a single gate that opens slowly in response to depolarization. As the K + flows out and repolarizes the membrane these slowly close.

12 The threshold for an action potential is reached when the opening voltage-gated sodium channels stimulates other channels to open in a positive feedback loop. A depolarization that does not generate an action potential is subthreshold. A depolarization that is above threshold elicits the same action potential as one that just reaches threshold. Action potentials are initiated according to an all-or-none principle. Either the depolarization does not reach threshold and triggers no action potential or it reaches threshold and elicits an action potential that is always the same.

13 Refractory Periods After an action potential there is a refractory period when the membrane is not as excitable. There are two kinds of refractory periods: 1. Absolute Refractory Period occurs 1-2 msec after the initiation of the action potential. During this time an action potential cannot be generated. 2. Relative Refractory Period immediately follows the absolute refractory period and lasts 5-15 msec. During this time a second action potential can be generated but only if a stronger stimulus is used.

14 The absolute refractory period contributes to the all-or-none property of action potentials by making it impossible for action potentials to add-up like graded potentials. Relative refractory periods make it possible to encode information by converting the strength of a stimulus into the frequency of action potentials. A suprathreshold graded potential can produce a higher number of action potentials within a given period of time then a lesser subthreshold or threshold stimulus.

15 A threshold graded potential can produce more than one action potential if it lasts for a longer period of time than the refractory period. A suprathreshold graded potential produces more action potentials by stimulating the membrane enough during the relative refractory period to elicit action potentials. The absolute refractory period imposes a maximum frequency of action potentials of per second. Propagation of Action Potentials Propagation of the Action Potential; Unmyelinated Axon Go to: Action potential propagation in an unmyelinated axon In unmyelinated axons, action potentials are spread by electrotonic conduction or the passive spread of voltage change along the membrane of the axon. When an action potential occurs at the trigger site (axon hillock) positive charges rush into the cell. This creates a local zone in both the extracellular and intracellular fluid where there is a sudden change in charge. If we concentrate only on the intracellular fluid, the positive charges that enter the cell move toward the surrounding areas where there is a high concentration of negative charges. This results in a depolarization that reaches threshold and continues the action potential.

16 The action potential moves along the axon in one direction because of the refractory period. The action potential travels continuously along the length of the axon like a wave. The larger the diameter of the unmyelinated neuron the less the resistance to current flow and the faster the propagation of the action potential. Myelinated Axon Myelin provides high resistance to ion flow across the membrane. This resistance is only lacking where there is a gap in this myelin covering at the node of Ranvier. Also at the nodes of Ranvier there is a concentration of voltage-gated sodium and potassium channels. When an action potential occurs at one node the same intracellular and extracellular currents are created except that the myelin dramatically reduces the current across the membrane so that the current that flows to the next node is strong enough to generate an action potential. This continues down the length of a myelinated axon with the action potential jumping from one node to the next in what is called saltatory conduction.

17 Saltatory conduction enables the action potential to travel faster. Hence, the larger the axon diameter the faster the conduction and myelination speeds up conduction speed even more. Conduction velocity is associated with nerve function (Table 7.4).