Neural Transmission


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Neural Transmission

  1. 1. Neural Transmission Part I – The Neuron at Rest
  2. 2. How a Nerve Impulse is Transmitted <ul><li>Impulses travel along nerve cells and from cell to cell. </li></ul><ul><li>These impulses are transmitted electrically within a neuron and chemically from cell to cell. </li></ul>
  3. 3. Electrical Signals ~ Key Ideas <ul><li>Information is carried by waves of impulses or spikes called action potentials </li></ul><ul><ul><li>The information is coded by the time and location of the action potential, not its size. </li></ul></ul><ul><li>When no signaling is going on, energy must still be expended to maintain the system </li></ul><ul><ul><li>about 70% of energy used by the brain is for this maintenance </li></ul></ul>
  4. 4. Why Electrical Transmission? <ul><li>The long distances and short times required for effective functioning of the nervous system requires electrical signaling. </li></ul><ul><li>Neurons are poorly insulated, badly conducting wires that are &quot;shorted out&quot; by sitting in conductive fluid. </li></ul><ul><li>The outside of neurons is more conductive than the inside. </li></ul><ul><li>Thus the mechanism for electrical signaling must be different from that used by a copper wire. </li></ul>
  5. 5. Background Information <ul><li>The electrical operation of neurons occurs in an aqueous medium </li></ul><ul><li>Water is a polar solvent </li></ul><ul><ul><li>Dissolves polar solids like salt (NaCl) </li></ul></ul><ul><ul><li>Polar molecules have charge separation on the molecule, i.e. they have electrical polarity </li></ul></ul><ul><ul><li>Non-polar molecules have no charge separation </li></ul></ul>
  6. 6. The Importance of Ions <ul><li>The dissolved substances of interest are sodium, potassium, calcium, and chloride (also dissolved proteins) </li></ul><ul><ul><li>Exist as ions </li></ul></ul><ul><ul><li>Cations - positively charged : Na + , K +, Ca ++ </li></ul></ul><ul><ul><li>Anions - negatively charged : Cl - </li></ul></ul><ul><li>Ions in water are surrounded by a sphere of water molecules so they aren't as small as one might think </li></ul>
  7. 7. Properties of the Cell Membrane <ul><li>The cell membrane is a phospholipid bilayer </li></ul><ul><li>Phospholipid bilayer is amphipathic </li></ul><ul><ul><li>Has both polar hydrophilic zones and non-polar hydrophobic zones </li></ul></ul><ul><li>The hydrophobic lipid tails are on the inside </li></ul><ul><li>The hydrophilic phosphate heads stick out into the aqueous environment </li></ul><ul><li>Proteins are embedded in the bilayer </li></ul><ul><ul><li>Embedded proteins can form ion channels or receptors </li></ul></ul>
  8. 8. Electrical Properties of the Membrane <ul><li>There is an unequal distribution of Na + , K + , Cl - and organic anions across the membrane </li></ul><ul><li>At rest, there are 10x as many Na + ions outside the axon as inside. </li></ul><ul><li>Inside the axon are negatively charged ions </li></ul><ul><li>The membrane keeps Na+ ions outside, negative ions inside. </li></ul><ul><li>K+ passes freely over the membrane, so there are 20x as many K + ions inside the membrane as outside. </li></ul>
  9. 9. Electrical Properties of the Membrane <ul><li>Thus the inside of the cell membrane is negatively charged relative to the outside </li></ul><ul><li>Therefore the axon is polarized </li></ul><ul><li>This produces voltage </li></ul>
  10. 10. The Resting Potential <ul><li>Neurons have charge difference of about -65 mV across the plasma membrane </li></ul><ul><ul><li>Outside charge is defined as 0 </li></ul></ul><ul><li>This comes from the concentration gradient and the high permeability of K + , low permeability of Na + </li></ul><ul><ul><li>K + tends to move out of the cell because of the concentration gradient, leaving the inside negative </li></ul></ul><ul><li>Changes in resting membrane potential can serve as a signaling mechanism </li></ul><ul><ul><li>Serves as a baseline from which change is sensed </li></ul></ul><ul><li>Differs in different cells; range of -40 to 80 mV </li></ul><ul><li>Neural signals are changes in this resting potential. </li></ul>
  11. 11. Maintaining Membrane Potential: Ion Channels and Ion Pumps <ul><li>To maintain the membrane potential ions must move into or out of the cell </li></ul><ul><li>Ion channels - pores in cell membrane specific for a given ion: Na + channels, K + channels, Cl - channels, etc. </li></ul><ul><li>Ion pumps - enzymes embedded in membrane that use energy from ATP to pump Na + out and K + in, or to pump Ca ++ out or cell.  </li></ul>
  12. 12. The Sodium Potassium Pump <ul><li>The unequal distribution of ions is maintained by membrane proteins that serve as a pump </li></ul><ul><li>Transport Na + in, K + out </li></ul><ul><li>Pump keeps Na + concentration low inside the cell; 10x higher outside than inside </li></ul><ul><li>K + concentration kept low; 20x higher inside than out </li></ul>
  13. 13. Movement of Ions <ul><li>Diffusion - movement down a concentration gradient from an area of higher concentration to an area of lower concentration </li></ul><ul><li>The diffusion pressure for each type of ion is balanced by an electrical force from the voltage that develops across the membrane. </li></ul><ul><li>Electric fields - movement of ions, as charged particles, in response to an applied voltage </li></ul>
  14. 14. Defining Electrical Terms <ul><li>Voltage (V) - electrical potential between an anode and cathode (volts or millivolts) </li></ul><ul><li>Current (I) - flow of charged particles, including ions (amperes) </li></ul><ul><li>Conductance (g) - measure of the ease of movement of charged particles (siemens) </li></ul><ul><li>Resistance (R) - 1/conductance, measure of resistance to movement of charged particles (ohms) </li></ul><ul><li>Ohm's Law - V = IR or I = gV </li></ul>
  15. 15. Equilibrium Potentials <ul><li>If a gradient exists across a membrane which is permeable to an ion: </li></ul><ul><ul><li>Ions will move across the membrane through ion channels from high concentration to low concentration </li></ul></ul><ul><ul><li>A voltage will develop at the membrane which opposes the movement of that ion </li></ul></ul><ul><li>At equilibrium the force of diffusion is balanced by the electrical force from the voltage that develops across the membrane. </li></ul><ul><li>The voltage that exactly balances each ion is the equilibrium potential for that ion. </li></ul>
  16. 16. Notes on the Equilibrium Potential <ul><li>If a cation is causing the potential, there must also be an anion in solution. </li></ul><ul><ul><li>A potential will only develop if the membrane is impermeable to the anion. </li></ul></ul><ul><li>In neurons, it is the existence of the A - proteins, which cannot cross the membrane, that indirectly causes the resting potential! </li></ul><ul><li>Membrane potential is a weighted average of equilibrium potentials </li></ul><ul><li>The more permeable the membrane is to a given ion, the closer the membrane potential will be to the equilibrium potential for that ion </li></ul>
  17. 17. The Nernst Equation <ul><li>Gives a numerical value of the equilibrium potential </li></ul><ul><li>E ion = 2.303 (RT/zF) log([ion] o /[ion] i )  </li></ul><ul><li>Where: </li></ul><ul><ul><li>E ion = equilibrium potential for a given ion </li></ul></ul><ul><ul><li>R = gas constant </li></ul></ul><ul><ul><li>T = temperature in degrees Kelvin </li></ul></ul><ul><ul><li>z = charge of the ion </li></ul></ul><ul><ul><li>F = Faraday's constant </li></ul></ul><ul><ul><li>[ion] o = ionic concentration outside neuron </li></ul></ul><ul><ul><li>[ion] i = ionic concentration inside neuron  </li></ul></ul>
  18. 18. Solving the Nernst Equation <ul><li>At body temp. (37 o C) the Nernst equation gives: </li></ul><ul><li>E K+ = 61.54 log([K + ] o /[K + ] i ) </li></ul><ul><ul><ul><li>= 61.54 log(5/100) </li></ul></ul></ul><ul><ul><ul><li>= -80 mV </li></ul></ul></ul><ul><li>E na+ = 61.54 log([Na + ] o /[Na + ] i ) </li></ul><ul><ul><ul><li>= 61.54 log(150/15) </li></ul></ul></ul><ul><ul><ul><li>= +62 mV </li></ul></ul></ul>
  19. 19. Solving the Nernst Equation (Continued) <ul><li>E cl- = 61.54 log([Cl - ] i /[Cl - ] o ) </li></ul><ul><ul><ul><li>= 61.54 log (13/150) </li></ul></ul></ul><ul><ul><ul><li>= -65 mV </li></ul></ul></ul><ul><li>E ca++ = 30.77 log([Ca ++ ] o /[Ca ++ ] i ) </li></ul><ul><ul><ul><li>= 30.77 log(2/.0002) </li></ul></ul></ul><ul><ul><ul><li>= +246 mV </li></ul></ul></ul>
  20. 20. The Goldman Equation <ul><li>The membrane potential is a weighted average of the equilibrium potentials </li></ul><ul><li>Calculated from the Goldman Equation </li></ul><ul><li>V m = </li></ul><ul><ul><li>61.54 log{(P K [K + ] o +P Na [Na+] o )/(P K [K + ] i + P Na [Na + ] i )}V m </li></ul></ul><ul><ul><li>= 61.54 log{(40[5]+ 1[150])/(40[100] + 1[15])} </li></ul></ul><ul><ul><li>= -65 mV  </li></ul></ul><ul><li>The Goldman equation means that the more permeable the membrane is to a given ion, the more that ion's equilibrium potential will dominate the membrane potential. </li></ul>
  21. 21. The Computational Goldman Equation <ul><li>Neurophysiologists generally use another equation based on a circuit model of the cell membrane </li></ul><ul><li>This uses conductance and equilibrium potential directly. </li></ul><ul><li>The “computational” form of the Goldman Equation:  </li></ul><ul><ul><li>V m = (g K E K + g Na E Na )/(g K + g Na ) </li></ul></ul><ul><li>This equation shows that as the conductance to either potassium or sodium increases, the membrane potential approaches the equilibrium potential for potassium or sodium. </li></ul>
  22. 22. Neural Transmission Part II – The Action Potential
  23. 23. The Action Potential <ul><li>A change in membrane potential causes an action potential </li></ul><ul><ul><li>increase in membrane potential = hyperpolarization (inhibitory; less likely to send signal) </li></ul></ul><ul><ul><li>decrease in membrane potential = depolarization (excitatory) </li></ul></ul><ul><li>Action potential = small electrical change that propagates along the axon </li></ul><ul><ul><li>The conducting signal of the neuron </li></ul></ul>
  24. 24. Transmission of a Nerve Impulse <ul><li>When the nerve fiber is stimulated, membrane becomes permeable to Na + ions </li></ul><ul><li>Na + rushes inside changing the electrical charge. </li></ul><ul><li>Neuron is depolarized </li></ul><ul><li>This creates an action potential . </li></ul><ul><ul><li>Only lasts .5 millisecond. </li></ul></ul><ul><li>Action potential moves down the nerve fiber. </li></ul><ul><ul><li>This electrical wave = nerve impulse (the movement of the action potential along a neuron) </li></ul></ul>
  25. 25. Stages of Neural Transmission <ul><li>Input Signal & Initiation </li></ul><ul><li>The Trigger </li></ul><ul><li>Conduction Component </li></ul><ul><li>Output </li></ul>
  26. 26. The Input Signal <ul><li>Threshold - to fire a neuron, the impulse must have certain level of strength. This is yes or no; not a continuum. </li></ul><ul><li>Begins when membrane potential in the postsynaptic neuron is turned on by the output of another (presynaptic) neuron </li></ul><ul><ul><li>Presynaptic neurons release a chemical transmitter at the synapse between 2 cells </li></ul></ul><ul><ul><li>Transmitters interact with receptor molecules </li></ul></ul><ul><li>Receptor molecules transduce chemical potential energy into an electrical signal = synaptic potential </li></ul>
  27. 27. Initiation <ul><li>When the nerve fiber is stimulated, conformational changes in ion channels cause the membrane to become permeable to Na + ions </li></ul><ul><li>Ionic current flows thru open channels, producing changes in the resting potential of the cell membrane </li></ul><ul><li>Change in membrane potential = input signal </li></ul><ul><ul><li>Can vary in amplitude & duration </li></ul></ul><ul><li>Receptor potential spreads along the axon </li></ul><ul><ul><li>Decreases with distance </li></ul></ul><ul><ul><li>A purely local signal which must be amplified or regenerated to reach rest of nervous system </li></ul></ul>
  28. 28. The Trigger <ul><li>When the membrane is depolarized, channels open & sodium rushes in </li></ul><ul><li>Action potentials are generated by the influx of Na + ions </li></ul><ul><li>  The input signal is spread passively </li></ul><ul><li>If the signal exceeds the threshold, it proceeds; signal is all or none: </li></ul><ul><ul><li>stimulation below threshold  no signal </li></ul></ul><ul><ul><li>all stimulation above threshold  same signal </li></ul></ul>
  29. 29. Ion Channels are Voltage Sensitive <ul><li>Depolarization of one area of the axon results in depolarization of the next area </li></ul><ul><li>This occurs because ion channels are voltage-gated </li></ul><ul><li>The ion channels controlling Na + and K + can be in four states </li></ul>
  30. 30. Resting State Neither Channel is Open.
  31. 31. Threshold Voltage potential to begin opening Na + channels is reached
  32. 32. Depolarizing Phase Na + channels open, K + channels closed
  33. 33. Repolarizing Phase Na + channels close and K + channels open
  34. 34. Undershoot Na + channels closed; K + channels still open – gates haven’t responded to repolarization
  35. 35. Action Potential Theory vs. Reality <ul><li>Reviewing the Theory: </li></ul><ul><ul><li>When the membrane is depolarized to the threshold, there is a transient increase in g Na+ </li></ul></ul><ul><ul><li>This allows entry of Na + ions which depolarize the neuron </li></ul></ul><ul><ul><li>Subsequent increase in g K+ allows K + ions to leave the depolarized neuron faster </li></ul></ul><ul><ul><li>This restores the negative membrane potential </li></ul></ul>
  36. 36. Testing the Action Potential <ul><li>Measure Na + & K + conductance of the membrane during the action potential </li></ul><ul><ul><li>Proved difficult </li></ul></ul><ul><li>Voltage clamp developed by Kenneth Cole made this possible (~1950) </li></ul><ul><li>Led to the pivotal experiments s of Alan Hodgkin & Andrew Huxley </li></ul>
  37. 37. The Hodgkin & Huxley Experiments <ul><li>Clamped membrane potential of axon at a given value </li></ul><ul><ul><li>Measured currents that flow across membrane </li></ul></ul><ul><li>Deduced changes in membrane conductance at different membrane potentials </li></ul><ul><li>Showed that: </li></ul><ul><ul><li>Rising phase of the action potential was caused by a transient increase in g Na+ & the influx of Na + ions </li></ul></ul><ul><ul><li>Falling phase of the action potential was associated with an increase in g K+ and an efflux of K+ ions </li></ul></ul><ul><li>Hypothesized the existence of voltage gated channels more than 20 years before they were actually directly demonstrated </li></ul><ul><li>Nobel Prize 1963 </li></ul>
  38. 38. The Patch Clamp <ul><li>Developed in mid 1970's by Bert Sakmann & Erwin Neher The tip of a glass capillary tube (1-5  in diameter) is pressed on the membrane of a neuron </li></ul><ul><li>Apply suction so a tight seal forms. </li></ul><ul><li>This leaves ions only one path, thru channels in the underlying membrane patch </li></ul><ul><li>Measures currents flowing through ion channels in the patch at different imposed voltages </li></ul><ul><li>Reveals inward or outward currents from membrane channels </li></ul>
  39. 39. Significance of Patch Clamp Experiments <ul><li>If the patch contains a single channel. it allows specific measurements </li></ul><ul><li>Example: lowering membrane potential from – 65 mv to –40 mv would cause Na + channels to open </li></ul><ul><li>At constant voltage, amplitude of current reflects membrane conductance </li></ul><ul><li>Duration reflects time the channel is open </li></ul><ul><li>Showed that most channels flip between 2 conductance states: open & closed </li></ul><ul><li>Proved the existence of voltage gated channels </li></ul><ul><li>Nobel Prize in 1991 </li></ul>
  40. 40. Recording Electrical Events in Neurons: Extracellular Recording <ul><li>A glass capillary tube, tapered to a small tip and filled with NaCl or a fine metal wire or a wet cotton wick - outside axon </li></ul><ul><li>Measures quick changes in voltage due to extracellular currents as the action potential passes </li></ul><ul><li>The recorded action potential is biphasic, going one way as the action potential approaches the electrode and going the other way as the action potential passes the electrode and recedes </li></ul><ul><li>The easiest recording technique </li></ul>
  41. 41. Recording Electrical Events in Neurons: Intracellular Recording <ul><li>A glass capillary tube, tapered to a small tip and beveled like a hypodermic needle, filled with KCl penetrates cell membrane </li></ul><ul><li>Measures quick changes in the membrane potential that constitute the action potential </li></ul><ul><li>The recorded action potential is monophasic, going from resting potential (-65 mV) toward E Na+ (+62 mV) and then toward E K+ (-80 mV) before returning to the resting potential </li></ul><ul><li>The smaller the neuron, the harder this is to do </li></ul>
  42. 42. Graded Electrical Potentials
  43. 43. Conduction <ul><li>Action potential moves down the nerve fiber. </li></ul><ul><ul><li>Wave of depolarization </li></ul></ul><ul><li>The signal does not decay fast  100 m/sec. </li></ul><ul><li>In myelinated neurons ions can only permeate and the impulse can only be passed, at the nodes of Ranvier. </li></ul>
  44. 44. Direction of the Action Potential <ul><li>Axon hillock - spike initiation zone </li></ul><ul><li>Generator potential - spike initiation; analog to digital conversion </li></ul><ul><li>Typically there are voltage-sensitive ion channels on one side of the axon hillock (the axon side) and no voltage-sensitive ion channels on the other side (the soma or dendrite side) </li></ul><ul><li>Once an action potential starts moving, the absolute refractory period keeps it going in only one direction </li></ul>
  45. 45. Conduction Velocity <ul><li>How far down the axoplasm the current goes before it passes through the membrane and triggers new Na + channels depends on the diameter of the axon </li></ul><ul><li>the larger the axon, the further the current will go. </li></ul><ul><li>The larger the axon, the faster conduction velocity </li></ul>
  46. 46. Saltatory Conduction <ul><li>In myelinated axons, only the open places at the Nodes of Ranvier allow current to exit. </li></ul><ul><li>Depolarization &quot;jumps&quot; from node to node = saltatory conduction </li></ul><ul><li>This gives faster conduction with smaller axon diameter </li></ul><ul><ul><li>Vertebrates need this or our nervous systems would be enormous </li></ul></ul><ul><li>Multiple sclerosis and Guillain-Barre syndrome are both demyelinating diseases </li></ul><ul><ul><li>Removing the myelin disrupts saltatory conduction, and leads to slowed conduction velocity </li></ul></ul>
  47. 47. Picturing Saltatory Conduction
  48. 48. How Fast Can a Neuron Fire? <ul><li>Since the sodium channels are deactivated for 1 msec after closing, there is an absolute refractory period of 1 msec </li></ul><ul><ul><li>the maximum firing rate is 1000 spikes/sec </li></ul></ul><ul><li>The undershoot caused by the potassium channels being open means that in the interval 1 msec to 2 msec after the initiation of an action potential, the amount of depolarization needed to reach threshold is increased </li></ul><ul><ul><li>relative refractory period   </li></ul></ul>
  49. 49. Interpreting Nerve Impulses <ul><li>Amplitude and duration are always the same, regardless of input </li></ul><ul><ul><li>What determines intensity of sensation is not magnitude or duration of action potentials, but their frequency (how many in an area) </li></ul></ul><ul><li>If signals all alike, how do neural messages translate to behavior? </li></ul><ul><ul><li>Message determined entirely by neural pathway in which it is carried </li></ul></ul>
  50. 50. Communication Between Neurons <ul><li>Impulses must travel not just along the neuron, but also from neuron to neuron. </li></ul><ul><li>Adjoining neurons don't touch each other. </li></ul><ul><li>Space between adjacent neurons = synapse </li></ul><ul><li>The impulse must cross from the axon of one neuron to dendrites on another neuron. </li></ul><ul><li>Causes the release of special chemicals that can diffuse across the synapse = neurotransmitters </li></ul><ul><li>Neurotransmitters generate a new impulse in the next neuron or stimulate an effector </li></ul>
  51. 51. Output <ul><li>When the action potential reaches the terminal region, it stimulates release of packets of chemical transmitters </li></ul><ul><li>Transmitters are stored in vesicles </li></ul><ul><li>Release their contents by fusing with surface membrane = exocytosis </li></ul><ul><li>Neurotransmitters can be small molecules: L-glutamate, acetylcholine, or peptides like enkephalin </li></ul><ul><li>Release of transmitters = output </li></ul><ul><ul><li>amount determined by number & frequency of action potentials </li></ul></ul>
  52. 52. Continuing the Process <ul><li>Transmitter diffuses across the synaptic cleft </li></ul><ul><li>Binds specific receptors on adjacent neuron </li></ul><ul><li>Neurotransmitters are reabsorbed and recycled by the cell </li></ul><ul><li>Electrical signal starts over in the next neuron </li></ul><ul><li>Controlled by negative feedback </li></ul><ul><ul><li>returns to resting state </li></ul></ul>