Hierarchical Brain

Movement of ions

This page describes how a neuron uses the movement of electrically-charged particles called ions across its membrane to send a signal to other neurons via synapses. Both the generation of the electrical signal within a neuron and the passing of that signal to other neurons depend on the movement of ions, and therefore the entire working of my brain is completely dependent on this.

This could be considered a second level of detail below the high-level descriptions of neurons and synapses. An understanding of this lower level is not required in order to explain the workings of the brain using my proposed hierarchy, but the detail on this page gives an idea of the complexity of the activity within and between neurons, and some of this detail is still uncertain.

Introduction

• Below the level of the high-level description of the functionality of neurons and synapses, there are further levels of detail that are not required to be understood in order to explain the higher levels of my hierarchical levels of description on these web pages.
  • The rather lengthy description below on how a neuron raises and passes a signal is based entirely on two physical forces and the detailed properties and behaviour of the membrane of neurons:
    1. The force of diffusion that affects all atoms and molecules;
    2. The electrostatic force that only affects ions (atoms or molecules that have an electric charge);
    3. The properties and behaviour of the membrane (the skin) of a neuron, and particularly channels through it.
  • It is the combination of these three features that enables the signalling capability of neurons.
    • It can be described as the movement of ions in relation to the membrane and its components when subjected to the two forces.
    • It is this functionality that allows the brain to react to either a tiny stimulus from external or internal senses or an internal connection between different brain areas by amplifying and broadcasting the signal to many other parts of the brain.
    • It is a mind-boggling thought that all our thoughts, memories, intelligence and consciousness are generated by the movement of ions in and out of neurons.
  • I have included copious Wikipedia links in the description below that provide even more information.

Physical forces involved

• There are two primary physical forces that can affect the flow of ions in relation to the cell membrane, diffusion and electrostatic forces:
  1. Atoms or molecules will always flow from areas of high density of that atom or molecule to areas of low density of that atom or molecule; this is called diffusion.
     • Diffusion does not affect a single atom or molecule, its movement is purely random (called Brownian motion), but when many atoms or molecules are involved, the overall movement from a higher level viewpoint is not random.
       • The particles spread out as far as they can (within whatever boundaries are encountered) until they are approximately evenly spaced.
       • This can also be described as motion that increases the entropy of the system.
     • The force of diffusion does not exist at the level of atoms or molecules but is an emergent concept at a higher level, and is known as an entropic force (see also levels of description).
     • Although at human scales diffusion seems quite a slow process, at the small scale of neurons it happens very quickly, because the distances involved are very small.
       • If you carefully pour some coloured liquid into a glass of water and do not stir it, it takes quite some time for the colour to spread throughout the whole glass.
       • But if you were able to zoom in with a microscope to examine just a small number of molecules, the movement across a very small space would appear very fast.
  2. Opposite electrical charges attract, and like charges repel, so electrostatic force only affects the movement of electrically-charged particles, which are called ions.
     • Positively-charged ions attract negatively-charged ions, and vice versa.
     • Positively-charged ions repel other positively-charged ions.
     • Negatively-charged ions repel other negatively-charged ions.
• There are additional complications relating to ions because they dissolve in the water that is plentiful both inside and outside the membrane (see membrane below).
  • What we mean when we say they dissolve in water is that the ions attract water molecules, and become surrounded by them, and this affects their behaviour¹.
    • Although a water molecule does not have an overall charge, it is dipolar, which means that its charge is separated within one molecule with the oxygen atom at one end having a negative charge and the two hydrogen atoms at the other end having a positive charge.
    • So when an ion is dissolved in water (when it is in solution), it has one or more solvation shells of water molecules surrounding it, and the smaller the ion, the more shells there are.
    • This has a significant effect on the effective size of an ion which affects its ability to pass through a membrane, as is explained below.
• Diffusion applies to all atoms and molecules, but the electrostatic force applies only to ions, so ions are affected by both forces.
  • Depending on the circumstances, the two forces can act in the same direction or in opposite directions.
  • If the two are in opposite directions, there will be a point of balance where the two exactly cancel each other out, which would mean there would be no overall movement of ions.
  • The combination or summation of the two forces on ions is sometimes referred to as the electrochemical gradient.

The membrane

• A neuron, like all other cells in a multicellular organism, has a skin, the cell membrane, to protect it from its environment and to separate the inside environment from the outside environment.
  • Most of the inside of a neuron consists of a liquid called the cytosol (part of the cytoplasm, which includes all the other things inside the cell). Outside the cell membrane, throughout the brain, is a similar liquid called the cerebrospinal fluid. Both of these liquids are mostly water, and both contain various ions, of both positive and negative charges, but there are differences in the concentrations of the ions between the inside and outside of a cell².
    • The cytosol inside a neuron is about 80% water and contains ions of which the majority are positively-charged potassium ions and negatively-charged molecules of proteins and amino acids.
    • The cerebrospinal fluid outside a neuron is about 99% water and contains ions of which the majority are positively-charged sodium ions and negatively-charged chloride ions.
  • The cell membrane is a very thin layer of fatty molecules called a lipid bilayer which is impermeable to all large atoms and molecules as well as all ions³.
    • Even though some ions are very small, they are not able to pass through the membrane because, as described above, they are surrounded by electrostatically-attached molecules of water in solvation shells, so are, in effect, much larger.
    • The fatty molecules of the membrane do not mix with water, so this prevents ions even getting close to the membrane.
    • An important strengthening component of the membrane is cholesterol, which is a type of lipid, but this cholesterol does not come from our diet, it is manufactured in the brain.
  • However, like all other animal cells, the membrane of a neuron is not completely impermeable.
    • All animal cell membranes contain various complex long-chain molecules, known as membrane proteins, that interact with the membrane in various ways.
      • There are hundreds of different types of membrane proteins, but an important sub-category are integral membrane proteins that are permanently attached to the membrane, and there are many different integral membrane proteins.
      • An important sub-category of integral membrane proteins is transmembrane proteins that span the membrane and can create pores or channels that allow certain atoms or molecules through in one direction or the other depending on their size, shape, charge, and in some cases on additional external factors.
      • There are more details on the four types of transmembrane proteins that are used in neurons to raise and pass a signal below.
    • Molecules of water can get through the membrane (water is not an ion).
      • Small number of water molecules can pass through by osmosis, although this is a relatively slow process.
      • There are also pores in the membrane called aquaporins, a specific type of integral membrane protein. These allow water to pass into or out of the cell much faster, and maintain the correct balance of water between inside and outside the membrane, and also the amount of water in the brain as a whole.
      • Aquaporins are found in many organs in mammals, not only in the brain, and there are a number of different types. Aquaporin-4 is the most common in the human brain, but it is found mostly in glial cells⁶.
    • Some non-ionic small atoms and molecules such as oxygen, carbon dioxide and nitrous oxide (and ethanol) can also get through, some via diffusion, some via the aquaporins⁷.
  • In all cells (not just neurons) there is an electrical potential difference, meaning a voltage across the membrane, so between the inside and the outside of the cell, which is caused by the movement of ions of potassium, sodium and chloride through the transmembrane proteins. This is called the membrane potential.
    • There is a static state when the difference stays the same for a period of time, called the resting potential, and cells return to this state after any changes to the difference.
    • All neurons have the ability (along with some other cells in muscles and glands) to actively change this difference over a small section of the membrane by moving ions between the inside and outside in either direction through the transmembrane proteins. This can be the start of an action potential that then travels down the axon resulting in the activation, or firing, of the neuron (more details below).
    • This is how an electrical signal can be generated by signals from other neurons and then passed on to further neurons.

Transmembrane proteins

• There are many types of transmembrane proteins; the details of how they work are very complex, and in some cases not yet fully understood. The four specific types in the following list are found in the membranes of neurons and enable the functionality of signalling. The first three are particular types of ion channels (of which the are many different types) that allow certain ions to flow through the membrane down an electrochemical gradient due to an imbalance of concentration or charge across the membrane. The second and third are gated channels, meaning they are only open in certain conditions.
  1. Non-gated ion channels allow certain ions to flow through the membrane via diffusion until there is a balance of either concentration or charge, or more likely a balance of one force against the other. These are sometimes called resting channels, because they are the primary means by which the resting potential is maintained.
  2. Voltage-gated ion channels allow certain ions to flow through the membrane, but they change their permeability depending on the voltage difference across the membrane.
  3. Ligand-gated ion channels allow certain ions to flow through the membrane, but they change their permeability depending on the presence of a chemical, in this case a neurotransmitter, so these channels are mainly associated with synapses (see synapse operation below).
  4. Ion transporters (also called ion pumps) use energy to force ions in the opposite direction up the electrochemical gradient. The energy comes from adenosine triphosphate (ATP) which is the most common source of stored energy in all cells. These pumps are a lot slower than channels in terms of the number of ions they can transport through the membrane in a given time period.

Signal production

• The following explanation of how a signal is produced and propagated within a neuron is in three parts: the first part is how the resting potential is generated and maintained, the second is how signals from other neurons can trigger the start of an action potential in a given neuron, and the third is how this signal then flows along the axon and is passed to other neurons. This is a circular process: the resting potential is only achieved after an action potential is finished, and an action potential can only start from a position of resting potential. Glial cells also maintain a resting potential, but glial cells do not generate signals.
  1. How the resting potential is created and maintained in both neurons and glial cells^{4, 8}.
     • A number of non-gated ion channels are always open in the membrane for ions to pass through at any time, and will allow ions to pass in either direction.
       • Some will pass through just because of random movement.
       • If they pass through because of the force of diffusion, the effect is to move towards balancing that ion’s concentration across the membrane.
       • Most non-gated ion-channels favour one type of ion over others, governed by their effective size.
       • In both neurons and glial cells, the most common non-gated channels are ones that allow potassium ions through.
     • When potassium ions, which are positively charged, flow out of the cell by this method, the result is to leave the inside of the cell with a more negative charge.
       • Potassium ions that have come out of a cell then tend to be attracted back towards the cell membrane because of the attraction of the opposite charge inside the cell, which means that a voltage difference builds up across the membrane.
       • There is a balancing point when the force of diffusion pushing the positive ions out is equal to the electromagnetic force trying to pull them back in.
     • This balance results in a voltage across the membrane being maintained at an approximate value of -75mV (75 millivolts, or 0.075 volts, with the inside more negative than the outside).
       • This is a small voltage but enough to do significant work at the small scale of the cell.
       • It means that the cell can act as a type of battery; it is storing a chemical potential that can later generate an electric current.
     For glial cells, that is the whole story, but for neurons, it is a little more complicated⁵.
     • In a neuron there are also ion channels that allow positively-charged sodium ions to flow in, although in much smaller numbers that the potassium ions that flow out, mainly because there are fewer sodium channels than potassium channels.
     • There are also sodium-potassium pumps which move ions of both potassium and sodium in the opposite direction to their gradient, and other types of pumps that move chloride and calcium ions.
     • However, pumps are only able to move very tiny numbers of ions in comparison to channels, so the effect is not large, and only has an effect when the balance is close to the resting potential.
     The end result is a resting membrane potential in a neuron of around -70mV. This is when the continuous movement of sodium and potassium ions through ion channels is exactly balanced by the movement of sodium and potassium ions through the sodium-potassium pumps.
  2. How a signal or action potential is generated within a neuron^{9, 10}.
     • Ions that come into a neuron via synapses (see synapse operation below) spread out and mix with each other.
       • Changes to the voltage across a membrane caused by these ions is called electrotonic potential.
       • These changes in membrane potential typically do not lead to the opening of gated ion channels and do not directly cause an action potential, but can contribute to them.
       • The spreading out, or dissipation, of the ions is partly due to diffusion, but also due to electrostatic forces between the charged ions, sometimes called electrotonic spread which is a graded response, as opposed to the all-or-nothing response of an action potential described below.
       • The spread can also be affected by channel and pumps in the intervening area.
       • Ions that arrive via synapses nearer the cell body have a much bigger influence on whether the neuron fires than ones that arrive via synapses at the end of long dendrites.
     • The particular place in the cell body where the axon joins to it, called the axon hillock, is the critical place where the mixing of ions is often described as a process of summation.
       • This process governs whether the neuron fires, or generates an action potential.
       • Sometimes the summation is described as if it is a calculating machine, but it is simply the presence and mixing of many ions of different charges near the membrane at the particular place¹¹.
       • The process is also sometimes described as if it were two processes of spatial summation and temporal summation (see electrotonic potential - summation, for example), but in reality both are always relevant and both contribute.
     • If a sufficient current builds up in the cell body to change the voltage across the membrane at the axon hillock from -70mV to about -50mV, then the threshold potential is reached and a cascade of actions is triggered that that causes the neuron to fire.
       • The axon hillock is the critical place because there are a particularly large number of voltage-gated sodium channels in this area.
       • A voltage change at this part of the membrane causes these to open and let in sodium ions, which are positively charged. They flow in very rapidly because the concentration outside is much higher than inside.
       • This causes the voltage across the membrane to change even more in the same direction, until it reaches about +20mV, so the inside of the neuron in this area is more positively charged than the outside.
       • This is called depolarisation.
     • This then triggers voltage-gated potassium channels to open and let positively-charged potassium ions out of the cell. This is called repolarisation. This drives the voltage difference back past the resting potential to around -80mV. This is called hyperpolarisation and briefly makes a new action potential less likely to happen.
     • Finally, the resting potential of -70mV is restored by the process outlined in the previous section.
  3. How an action potential can flow along the axon to other neurons.
     • This positive-voltage signal can propagate down the length of the axon simply by diffusion of positive ions inside the axon, and it can only go in only one direction because of the follow-on effect of the hyperpolarisation; but this is a very slow process and would die out quite quickly.
     • However, all along the axon, there are further voltage-gated sodium channels, so that when the action potential reaches this point, the voltage change causes these channels to open and let in positively-charged sodium ions.
     • The result is a wave of a positive voltage that passes all the way down the axon, which is what is called an action potential, signal, or spike.
     • Myelin is insulation created by one type of glial cell called oligodendrocytes that wraps tightly round the axons of many neurons in sections.
       • The effect is to cause the action potential to jump in sections down the axon, making the transmission of the signal very much faster than it would otherwise have travelled, and also more efficient.
       • This is called saltatory conduction, from the Latin word saltare, meaning “to jump or leap”.
       • An important component of myelin is cholesterol, but as with the cholesterol in the membrane of a cell (mentioned above), this cholesterol does not come from our diet, it is manufactured in the brain.
       • On a myelinated axon, the gaps between the myelinated sections, called Nodes of Ranvier, are the only places that need to have the voltage-gated sodium channels, so that when the action potential reaches these points, the voltage change causes these channels to open and let in positively-charged sodium ions.
     • When the action potential reaches an end of the axon where a synapse junction to another neuron is located, the membrane at that place is depolarised enough to cause the synapse to release neurotransmitter chemicals into the gap between the two neurons which are then received by the other neuron, and so the signal is passed on (more details immediately below).

Synapse operation

• The movement of ions is crucial to the operation of synapses, but in different ways and to a different extent in the two types of synapse. This section is a summary of the functionality of synapses that involves the movement of ions, more details are on the synapse page.
  • Electrical synapses have ion channels that link the presynaptic and postsynaptic neurons, so ions can move directly between the two, and this is the method by which an electrical signal is passed from one to the other.
  • Chemical synapses are far more complicated: they involve the transfer of neurotransmitter chemicals, which are nearly all non-charged molecules, so not ions, but the mechanism of their release by the presynaptic neuron and the mechanisms by which they alter the charge in the postsynaptic neuron both involve the movement of ions.
• An electrical synapse requires that the membranes of the two neurons physically touch each other.
  • Ion channels span both membranes where they touch, and these allow electrically charged particles to flow directly from one neuron to another, whether or not the presynaptic neuron raises an action potential.
  • Many electrical synapses have voltage-gated ion channels, which should mean that ions can only move in one direction, but if they are not voltage-gated then the ions can move in both directions (but see electrical synapses for some more details on this).
• A chemical synapse requires that the membranes of the two neurons have a gap between them, called the synaptic cleft.
  • When an action potential reaches the presynaptic site of a synapse, the membrane is depolarised by the influx of positively-charged sodium ions (see signal production above, sections 2 and 3), and this causes the opening of voltage-gated calcium channels in the membrane of presynaptic neuron at the synapse.
  • This causes positively-charged calcium ions to flow down their electrochemical gradient through the presynaptic membrane, so increasing the calcium concentration in the interior. This causes vesicles that are docked with the presynaptic neuron membrane within the active zone at the synapse to open, releasing the neurotransmitter molecules that they contain into the synaptic cleft.
  • The released neurotransmitter molecules dock with receptors on the postsynaptic neuron membrane, and this causes, either directly or indirectly, the opening of voltage-gated ion channels in the post synaptic membrane.
  • Ions can then flow through these open channels, so creating a postsynaptic potential, a voltage across the postsynaptic membrane, which can contribute to whether or not the postsynaptic neuron raises an action potential.

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References For information on references, see structure of this website - references

1. ^ Principles of Neural Science Fifth edition - Kandel et al. McGraw-Hill US 2012 - see GoogleScholar.
   A very comprehensive reference work.
   Page 101 (last three lines) to page 103. “The oxygen atom in a water molecule tends to attract electrons and so bears a small net negative charge, whereas the hydrogen atoms tend to lose electrons and therefore carry a small net positive charge. As a result of this unequal distribution of charge, positively charged ions (cations) are strongly attracted electrostatically to the oxygen atom of water, and negatively charged ions (anions) are attracted to the hydrogen atoms. Similarly, ions attract water; in fact they become surrounded by electrostatically bound ‘waters of hydration’.”
2. ^ Ibid. Principles of Neural Science Fifth edition
   Page 129, first paragraph, in the section “The Resting Membrane Potential Is Determined by Nongated and Gated Ion Channels”: “Of the four most abundant ions found on either side of the cell membrane, Na⁺ and Cl^- are concentrated outside the cell and K⁺ and organic anions (A^-, primarily amino acids and proteins) inside.”
3. ^ Ibid. Principles of Neural Science Fifth edition
   Page 101-103, in the section “Ion Channels Are Proteins That Span the Cell Membrane”: “The lipids of the membrane do not mix with water - they are hydrophobic. In contrast, the ions within the cell and those outside strongly attract water molecules - they are hydrophilic. Ions attract water because water molecules are dipolar: although the net charge on a water molecule is zero, charge is separated within the molecule. The oxygen atom in a water molecule tends to attract electrons and so bears a small net negative charge, whereas the hydrogen atoms tend to lose electrons and therefore carry a small net positive charge. As a result of this unequal distribution of charge, positively charged ions (cations) are strongly attracted electrostatically to the oxygen atom of water, and negatively charged ions (anions) are attracted to the hydrogen atoms. Similarly, ions attract water; in fact they become surrounded by electrostatically bound waters of hydration. An ion cannot move away from water into the noncharged hydrocarbon tails of the lipid bilayer in the membrane unless a large amount of energy is expended to overcome the attraction between the ion and the surrounding water molecules. For this reason it is extremely unlikely that an ion will move from solution into the lipid bilayer, and therefore the bilayer itself is almost completely impermeable to ions.”
4. ^ Ibid. Principles of Neural Science Fifth edition
   Some information summarised from pages 129-130, under the heading “Open Channels in Glial Cells Are Permeable to Potassium Only.”
5. ^ Ibid. Principles of Neural Science Fifth edition
   Some information summarised from pages 130-131, under the heading “Open Channels in Resting Nerve Cells Are Permeable to Several Ion Species” and following.
6. ^ Aquaporins in Brain Edema and Neuropathological Conditions - Filippidis, Carozza and Rekate 2017
   doi: 10.3390/ijms18010055 downloadable here or see GoogleScholar.
   Middle of abstract, page 1: “AQP1 [Aquaporin] and AQP4, the two primary aquaporin molecules of the central nervous system, regulate brain water and CSF [CerebroSpinal Fluid] movement and contribute to cytotoxic and vasogenic edema, where they control the size of the intracellular and extracellular fluid volumes, respectively. AQP4 expression is vital to the cellular migration and angiogenesis at the heart of tumor growth; AQP4 is central to dysfunctions in glutamate metabolism, synaptogenesis, and memory consolidation;”
7. ^ Aquaporin water channels in the nervous system - Papadopoulos and Verkman 2013
   doi: 10.1038/nrn3468 downloadable here or see GoogleScholar.
   Middle of first column on page 265: “Under some conditions, certain AQPs [Aquaporins] may transport various gases (CO₂, NH₃, NO and O₂), small solutes (H₂O₂) and ions (K⁺ and Cl^-), although the biological importance of gas, solute and ion transport by mammalian AQPs is unclear.”
8. ^ Cognitive Neuroscience: The Biology of the Mind - Gazzaniga, Ivry and Mangun, Fourth Edition 2014 Norton & Company USA
   A comprehensive text book edited by Michael Gazzaniga, Richard Ivry and George Mangun.
   Some information in this paragraph summarised and restructured from pages 27-29 under the headings “The Membrane Potential” and “Ion Pumps”.
   In particular, page 29: “The neuronal membrane is more permeable to K+ than to Na+ (or other) ions... The membrane permeability to K+ is larger because there are many more K+-selective channels than any other type of ion channel.”
9. ^ Ibid. Cognitive Neuroscience: The Biology of the Mind
   Some information in this paragraph summarised and restructured from pages 30-32 under the heading “The Action Potential”.
10. ^ In Search of Memory - Kandel 2006 Norton & Company USA - see GoogleScholar.
    This very readable book by Nobel prize winner Eric Kandel is an autobiography, history and text book all in one.
    Some information in this paragraph summarised and restructured from pages 81-86 in the chapter 5 entitled “The Nerve Cell speaks”.
11. ^ The process that takes place at the neuron axon hillock to decide whether or not to raise an action potential, called summation, is sometimes described as if there is a complex calculation going on. However, there is no more calculating going on than there is in my morning cup of coffee.
    My cup of coffee, just like the cytosol, is mostly water, but I have added some granules of instant coffee, some crystals of sugar and an amount of milk. If I don’t stir the resulting mixture, and rely on diffusion to mix these three components into the water, and occasionally taste the result, my taste buds are unlikely to reach their “threshold potential” for some time, because the coffee, and particularly the sugar could take a long time to fully diffuse. I don’t think you could claim that there is any integration or algebraic summing going on that allows me to taste some coffee, but not enough, or some sugar but nowhere near enough.
    I could test the pH level of my coffee; water is neutral, coffee is medium-acidic, and adding milk will neutralise the coffee’s acidity to quite a large extent (milk is only very slightly acidic). If I used a pH meter I could arrange to stop putting in milk when the mixture reached a certain pH level, which is another way of measuring what the balance of ions is in the solution, so actually would do exactly what voltage-gated ion channels do.

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Page last uploaded Wed Jan 31 07:25:03 2024 MST