How Brain Cells Talk

Wow.  I just wrote a post that was almost completely about dopamine receptors, without actually explaining how neurotransmitters work.

Bruce Banner admitting that that was mean.

I’ve lost my link for this gif so I can’t cite it properly. If you know where its’ from, please let me kow.

That’s okay, I can fix it.

The first thing to know about neurotransmitters is how they fit into the electrochemical signalling between neurons.

A cartoon synapse.

Figure 1. Note how the neurotransmitters move across the synapse (the little gap) and stick to the receptors, pay attention to those. From lecture notes Dyck, R. (2010, Personal Communication).

Signalling occurs when neurotransmitter molecules bind to receptors (Figure 1).  Don’t take it to heart when magazine articles refer to neurotransmitters as having specific functions like “cuddle hormone” or “reward chemical” it’s the receptors which do all the interesting work.  This particular science article trope is one of my least favourite things; it’s meant to be a helpful simplification but it’s actually just straight up wrong.

The function of a neurotransmitter depends on which receptor it binds to and where it is in the brain.  This is why dopamine can both create and prevent attraction in voles by binding to different dopamine receptors.

Receptors can be classified based on either what they make the cell do, or how they work.

Ionotropic receptors (Figure 2A) are directly attached to ion channels so when they are activated they let ions in and out of the cell which is what generates the electrical current in the neurons

Metabotropic receptors turn on a g-protein, a member of a group of small molecules that transmit signals inside the cell.  G-proteins can open and shut ion channels just like ionotropic receptors but when they do they act more slowly and last for longer (Figure 2B).  They can also activate signalling cascades; chains of chemical reactions which alter the overall behaviour of the cell (Figure 2C).  These cascades don’t create electrical signals immediately, but they can change how the cell responds to subsequent signals.  They might, for instance, cause the cell to have a larger response to a specific neurotransmitter the next time it binds.

Different receptor types

Figure 2. Three different kinds of neurotransmitter receptor. From lecture notes: Dyck, R. (2010) Personal Communication

When receptors open or shut ion channels they can be excitatory, in which case the cell will fire a signal of its own or they can be inhibitory, in which case the cell will be prevented from firing.  The receptors which alter the cell’s behaviour in other ways, by activating different signalling cascades, they are referred to as neuromodulatory.  Neuromodulatory effects include things like changing the number or type of receptors on a cell’s surface, which doesn’t make the cell fire immediately but changes how it responds to the next round of neurotransmitter that is released; more receptors will create a bigger response to a neurotransmitter, for instance.

But those are just individual cells, what does opening ion channels have to do with adorable vole romance?  Well, these individual cells are organized into much larger networks, and it is the activity in networks in the brain, groups of cells communicating with other groups, sometimes in distant regions of the brain, that produces thoughts and behaviours.  The activity of specific cell types in specific networks is what creates behaviour.

So, to put it all together

  1. Neurotransmitters turn on neurotransmitter receptors – each neurotransmitter can bind to several different receptor types.
  2. Neurotransmitters change the way their cells behave – different receptor types create different changes, but a receptor typically only does a set thing, like making it easier for a cell to fire.
  3. The activity of big groups of cells in the brain come together to create behaviour – the same transmitter, binding to the same receptor, will create different results depending on which cell is being affected, and where it is.

Now go forth, and view lifestyle articles about neurotransmitters with the same grumpy skepticism I do, quite frankly I could use the company.


How to Make a Vole Fall in Love

It’s Valentine’s day (or at least, it was when I was writing this) and what Valentine’s day would be complete without articles of very dubious quality extolling the virtues of the neurohormone oxytocin (I can’t seem to avoid them anways)?  Oxytocin, for those who have been lucky enough to avoid these articles is a peptide (a small protein) and functions both as a neurotransmitter in the brain, and as a hormone circulating around the rest of the body.  Oxytocin actually does a lot of different things, but it is most famous for inducing social bonding, both romantic and otherwise.  No article about oxytocin is complete without a mention of the prairie vole, a rodent most widely known for forming a long term mated pairs which raise their litters of pups together, these pairs rarely divorce, and if the pairs are split up, voles don’t remarry.  Oxytocin is widely credited for making the prairie vole into a small fluffy paragon of romantic bliss.

An image of a mated pair of prairie voles

Mated pairs of prairie voles, like this one, like to spend a lot of time in contact like this.

Except that vole love is rather more complicated than it seems and involves more than just oxytocin.  Aratonga et al1, have found that if you really want to make a vole fall in love oxytocin shouldn’t be your target at all, what you want is a different neurotransmitter, called dopamine.

Actually convincing two voles to form a mated pair in the lab isn’t very difficult, just leave a male and a female vole in a cage together for twenty-four hours and they will mate and eventually form a pair bond.  The two are considered pair bonded when they both prefer their partner to other voles, and when treat all other voles aggressively.  If you don’t have twenty-four hours, you can speed up the process by activating the D2 dopamine receptors.

A quick aside about dopamine and its receptors.  Dopamine is a neurotransmitter and once released from a neuron, it can bind to several different kinds of receptors.  Which kind of receptor it binds to determines what dopamine makes the post-synaptic cell do, so dopamine binding to a D1 receptor can produce totally different response to dopamine binding to a D2 receptor, even though it’s all the same dopamine.

Male voles (this whole study focused on males) will very rapidly form a preference for a female if the D2 receptors in one part of its brain are activated, even if they haven’t mated yet.  For this to happen though the shell (the outer layer) of an area called the nucleus accumbens must be activated specifically.  A brain wide activation, or even one that occurs in the central core of the nucleus accumbens won’t work.  Activating the D1 receptors in the same area will actually block pair bonding.

The location of the nucleus accumbens in the vole brain

Clusters of dots indicate the outer shell of the nucleus accumbens, This is where the dopamine receptor agonists and antagonists were injected during the experiment

This was determined using a set of drugs called D1 and D2 agonists and antagonists, which were injected into the shell of the nucleus accumbens.  Dopamine will bind to all the dopamine receptors in the area it is released, but these drugs will bind specifically to one receptor but not the other.  An agonist is a drug which turns a receptor on, while an antagonist turns it off, to recap:

D1 agonists activate D1 receptors

D1 antagonists deactivate D1 receptors

D2 agonists activate D2 receptors

D2 antagonists deactivate D2 receptors

D2 agonists can create a pair bond.  D1 agonists don’t create pair bonds, and when D1 and D2 agonists are injected together the D1 agonists will actually prevent the D2 agonist from creating a pair bond.  When a D2 agonist and D1 antagonist are injected together, however, pair bonding can occur.

So, the activity of different dopamine receptors in the shell of the nucleus accumbens can either promote or prevent pair bonding.  But when voles pair bond without the help of drugs they don’t have specific ways of activating just the D1 or just the D2 receptors, dopamine will act on them both.  We just saw that when these two are activated together pair bonding is blocked, so how do voles ever fall in love?

Well, the two receptor types aren’t actually activated together.  Which receptors a cell has isn’t static.  A neuron can alter which receptors are expressed on its surface, where they are expressed and how many of them there are, and this can drastically alter how that cell responds to a signal from one of its presynaptic neuron.  This is what happens to the male prairie voles.

Unpaired voles initially have lots of D2 receptors in their nucleus accumbens, and very few D1 receptors, so they initially form pair bonds with females when they are allowed to interact and mate for twenty-four hours.  Initially, even though these voles have a preference for their new mates, they aren’t fully pair bonded and will still approach other voles.  It takes about two weeks before they develop antagonism towards all other voles and are considered fully pair bonded.  Males which are fully pairbonded have about 60% more D1 receptors in their nucleus accumens than unpaired males, and blocking these receptors with D1 agonists blocks their aggression and weakens their bond with their mates.

So here is how voles fall in love.  When two unpaired voles meet they have lots of D2 dopamine receptors in the shell of the nucleus accumbens and activity of these receptors cause them to form a preference for their partner above all other voles.  As they continue to associate the numbers of D1 dopamine receptors increases.  The activity of D1 receptors blocks the activity of D2 receptors.  This means that in addition to preferring their mate, the voles also become aggressive towards other voles and this is permanent.  Once a vole has a mate, it almost never remarries for any reason because the D1 receptors are still there.  Essentially, its ability to form a new pair bond, or ‘fall in love’ has now been removed.  Voles have only one true love.

Is this how humans fall in love?  Probably not.  Despite the endearing resemblance to the first ten minutes of Up voles aren’t tiny fuzzy people and forming a monogamous pair bond is not in the strictest sense falling in love.  Also, although this will upset the makers of Valentine’s day cards and most romance novels humans aren’t actually monogamous.  If we were, serial dating, polyamory and the various forms of polygamy which have existed throughout human history would all be literally impossible.  So we probably don’t use this dopamine system for this purpose.

Animal studies are a wonderful, powerful, versatile research tool.  If they weren’t we’d have stopped doing them.  But figuring out to what extent the results of an animal study can be applied to people is hard and requires a lot of careful analysis.  We study vole pairbonding to learn about humans because there are a large number of behavioural analogues between human relationships and vole mated pairs and there are some shared neurological bases for those relationships, but we probably don’t cement long term relationships the same way voles do.  One of the reasons why the role of oxytocin in vole pairbonding gets more attention than the role of dopamine is that its much more directly relevant to people than the system studied in this article.

So remember, you are not a prairie vole, and unless you plan to fall in love with the first person you ever have sex with and spend the rest of your life attacking everyone you aren’t married to, don’t ask small monogamous rodents for relationship advice.  Some nice stories of human social bonding can be found here instead.  Its less rigorous, and its only behavioural, but since all behaviour is generated by neurotransmitter systems in our brains anyway, you might still pick up some good advice.

Happy Valentine’s Day.

References

1.        Aragona, B. J. et al. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nature neuroscience 9, 133–9 (2006).


Zap-Poof

If the job of the brain is to process information and generate thoughts, feelings and behaviour, how does it work?  The brain is made of two kinds of highly specialized cells, neurons and glia.  Neurons communicate with each other to process information.  Glia, broadly speaking, are support cells, helping neurons function.  It is the communication between the neurons that is primarily responsible for what the brain does. Neurons have a very specific structure (Figure 1) which is related to how they function.  The bushy dendrites take in information from other neurons.  The architecture of the dendrites is carefully organized to allow the neuron to get input from where it needs it, and is referred to as its dendritic tree.  Information travels through the neuron in the form of small electrical signals called membrane potentials, these can be either excitatory, making the cell more likely to generate a signal of its own, or inhibitory, making it less likely.  These signals travel down the dendrites and through the cell body.  At the base of the cell body (the axon hillock) all these membrane potentials are summed together, if the resulting signal excites the cell above a set threshold the then the neuron will fire a signal of its own called an action potential which travels down the axon (the difference between an action potential and a membrane potential is related to their electrical properties).  The myelin wrapped around the axon acts like an insulator so the electrical signal can bounce between the nodes of Ranvier, and travels much faster than it would otherwise.

Figure 1. Anatomy of a typical neuron from http://www.daviddarling.info/encyclopedia/N/neuron.html

While schematic neurons, like the one here, are a convenient way to see all the parts of a neuron different types of neurons actually all look slightly different and their shape is determined by their function. Neurons that gather input from all over the brain will have immense dendritic trees and small nearly invisible axons (Figure 2).  The pyramidal motor neurons which carry the information used to signal the muscles to move have small trees, but very large axons needed to transmit information down the body (Figure 3).   Typically neurons which transmit information out to the body are called motor neurons, those which carry information from the body to the brain are called sensory neurons, and those within the brain and spinal cord which process and transfer information are referred to as interneurons.

Figure 2. A thalamic interneuron, one of the classes of neurons which receives and directs information all over the brain, from http://berkeley.edu/news/media/releases/2008/12/11_winerobit.shtml

Figure 3. A motor neuron, with part of its very long axon shown, from http://anatomy.ucsf.edu/Anatomy103/Neurohistology/nissl-slides.html

Signalling between neurons involves first a burst of electricity and then a puff of chemicals called neurotransmitters, so it is referred to, imaginatively, as electrochemical signalling.  When the electrical signal reaches the axon terminals, they release a small burst of neurotransmitters.  Individual neurons are separated by a small gap called a synapse.  The neurotransmitters cross the synapse and bind to special receptors on the dendrites of the next neuron which is what creates the membrane potentials.  The combination of a neurotransmitter and a receptor is what determines whether a signal is inhibitory or excitatory each one can bind to multiple receptors, meaning that each transmitter can cause excitation or inhibition by binding to different receptors.  Different receptor types occur in different parts of the brain, which help control the effects of neurotransmitters, and determine the function of the different brain regions.


You Are Here

Since you are reading this post it’s a pretty safe assumption that you are a human being, and have a brain.

What is a brain?  The brain is a located inside the skull, it weighs approximately 3 pounds, on average, and has the consistency of Jello (a fact I have never personally tested).  The large wrinkly surface is called the cerebrum, this is the largest and most complex part of the human brain.  The smaller wrinkly knob at the bottom is called the cerebellum, and the stalk is the brainstem, which tapers down into the spinal cord.  Nerves from through the body run into and out of the spine (with the exception of a few who run directly into the brain), and carry information in and out.  Under the cortex, things get much more complicated.  Your brain isn’t a homogenous mass, but, instead, is made of dozens of specialized structures, all with different functions.  The cortex is also made of many different functional areas, although they can’t be differentiated by the naked eye).

What does a brain do?  The main job of the brain is information processing.  All the information about the outside world, and your internal environment is picked up by your nerves and carried to your brain, which interprets it and integrates it.  This is where sound waves turn into words and music, photons turn into pictures, and then they both get combined to give you the show you are watching on TV.

The brain is also the source of thoughts and feelings about all the information you feed it by seeing, hearing, smelling, etc.  Your brain generates emotions (aided and abetted by your hormones and immune system), remembers things to use later and generates new thoughts and ideas.  Finally, the brain also turns thoughts into behaviour, generating movement, speech, facial expressions.

All of your thoughts, sensations, feelings, impressions, memories, ideas and general you-ness, are in your brain.  Of course, it’s more complicated than that (in biology, everything is more complicated than that).  The body isn’t an army, the brain doesn’t take in information and give out orders, it gives and receives constant feedback to and from the rest of the body more like a conversation and the other participants in the conversation contribute to how the brain functions.


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