Neural Transmission

Neural Transmission Part I – The Neuron at Rest

How a Nerve Impulse is Transmitted Impulses travel along nerve cells and from cell to cell. These impulses are transmitted electrically within a neuron and chemically from cell to cell.

Electrical Signals ~ Key Ideas Information is carried by waves of impulses or spikes called action potentials The information is coded by the time and location of the action potential, not its size. When no signaling is going on, energy must still be expended to maintain the system about 70% of energy used by the brain is for this maintenance

Why Electrical Transmission? The long distances and short times required for effective functioning of the nervous system requires electrical signaling. Neurons are poorly insulated, badly conducting wires that are "shorted out" by sitting in conductive fluid. The outside of neurons is more conductive than the inside. Thus the mechanism for electrical signaling must be different from that used by a copper wire.

Background Information The electrical operation of neurons occurs in an aqueous medium Water is a polar solvent Dissolves polar solids like salt (NaCl) Polar molecules have charge separation on the molecule, i.e. they have electrical polarity Non-polar molecules have no charge separation

The Importance of Ions The dissolved substances of interest are sodium, potassium, calcium, and chloride (also dissolved proteins) Exist as ions Cations - positively charged : Na + , K +, Ca ++ Anions - negatively charged : Cl - Ions in water are surrounded by a sphere of water molecules so they aren't as small as one might think

Properties of the Cell Membrane The cell membrane is a phospholipid bilayer Phospholipid bilayer is amphipathic Has both polar hydrophilic zones and non-polar hydrophobic zones The hydrophobic lipid tails are on the inside The hydrophilic phosphate heads stick out into the aqueous environment Proteins are embedded in the bilayer Embedded proteins can form ion channels or receptors

Electrical Properties of the Membrane There is an unequal distribution of Na + , K + , Cl - and organic anions across the membrane At rest, there are 10x as many Na + ions outside the axon as inside. Inside the axon are negatively charged ions The membrane keeps Na+ ions outside, negative ions inside. K+ passes freely over the membrane, so there are 20x as many K + ions inside the membrane as outside.

Electrical Properties of the Membrane Thus the inside of the cell membrane is negatively charged relative to the outside Therefore the axon is polarized This produces voltage

The Resting Potential Neurons have charge difference of about -65 mV across the plasma membrane Outside charge is defined as 0 This comes from the concentration gradient and the high permeability of K + , low permeability of Na + K + tends to move out of the cell because of the concentration gradient, leaving the inside negative Changes in resting membrane potential can serve as a signaling mechanism Serves as a baseline from which change is sensed Differs in different cells; range of -40 to 80 mV Neural signals are changes in this resting potential.

Maintaining Membrane Potential: Ion Channels and Ion Pumps To maintain the membrane potential ions must move into or out of the cell Ion channels - pores in cell membrane specific for a given ion: Na + channels, K + channels, Cl - channels, etc. 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.

The Sodium Potassium Pump The unequal distribution of ions is maintained by membrane proteins that serve as a pump Transport Na + in, K + out Pump keeps Na + concentration low inside the cell; 10x higher outside than inside K + concentration kept low; 20x higher inside than out

Movement of Ions Diffusion - movement down a concentration gradient from an area of higher concentration to an area of lower concentration The diffusion pressure for each type of ion is balanced by an electrical force from the voltage that develops across the membrane. Electric fields - movement of ions, as charged particles, in response to an applied voltage

Defining Electrical Terms Voltage (V) - electrical potential between an anode and cathode (volts or millivolts) Current (I) - flow of charged particles, including ions (amperes) Conductance (g) - measure of the ease of movement of charged particles (siemens) Resistance (R) - 1/conductance, measure of resistance to movement of charged particles (ohms) Ohm's Law - V = IR or I = gV

Equilibrium Potentials If a gradient exists across a membrane which is permeable to an ion: Ions will move across the membrane through ion channels from high concentration to low concentration A voltage will develop at the membrane which opposes the movement of that ion At equilibrium the force of diffusion is balanced by the electrical force from the voltage that develops across the membrane. The voltage that exactly balances each ion is the equilibrium potential for that ion.

Notes on the Equilibrium Potential If a cation is causing the potential, there must also be an anion in solution. A potential will only develop if the membrane is impermeable to the anion. In neurons, it is the existence of the A - proteins, which cannot cross the membrane, that indirectly causes the resting potential! Membrane potential is a weighted average of equilibrium potentials The more permeable the membrane is to a given ion, the closer the membrane potential will be to the equilibrium potential for that ion

The Nernst Equation Gives a numerical value of the equilibrium potential E ion = 2.303 (RT/zF) log([ion] o /[ion] i ) Where: E ion = equilibrium potential for a given ion R = gas constant T = temperature in degrees Kelvin z = charge of the ion F = Faraday's constant [ion] o = ionic concentration outside neuron [ion] i = ionic concentration inside neuron

Solving the Nernst Equation At body temp. (37 o C) the Nernst equation gives: E K+ = 61.54 log([K + ] o /[K + ] i ) = 61.54 log(5/100) = -80 mV E na+ = 61.54 log([Na + ] o /[Na + ] i ) = 61.54 log(150/15) = +62 mV

Solving the Nernst Equation (Continued) E cl- = 61.54 log([Cl - ] i /[Cl - ] o ) = 61.54 log (13/150) = -65 mV E ca++ = 30.77 log([Ca ++ ] o /[Ca ++ ] i ) = 30.77 log(2/.0002) = +246 mV

The Goldman Equation The membrane potential is a weighted average of the equilibrium potentials Calculated from the Goldman Equation V m = 61.54 log{(P K [K + ] o +P Na [Na+] o )/(P K [K + ] i + P Na [Na + ] i )}V m = 61.54 log{(40[5]+ 1[150])/(40[100] + 1[15])} = -65 mV 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.

The Computational Goldman Equation Neurophysiologists generally use another equation based on a circuit model of the cell membrane This uses conductance and equilibrium potential directly. The “computational” form of the Goldman Equation: V m = (g K E K + g Na E Na )/(g K + g Na ) This equation shows that as the conductance to either potassium or sodium increases, the membrane potential approaches the equilibrium potential for potassium or sodium.

Neural Transmission Part II – The Action Potential

The Action Potential A change in membrane potential causes an action potential increase in membrane potential = hyperpolarization (inhibitory; less likely to send signal) decrease in membrane potential = depolarization (excitatory) Action potential = small electrical change that propagates along the axon The conducting signal of the neuron

Transmission of a Nerve Impulse When the nerve fiber is stimulated, membrane becomes permeable to Na + ions Na + rushes inside changing the electrical charge. Neuron is depolarized This creates an action potential . Only lasts .5 millisecond. Action potential moves down the nerve fiber. This electrical wave = nerve impulse (the movement of the action potential along a neuron)

Stages of Neural Transmission Input Signal & Initiation The Trigger Conduction Component Output

The Input Signal Threshold - to fire a neuron, the impulse must have certain level of strength. This is yes or no; not a continuum. Begins when membrane potential in the postsynaptic neuron is turned on by the output of another (presynaptic) neuron Presynaptic neurons release a chemical transmitter at the synapse between 2 cells Transmitters interact with receptor molecules Receptor molecules transduce chemical potential energy into an electrical signal = synaptic potential

Initiation When the nerve fiber is stimulated, conformational changes in ion channels cause the membrane to become permeable to Na + ions Ionic current flows thru open channels, producing changes in the resting potential of the cell membrane Change in membrane potential = input signal Can vary in amplitude & duration Receptor potential spreads along the axon Decreases with distance A purely local signal which must be amplified or regenerated to reach rest of nervous system

The Trigger When the membrane is depolarized, channels open & sodium rushes in Action potentials are generated by the influx of Na + ions The input signal is spread passively If the signal exceeds the threshold, it proceeds; signal is all or none: stimulation below threshold  no signal all stimulation above threshold  same signal

Ion Channels are Voltage Sensitive Depolarization of one area of the axon results in depolarization of the next area This occurs because ion channels are voltage-gated The ion channels controlling Na + and K + can be in four states

Resting State Neither Channel is Open.

Threshold Voltage potential to begin opening Na + channels is reached

Depolarizing Phase Na + channels open, K + channels closed

Repolarizing Phase Na + channels close and K + channels open

Undershoot Na + channels closed; K + channels still open – gates haven’t responded to repolarization

Action Potential Theory vs. Reality Reviewing the Theory: When the membrane is depolarized to the threshold, there is a transient increase in g Na+ This allows entry of Na + ions which depolarize the neuron Subsequent increase in g K+ allows K + ions to leave the depolarized neuron faster This restores the negative membrane potential

Testing the Action Potential Measure Na + & K + conductance of the membrane during the action potential Proved difficult Voltage clamp developed by Kenneth Cole made this possible (~1950) Led to the pivotal experiments s of Alan Hodgkin & Andrew Huxley

The Hodgkin & Huxley Experiments Clamped membrane potential of axon at a given value Measured currents that flow across membrane Deduced changes in membrane conductance at different membrane potentials Showed that: Rising phase of the action potential was caused by a transient increase in g Na+ & the influx of Na + ions Falling phase of the action potential was associated with an increase in g K+ and an efflux of K+ ions Hypothesized the existence of voltage gated channels more than 20 years before they were actually directly demonstrated Nobel Prize 1963

The Patch Clamp 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 Apply suction so a tight seal forms. This leaves ions only one path, thru channels in the underlying membrane patch Measures currents flowing through ion channels in the patch at different imposed voltages Reveals inward or outward currents from membrane channels

Significance of Patch Clamp Experiments If the patch contains a single channel. it allows specific measurements Example: lowering membrane potential from – 65 mv to –40 mv would cause Na + channels to open At constant voltage, amplitude of current reflects membrane conductance Duration reflects time the channel is open Showed that most channels flip between 2 conductance states: open & closed Proved the existence of voltage gated channels Nobel Prize in 1991

Recording Electrical Events in Neurons: Extracellular Recording 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 Measures quick changes in voltage due to extracellular currents as the action potential passes 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 The easiest recording technique

Recording Electrical Events in Neurons: Intracellular Recording A glass capillary tube, tapered to a small tip and beveled like a hypodermic needle, filled with KCl penetrates cell membrane Measures quick changes in the membrane potential that constitute the action potential 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 The smaller the neuron, the harder this is to do

Conduction Action potential moves down the nerve fiber. Wave of depolarization The signal does not decay fast  100 m/sec. In myelinated neurons ions can only permeate and the impulse can only be passed, at the nodes of Ranvier.

Direction of the Action Potential Axon hillock - spike initiation zone Generator potential - spike initiation; analog to digital conversion 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) Once an action potential starts moving, the absolute refractory period keeps it going in only one direction

Conduction Velocity 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 the larger the axon, the further the current will go. The larger the axon, the faster conduction velocity

Saltatory Conduction In myelinated axons, only the open places at the Nodes of Ranvier allow current to exit. Depolarization "jumps" from node to node = saltatory conduction This gives faster conduction with smaller axon diameter Vertebrates need this or our nervous systems would be enormous Multiple sclerosis and Guillain-Barre syndrome are both demyelinating diseases Removing the myelin disrupts saltatory conduction, and leads to slowed conduction velocity

Picturing Saltatory Conduction

How Fast Can a Neuron Fire? Since the sodium channels are deactivated for 1 msec after closing, there is an absolute refractory period of 1 msec the maximum firing rate is 1000 spikes/sec 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 relative refractory period

Interpreting Nerve Impulses Amplitude and duration are always the same, regardless of input What determines intensity of sensation is not magnitude or duration of action potentials, but their frequency (how many in an area) If signals all alike, how do neural messages translate to behavior? Message determined entirely by neural pathway in which it is carried

Communication Between Neurons Impulses must travel not just along the neuron, but also from neuron to neuron. Adjoining neurons don't touch each other. Space between adjacent neurons = synapse The impulse must cross from the axon of one neuron to dendrites on another neuron. Causes the release of special chemicals that can diffuse across the synapse = neurotransmitters Neurotransmitters generate a new impulse in the next neuron or stimulate an effector

Output When the action potential reaches the terminal region, it stimulates release of packets of chemical transmitters Transmitters are stored in vesicles Release their contents by fusing with surface membrane = exocytosis Neurotransmitters can be small molecules: L-glutamate, acetylcholine, or peptides like enkephalin Release of transmitters = output amount determined by number & frequency of action potentials

Continuing the Process Transmitter diffuses across the synaptic cleft Binds specific receptors on adjacent neuron Neurotransmitters are reabsorbed and recycled by the cell Electrical signal starts over in the next neuron Controlled by negative feedback returns to resting state

Neural Transmission

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Neural Transmission