Electrical Signals

• How does the brain transmit signals?

  • Benjamin Franklin, 1751
  • Kite Experiment: attached long wire to kite made of silk. drew electricity from storm clouds and charged a Leyden Jar.
  • proved that storm clouds carried electricity and electricity passes through objects and not along the surfaces.
• How does the brain transmit signals?

  • Ben Franklin, 1751
  • coined the term positive and negative charge and ‘electric battery’ (storing charge in lead plates between glass sheets)
  • discovered that electricity can be transferred from one object to another
  • although +ve and -ve charge is always balanced in a naturally occurring object, +ve charge is ‘conserved’ as it moves from a higher charged body to a lower charged body.
• Electricity makes animal muscles move

  Luigi Galvani, 1781

  • Electricity makes frogs’ leg muscles contract
  • “animal electricity” was present in the nerve.
• Is it the same for humans?

  Giovanni Aldini (Galvani’s nephew), 1802

  • Electricity makes criminals’ corpses twitch
• Neuronal transmission


  Stimulating a nerve induces a muscle contraction

  Signals are generated by electrochemical gradients across membranes.

  Within a cell this passes along as an action potential
• Neurons signal using voltage changes

  Electrical signalling in the brain is continuously occurring.

  Can be measured with an oscilloscope (voltmeter).

  
• Electrochemical gradients

  
• Electrochemical gradients (II)

  
• Equilibrium potential


  The transmembrane voltage at which electrochemical forces counterbalance, so that there is no net ion flow (or current) across the membrane.

  This value can be calculated with the Nernst Equation

  
• For a monovalent ion such as K+, this can be more simply remembered as...

  
• Resting distributions of ions across a membrane

  
• Ion channels


  • Holes in the membrane that allow ions to enter and leave the cell.
  • Are selective for different ions
  • Can be open all the time (e.g. K+ leak channels that set the resting membrane potential)
  • Others are opened by different stimuli – e.g. a change in voltage, binding specific molecules
  • Ions flow down electrical and chemical (concentration) gradients

  
• [Ion] generate the resting membrane potential (I)

  
• [Ion] generate the resting membrane potential (II)

  
• Resting membrane potential (I)

  • When the cells are permeable to more than one ion, the cell potential can be determined from the Goldmann-Hodgkin-Katz Equation.
  • This also takes into account the permeability for each ion
  • So because PK+  >> PNa+ , the equilibrium potential for potassium (EK+) contributes more to the resting membrane potential than sodium’s equilibrium potential (ENa+).

  So Em = -70mV (nearer to EK = -90 mV than to ENa = 60 mV)

  
• Four factors contribute to the resting membrane potential (II)

  1. Selective permeability of the membrane to potassium ions
  2. Potassium ions – freely move across the membrane, down the concentration gradient to the outside. Potassium equilibrium potential = -90mV
  3. Sodium ions – Membrane is slightly permeable to sodium ions which shift the resting membrane potential from -90mV (if it was only permeable to K+) to -70mV.
  4. The Na+/K+ pump – moves two potassium ions into the cell for every three sodium ions out. This keeps the intracellular potassium concentration high.
• The action potential: Neuronal Transmission

  The basic unit of intracellular information transfer is the action potential.

  • conveys a fast signal from one place to another in the body.
  • are generated by changes in membrane permeability due to opening and closing of voltage gated ion channels.

  
• Action potential events (I)

  1. Threshold potential reached
  2. Depolarisation due to opening of sodium channels
  3. Repolarisation due to inactivation of sodium channels and opening of potassium channels
  4. Hyperpolarisation as potassium channels are still open.

  
• Action potential events (II)

  
• Threshold and the All of Nothing Effect

  For APs to be generated:

  • local depolarisation must reach a threshold point, which is the voltage at which sodium channels start to open -> positive feedback:
  • APs either happen completely or they don’t.

  
• The action potential membrane permeability changes

  • Relatively few ions move during an action potential.
  • 1 picomole of Na+ enters the axon per cm2 of membrane.
  • In large axons, this raises [Na+]i by only 1:600,000, and decreases K+ by 1 in 5,000,000.
  • Since the axon has thousands of pumps, this change is quickly corrected (unless an incredibly fast burst of action potentials occurs over a prolonged period of time. Then it is important for glial cells to mop up the excess K+).

  
• Action potential propagation


  • APs propagate (transmit) along axons
  • same size all along
  • as the AP moves it depolarises the next bit of membrane and opens Na+ channels.
  • If enough Na+ channels are opened, the membrane potential reaches the threshold potential and the AP propagates along.

  The area that has just generated an AP cannot fire another as the Na+ channels are now inactivated.

  
• Absolute and Refractory periods

  Once a patch of membrane is generating AP and its Na+ channels have inactivated:

  • a neuron is incapable of responding to another stimulus, no matter how strong.
  • This is the absolute refractory period.
  • This enforces one-way transmission.
• Relative refractory period


  • When some Na+ gates are inactivated, K+ open and the neuron is repolarising.
  • A normally supra-threshold stimulus does not generate an AP, but a very strong stimulus can re-open the Na+ channels and generate an AP.
  • Therefore strong stimuli can generate high frequency APs by intruding into the relative refractory period.

  
• How do action potentials code information?

  NOT size of action potential – as it is all-or-nothing

  Frequency of firing

  Timing of firing

  Which neurons fire?

  “labelled line” e.g. vibration sensation

  
• What decays action potentials as they cross the brain?

  Signals decay along the axon because of three things:

  • membrane resistance (Rm)
  • axial resistance (Ri)
  • membrane capacitance (Cm)

  
• Membrane capacitance


  • Oppositely charged particles are electrostatically attracted to each other across membranes.
  • This charging of the membrane is measured as capacitance.
  • The thicker the membrane, the less capacitance there is.
  • Therefore the current (ion movement) that should be travelling down the axons is slower as the charge is initially neutralised when it is attracted to the membrane.
  • A larger capacitance also means a greater concentration change is needed to create the same potential difference across the membrane.
• What decays action potentials as they cross the brain?

  
• Myelin

  
• Myelin increases the speed of action potentials when space is limited

  
• Evolution of myelin and white matter

  The importance of myelin means it has evolved independently many times in different orders of animals

  
• Saltatory conduction and the myelin sheath


  Nodes of Ranvier:

  • Gaps (nodes) between the myelinating sheath (internodes) where the action potential is regenerated.
  • Filled with lots of sodium channels, and pumps which keep the necessary ion gradients.

  
• Myelination recap (I)


  • Myelin reduces charge loss across the axon membrane by decreasing its capacitance (“insulation”), making APs travel faster.
  • APs travel from one node of Ranvier to the next = saltatory conduction, even though the AP can be measured at several nodes at the same time.
• Myelination recap (II)


  • More efficient: less ion influx is needed to generate APs, so less pumps needed to keep membrane potential negative (by pumping Na+ out of the cell, and K+ back in), after an AP has passed.
  • For a given conduction speed, a myelinated axon occupies less space than an unmyelinated one. This is important in a size-constrained skull
• Myelin support of axons

  • Removing MCT1 from oligodendrocytes leads to axonal damage and loss of neurones (Lee,...Rothstein et al., Nature 2015).
  • Decrease in MCT1 is implicated in the pathology of Amytropic Lateral Sclerosis and Multiple Sclerosis.

  
• Multiple Sclerosis (MS)


  • Autoimmune disease
  • Immune cells enter the brain and attack myelin.
  • Loss of myelin stops neurons from firing APs properly.
  • Any part of the brain can be affected, symptoms vary
  • At first the axons get remyelinated by the pool of oligodendrocyte progenitors that reside in the brain, but after some time, remyelination fails and the neurons die.
• Multiple Sclerosis (MS): Symptoms

  Fatigue

  Vision problems

  Numbness and tingling

  Muscle spasms

  Weakness

  Pain

  Mobility problems

  Cognitive problems

  Depression

  Anxiety
• Normal nerve vs MS nerve

  
• Channelopathies


  Disease following the dysfunction of a channel.

  • Dysfunction can be due to genetic mutation or an autoimmune disease leading to attack of the channel.
  • Voltage gated Na+channels are integral to normal signalling in the brain. Mutations in the channels can be fatal or lead to numerous disease states.
  • Channelopathies associated with voltage gated Na+ and K+ channels often result in epilepsy syndromes.
  • Different mutations within the same protein can cause a gain or a loss of function and thus a similar or different channelopathy.