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LESSON 3.3 WORKBOOKWhy does applying pressure relieve pain?

Why does opening sodium or calcium ion channels cause a neuron to depolarize? _______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Why does opening chloride ion channels cause a neuron to hyperpolarize?______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

DEFINITIONS OF TERMS

Depolarize – to decrease the resting membrane potential.

Decreasing membrane potential means that the membrane potential is becoming more

positive.

Excitatory postsynaptic potentials (EPSP) – graded postsynaptic depolarizations, which increase the likelihood

that an action potential will be generated

Hyperpolarize – to increase the resting membrane potential. Increasing membrane potential

means that the membrane potential is becoming more

negative.

Inhibitory postsynaptic potentials (IPSP) – graded

postsynaptic hyperpolarizations, which decrease the likelihood that an action potential will be

generated

In the last lesson, we learned how neurons send signals across the synaptic cleft via synaptic transmis-sion. But two questions remain - how does this type of signaling result in an action potential in the postsyn-aptic cell? And thinking back to our pain framework, how does communication between neurons in the pain pathway allow us to control how we perceive pain-ful stimuli? The answer to both questions lies in the specialized structure at the start of the axon where the action potential originate - the axon hillock.

Postsynaptic potentials

Remember that the local changes in membrane potential created by neurotransmitters binding to their receptors at the synaptic cleft are referred to as postsynaptic potentials. Interestingly, the kind of post-synaptic potential a particular synapse produces does not depend on the neurotransmitter itself. Instead, it is determined by the characteristics of the postsynaptic receptors the neurotransmitter binds to – in particular, by the specific type of ion channel they open. Receptor-gated ion channels in the postsynaptic membrane are much more versatile than the voltage-gated ion channels in the axon. For one thing, there are other types of channel besides Na+ , anion channels (permeable to negatively charged ions) as well as other cation channels (permeable to positively charged ions). Second they can move ions out of the postsynaptic cell as well as into it. This means that the receptor-gated ion channels can have a varied range of effects on the postsynaptic cell, as we shall see. The end goal of all these effects is on the threshold that regulates whether an action potential will fire.

We can identify two major types of neurotransmitter receptor dependent ion-channels in the postsynap-tic membrane, cation channels (permeable to positively charged ions) and anion channels (permeable to negatively charged ions):

Two cation channels permeable to: One anion channel permeable to:

Sodium (Na+) Chloride (Cl-)

Calcium (Ca2+)

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LESSON MATERIALSWhy do EPSPs increase the likelihood of fir-ing an action potential?__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Why do IPSPs decrease the likelihood of fir-ing an action potential?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Note that these channels are different from the voltage-gated sodium and calcium channels we talked about on the axon and the presynaptic terminal because they are stimulated to open by a neurotransmitter binding to its receptor. But when they do open, Na+ or Ca2+ ions can enter the cell, as we saw before. This entry of positive ions depolarizes the postsynaptic membrane, making the membrane potential less nega-tive. This is called an excitatory postsynaptic potential (EPSP) and it brings the postsynaptic cell closer to the threshold for firing an action potential. However, when channels that are permeable to chloride (Cl-) open, the negatively charged Cl- ions that are in high concentration outside the cell, are pushed inside by the force of diffusion. This entry of negative ions hyperpolarizes the postsynaptic membrane, making the membrane potential more negative. This is called an inhibitory postsynaptic potential (IPSP)

Recall that an action potential is only initiated after the threshold that opens the axon’s voltage-gated Na+ channels is reached. Because EPSPs depolarize the postsynaptic membrane they bring the membrane potential closer to threshold, increasing the likelihood that the voltage-gated Na+ channels will open and the postsynaptic neuron will fire an action potential. Conversely because IPSPs hyperpolarize the postsyn-aptic membrane they move the membrane potential further away from threshold, decreasing the likelihood the voltage-gated Na+ channels will open and the postsynaptic neuron will fire an action potential. (Figure 7).

Remember though that a single dendritic tree may have hundreds of thousands of synapses, all of which receive inputs from presynaptic terminals. What happens when an EPSP and an IPSP arrive at the same time close to each other? Do they simply cancel each other out in the membrane? Obviously this isn’t a good solution and each neuron has the job of integrating all these many different types of inputs into a coherent output. through the process of integration.

DEFINITIONS OF TERMS

For a complete list of defined terms, see the Glossary.

Figure 7: Getting to threshold. IPSPs decrease the chance of reaching threshold because they make the membrane potential more negative. EPSPs increase the chance of reaching thresh-old because they make the membrane potential more positive.

Inhibitory  Postsynap/c  poten/als  (IPSP)    caused  either  by  entry  of  Cl-­‐  ions,  or  exit  of  K+  ions  

Threshold  –    Voltage  at  which  Na+  channels  open  

Excitatory  Postsynap/c  poten/als  (EPSP)  caused  by  entry  of  either  Na+  or  Ca2+  ions  

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LESSON MATERIALSWhen will the axon hillock initiate an action potential? When will the axon hillock not initi-ate an action potential? Why?______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

The integration of all local postsynaptic potentials (EPSPs and IPSPs) occurs in the axon hillock (Figure 8). The goal of input integration is to put the neuron into a final electrical state whereby it can either fire an action potential or not.

Generally:

• The axon will only fire an action potential if the postsynaptic membrane reaches the threshold to open the axon’s voltage-gated Na+ channels. This can only happen when the excitatory inputs are greater than the inhibitory inputs.

• The axon will not fire an action potential if the postsynaptic membrane does not reach the threshold to open the axon’s voltage-gated Na+ channels. This happens when the excitatory inputs aren’t great enough, and/or when the inhibitory inputs are greater than the excitatory inputs.

The process of synaptic integration is in continuous operation in every neuron in the nervous system. Each cell integrates all of the synaptic information it receives at any one time, and depending on the balance of excitation and inhibition, it either fires an action potential or it doesn’t.

To further explore this idea let’s examine how applying pressure can relieve pain, but before we dive into that discussion, let’s first remind ourselves of the pathway to get pain to the brain.

DEFINITIONS OF TERMS

For a complete list of defined terms, see the Glossary.

Figure 8: Axon hillock. The axon hillock gener-ates an action potential if the excitatory inputs reach threshold to open the voltage-gated Na+ channels. The axon hillock will not generate an action potential if the inputs do not reach the threshold to open the voltage-gated Na+ channels.

Excitatory  Synapse:  Neurotransmi4ers  open  Na+      or  Ca2+  channels  producing  EPSPs.  

Inhibitory  Synapse:  Neurotransmi4ers  open    either  K+  or  Cl-­‐  channels  producing  IPSPs.  

Axon  hillock  reaches  threshold  and  acDon  potenDal  is  fired.  

IPSPs  encounter  EPSPs.  Threshold  is  not  reached  and  no  acDon  potenDal  is  fired.  

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LESSON MATERIALSWhat is the benefit of having both pain and pressure sensitive neurons synapsing on the same projection neuron?_______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does applying pressure relieve some of our pain?______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

The pain synapse in the spinal cord

Recall that the pain pathway has three neurons. The first is in the periphery, the second is in the spinal cord, and the third is in the thalamus. Let’s take a closer look at the synapse between the first neuron and the second in the spinal cord.

In the spinal cord, neurons carrying pain stimuli make synaptic connections within the grey mat-ter in the area that deals with sensory information called the dorsal horn. Specifically, the first pain neurons connect to projection neurons that then project up the spinal cord, carrying pain informa-tion to the third neuron in the thalamus (Figure 9).

But the first pain neurons aren’t the only neurons that make connections with the projection neurons. A different type of neuron that is sensitive to pressure, not to pain, also connects with the same projection neuron. We call these con-nections between pain, pressure and projection neurons a circuit. This circuit is the first way we manage our respons-es to painful stimuli. We can diagram how the circuit is wired (Figure 10).

How the circuit works

Now that we know how the circuit is “wired”, let’s look at how it works.

Remember, that the neurons carrying pain stimuli synapse on the projection neurons. These pain neurons make excitatory synapses with projection neurons. This means that when pain neurons are activated by painful stimuli they will always excite the projection neurons to produce an action potential.

DEFINITIONS OF TERMS

For a complete list of defined terms, see the Glossary.

Figure 9: Pain and pressure synapse in the spinal cord. Neurons carrying painful information, as well as neurons carrying pressure information both syn-apse on the same projection neuron that carries information to the brain.

Pain  neuron    

Pressure  neuron  

Projec-on  neuron  

To  Brain  Interneuron  

Figure 10: Wiring of pain and pressure synapse in the spinal cord.

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Can you predict the effects of damage to our neurons that prevent us acting out our dreams?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

However, remember that the projection neurons are also connected to pressure sensitive neurons. But these neurons make inhibitory synapses with the projection neurons. This means that when pressure-sensitive neurons are activated by pressure stimuli, they will always inhibit the projection neurons, prevent-ing them from producing an action potential.

We can see this circuit in action when we bang our elbow or stub our toe, and then immediately go to rub it. By rubbing the painful area we’re applying pressure that will activate our pressure-sensitive neurons. These neurons will then communicate with the projection neurons in the spinal cord and inhibit them so they’ll no longer tell the brain that they’re getting painful information from the first pain neurons. It’s all a matter of balancing excitatory and inhibitory inputs. It’s not quite the same as “No brain, no pain”, but if the pain never gets to the brain, we certainly can’t feel it.

Excitation vs Inhibition – It’s just a bit more complicated

Note that an inhibitory postsynaptic potential, which leads to neural inhibition does not always produce be-havioral inhibition. For example, suppose a group of neurons actually prevents a particular movement from taking place, for instance if they hold your head erect, preventing it from falling forward. If these neurons experience enough IPSPs they won’t fire an action potential and will experience neural inhibition. But what effect will this have on your head? In fact if these neurons are inhibited, i.e. prevented from functioning, they will no longer be able to prevent your head falling onto your chest. Thus, inhibiting inhibitory neurons makes the behavior more likely to occur.

If we think about neural excitation we can see that the same thing occurs: If we activate neurons that inhibit a behavior, we will tend to suppress that behavior. For example, when we are dreaming, a particular set of inhibitory neurons in the brains becomes active and prevents us from getting up and acting out our dreams.

It is important to remember that all neurons need to reach threshold before they can fire an action potential and communicate with other neurons via synaptic transmission. Whether they will reach that threshold depends on how the axon hillock integrates the hundreds of thousands of excitatory and inhibitory inputs that fall onto the dendritic tree. If the action potential is fired, whether that neuron will have an excitatory or inhibitory effect on the postsynaptic cells it communicates with will depend on which neurotransmitters it releases, how they interact with their receptors on the postsynaptic side and which ion channels they open.

In summary, an action potential always precedes synaptic transmission, and an action potential is always preceded by reaching threshold, and to reach threshold more excitatory inputs than inhibitory inputs are required (even if the neuron is inhibitory).

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Remember to identify your sources

STUDENT RESPONSES

What must always precede the release of neurotransmitter?

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What must always precede the firing of an action potential ?

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Therefore, even in the case of an inhibitory neuron, what sequence of events must occur before it can release neurotransmitter

to inhibit the postsynaptic cell?

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