Transcribed by Dascher Branch-Elliman [Neuroscience][lecture 22]- [Sensory Transduction] by Schiff

2/10/14

Oh, Good morning. Weve been talking about action potentials and then we talked about how an action potential in one neuron can trigger by iontropic synapse action potentials in another neurons. The question remains now where did that original action potential come from? Now basically there are 3 ways to initiate an action potential. One is by a synapse which weve gone over. But that doesnt bring us back to the primary trigger. The second is the possibility of a spontaneously active neuron that just generates action potentials. Now as far as we know these are either nonexistent or very rare in vertebrates. They exist in invertebrates. But these which we call pacemaker neurons, ours tend to be in other neurons like the heart. And the third possibility is some sort of external stimulus, a sensory trigger Now this is what Im going to be talking about for the next few days. Sort of a general idea is that certain sensory neurons, for the most part the somatic sensory neurons, which have their cell bodies in dorsal root ganglia. These send one axon, as youve seen already, into the spinal cord, where it carries the message from the cell body, but the message gets to the cell body from a branch of that axon that goes out to the periphery and either forms or connects with in some way a specialized transducer membrane that converts some other form of energy into action potentials, or a depolarization in any case. So, what youve got here, and there are two possibilities. Remember I said it either forms or connects with the transducer. Either the transducer is the end of that sensory axon. So here is an axon and something happens in the end of that axon so that the end of that axon becomes tranducers. Something that is sensitive to another form of energy, might be temperature, might be touch, might be pressure, might be something more complicated like vibration. And this which I drew in pink chalk, I hope you can see the distinction, is the transducer membrane Another possibility is that sometimes the transducer itself is a cell unto itself, the transducer. And this sort of has a synaptic relationship to this sensory or afferent neuron or axon. So that the transducer causes transmitter release and theres a synapse that produces an epsp, a depolarization on the sensory neuron and can trigger action potentials under certain circumstances. Now what have we got here? We have two distinct forms here. Here you have the afferent neuron is the same cell, part of the same cell as the transducer, or the transducer is part of the same cell. This is a one cell transducer. Here you have a two cell transducer where transduction takes place on a different cell than the sensory axon. Now how does all this work? What typically happens is you apply a stimulus. And in the one cell case, what the stimulus does is it leads to a permeability change, increase of permeability or decrease in permeability to some ion. And if this leads to a hyperpolarization or no significant depolarization than nothing happens and you dont feel anything, you dont sense anything, so thats not very interesting to talk about. So lets say there is a depolarization, this depolarization is generally referred to as a receptor event. Let me just say a little word about the vocabulary

In the old days when these were first study, the sensory transducer was referred to as a receptor. Nowadays, weve gotten a new vocabulary, but of course the old terminology tends to linger. We now refer to receptors as receptors to ligands, to hormones, to transmitters. Some sort of a chemical structure on a membrane that responds to a chemical that arrives, either a transmitter or a hormones from the outside. This is what we call a receptor nowadays And this, which changes a form of energy to another form, eventually an action potential, is referred to as a transducer. However, the change in permeability that the stimulus causes is still called a receptor event. Because that term was coined many decades ago when I was a little kid and dinosaurs roamed the earth. This permeability change causes a change in the membrane potential, a depolarization. so this leads to (because if it causes a hyperpolarization, it causes no action potential so were not interested) a depolarization of the transducer of this cell here in the two cell situation. And this depolarization is by the old classic formation called a receptor potential. Which is a two word label, both of the words are wrong, its not a potential, its a potential change, but weve gone through that already with EPSP and IPSP. And its not a receptor its a transducer Lets say you get a depolarization here, membrane potential, this is getting crowded, out here on this one cell. Transducer. The stimulus produces a depolarization, so instead of -70 or whatever, where you apply the stimulus you have a depolarization to (well, in most cases its going to be an increase in sodium permeability, there are some transducers, as you will hear from dr. spielman, some taste transducer where the ion permeability change is a decrease in potassium and that as we know is a depolarization because if you decrease potassium permeability than effectively you are increasing sodium permeability even though youre not). Did I make that clear? Or did I just muddle everything up. If this is a decrease in Pk, that will depolarize the cell because the membrane potential will move away from the potassium nerdst potential towards whatever nerdst potentials are around, and so you will get a depolarization. What about the two cell situation? And were going to be getting to that on Thursday if we dont get totally snowed out. And I have 6 lecture hours on Thursday. Because I start my day in basic tissue, anyway. So Im here from 8-6, so are you of course. So I dont expect any sympathy, but youre young. If you have a decrease in the potassium permeability or an increase in the sodium permeability or maybe something else, I cant think of anything else off hand that will give a significant depolarization. Now one of the hypotheses that has held up over the years, we havent actually studied every sensory transducer, there are many of them. Im not going into this, not to mention the bare nerve endings, which are usually known as nociceptors. Oh Dr. Siriois probably did that all. You have this whole zoo of transducers here, they respond to the stimulus and they produce depolarization on the transducer itself, but one of the models, thought models, that seems to be holding up is that the transducer has sodium or potassium channels that are sensitive to (respond to) the specific stimulus. A nerve ending that responds to pressure might not respond to temperature or heat. Each one is specific. But what they dont have on the pink membrane here are voltage gated sodium channels. Sodium channels that increase pNA in response to depolarization. Now immediately you respond but then they cant have action potentials. Because the action potential, remember, requires the positive feedback and an increase in sodium permeability leading to more depolarization and so on. And if you dont have voltage gated sodium channels on this membrane than you dont get action potentials here. But over here, the white membrane, is normal axon. I hope we dont get into the kind of

fights I used to have with Dr. Roy who retired last year. He was one of those who insisted that an axon is defined as something that carries an action potential away from a cell body. So by that definition, this is really a long dendrite. And I used to argue, that if something is a meter long and in many cases it is myelinated, damn it, its an axon. Now hes retired, so its an axon Somewhere here, the very close nearby, youve got voltage gated sodium channels, so you can have an action potential here, you cant get one here. What you can get though if this depolarizes in response to the stimulus, to lets say, it could be anything, never quite reaching +60, so lets say it goes to 0, or -10, or +10, whatever. This depolarization spreads, remember electrotonic spread. So exponentially you are heading back to -70, with the relationship the depolarization is proportional to e to the minus distance divided by the length constant lambda. Youve seen all that before In order to trigger an action potential on this normal axon, you have to depolarize the normal axon to 55. So if some normal axon gets to -55, and here is does, you trigger an action potential here. Where does the action potential propagate? Well its going to spread its depolarization as it goes up to +40 or whatever, its going to spread its depolarization in both directions, but this side cant get an action potential. So you are essentially send this action potential propagating along this sensory axon towards the dorsal root ganglion or cranial nucleus thats appropriate depending on what sensory you are dealing with Okay, so its nice to be able to generate an action potential that lets you know there was a stimulus. The next question is this, if you apply a stimulus to the transducer, youre going to get an action potential and then what? If the stimulus is still there youre going to want to get a message to the brain that the stimulus is still there. Also it would be nice to know how strong the stimulus this. Is this something you can shrug off or is it something you should respond to. You have to be able to encode, that is carry this information about the stimulus amplitude, the strength of the stimulus encoded in the action potentials that are produced that are sent to the spinal cord and then the brain. First one more term from the classic. The depolarization at the regular axon, this depolarization here, which is what results from electrotonic spread from where the stimulus was, this depolarization is always going to be smaller than the depolarization where the stimulus was because this is an e to the minus something term, but if it reaches -55, its a liminal depolarization, that is it triggers an action potential. This depolarization here is referred to as a generator potential. And the generator potential is always smaller than the receptor potential because of the loss of electrotonic spread. But the generator potential is what generates action potentials. Now as I said, how does this sensory neuron, this afferent neuron, carry information about the intensity of the stimulus? And once an action potential is produced in an axon, every action potential produced in that axon is going to be exactly the same. Same amplitude, same propagation speed, same duration, same slope, same decay, same post depolarization. Each action potential is exactly the same as every other. But what you can carry information in the form of is how frequently these action potentials are produced. In other words what we have developed is a system in which action potentials are propagated one after another after another as long as that stimulus is there and how close together they are, in other words the frequency with which they are produced depends on the intensity of the stimulus, because that determines the amplitude of the generator potential

Now how does this work? Lets take a look, suppose you have: heres youre membrane potential, heres youre -70, heres youre -55. And lets apply a stimulus here so that membrane potential goes up above 55, this is essentially youre generator potential because its the depolarization from the stimulus thats added on to the resting potential at the point where action potentials are triggered. So this is youre generator potential and assuming you apply a stimulus, turn it on, keep it for a long time, turn it off. The generator potential will go along something like this, and then it will turn off and youll go back to your -70. The generator potential depolarizes the membrane to beyond -55, so you get an action potential. Ill draw a vertical line, it goes up it goes down, it dips a little, you get an action potential. Now what happens right afterwards? Remember this is a time axis, this horizontal axis, what happens? In the course of producing an action potential, youve opened all the available sodium channels, and then theyve all gone into the refractory state. So theres a period of time, very short, when all the sodium channels are refractory, but then they begin to recover. Now, heres what happens. In order to produce the next action potential, or another action potential, you have to be able to open some number of sodium channels because that will give you enough positive feedback so that number overwhelms the reclosing of those sodium channels. Remember if you have a depolarization that didnt reach -55 or so initially there would be some additional sodium channels open but less than were closing to the refractory state so you dont continue to deplolarize. When you reach the -55, the threshold, the rate of opening channels in response to the depolarization exceeds the closing by going into refractory states of the open channels, and therefore it keeps going up. Thats how you get youre action potential But, lets say you have a total of 10,000 sodium channels. And lets say in order to trigger an action potential you have to open 4,000 sodium channels. These are totally numbers out of a hat. Because obviously the bigger the amount of membrane you have, the more channels that can be open, Im just giving an analogy here, its proportional. Immediately, all of the sodium channels are refractory, so there are none available to open. Now whats going to happen is gradually, the number of sodium channels that can open is going to start to increase as they recover from the refractory state. Remember there is a big time spread but they average about 5-10 milliseconds before they can open again. 10,000 sodium channels are refractory, and then the number that are refractory begin to recover over the next 10 seconds, and eventually the threshold gets down to -55. Because when you have a lot of refractory sodium channels, then its hard to open the 4000 you have in order to get an action potential. So, theres a period of time here during which at least 6,000 sodium channels are refractory. If theres at least 6,000 sodium channels refractory out of the 10,000 then you cant open 4000, so you cant get an action potential. You absolutely cant produce another action potential during this time internal. Thats referred to as the absolute refractory period because no matter how much you depolarize this axon, after an action potential, you cant produce an action potential. Once you have recovered 4,000 and there is less than 6000 still refractory, now theoretically its possible to have an action potential. But the question is how do you get it? Youd have to open all the channels. But the threshold to open all those channels isnt -55 anymore. Each channel has a slightly different threshold for opening. When you reach -55 at a resting axon that hasnt been used, at -55 you start getting this positive feedback, exceeding the closing, and so on. But when you have only 4000 or 4000 plus a few, some of those channels will have thresholds that are very much higher. And to open all of those, you might have to depolarize as higher as +10mv. As more and more sodium channels become available to open, the threshold, what was -55, is much more positive and then gradually returns to the -55. So with a generator potential thats here, its not until you get down to this level that you can trigger a second action potential. So now you get a

second action potential here, and if the stimulus is still around, you might get more action potentials further downstream. Its possible to get more than one action potential here, you just have to sit around and wait till enough sodium channels have recovered from their refractory state to allow you to trigger another action potential. Lets try something else. Suppose this stimulus were stronger, something more powerful. Lets apply a bigger stimulus. That will produce a generator potential, it will have a greater receptor potential and therefore produce a greater generator potential. The generator potential might be up here. Now what? Well now you can get your second action potential here. That will start another absolute refractory period, and then you start recovering. Now this period of recovery of the channels is referred to as the relative refractory period, as opposed to absolutely. Relative refractory refers to the period of time where enough sodium channels have recovered from the refractory state so that you could trigger an action potential EXCEPT that the threshold potential is still elevated compared to what it was at rest. You have to hit it harder, you have to depolarize more, but now you get this action potential. So you have an absolute refractory period, you have a relative refractory period during which the same as this curve, this curve and then somewhere here you get another action potential and so on. The whole point is that with the larger generator potential the generator potentials will be liminal as the threshold comes down, sooner. And therefore youll get your second action potential sooner, and then your third action potential sooner, and so on. So the larger stimulus leads to a higher action potential frequency and therefore your afferent axon conveys the strength of the stimulus in the form of the action potential frequency is. Now you notice that the stimulus is steady, the generator potential seems to be sagging a little bit. Maybe not so much here, but there. That was me being sneaky. The point is, in most cases when you apply a constant stimulus to a transducer, the generator potential thats produced, and the receptor event and receptor potential that are produced, gradually decline with time. And thats an example compared to this level thing, this decrease here is referred to as adaptation. And its different for different transducers. Ill just refer back to the zoo that youve seen a couple of times that youve seen in other peoples lectures. Pacinian corpuscles adapt very fast. Others are intermediate and hair cells of the utricle, which well be getting to Thursday if were not snowed out, are the slowest adapting, for all intents and purposes they dont adapt. Where as pacinian corpuscles adapt so quickly that you could apply a stimulus that lasts forever and youll get one action potential and thats all. Because, whats happening? The generator potential goes up, and then falls off so rapidly that you never get a second action potential. So, you might ask, how does a pacinian corpuscle encode information about the strength of a stimulus? Well the answer is it cant. Okay. What about this fellow here? This two cell transducer? And youll be hearing about this again when I talk about hearing and the vestibular system on, well Ill be talking about a two cell system here in the second hour but it doesnt work that way. Everything works different that the visual system, everything works the opposite of what youd expect and its thoroughly confusing .but youll see these (referring to the two cell transducer system) in the form of hair cells in the auditory system and in the vestibular system where theres a transmitter released and theres an actual synapse here. So what happens it that the stimulus in these cases the stimulus leads to lets say an increase in P(Na) although it might be a decrease in P(K) something excitatory. So that leads to a depolarization which is your receptor potential. Same thing here. And then what happens is, since these are two different cells, you

dont have electrotonic spread. What you have is, if the depolarization of this receptor potential is more positive that -40 mv, you get an increase in Pcalcium, just as you did in presynaptic neurons, at that leads to transmitter release. So the transmitter then leaves here, and acts on receptors on the afferent neuron. Ionotropic synapse and you get a depolarization here, which is strictly speaking an EPSP. Because it is a depolarization that makes, producing an action potential in the afferent neuron more likely, and therefore its an EPSP by the rules of defining an ionotropic synapse. But this EPSP IS the generator potential, because from that point on all of these rules follow. And the larger the generator potential is the more frequently you produce action potentials and so on and so forth. Is there anything else I wanted to say? Not really. Okay. So basically in most transducers, either one cell where the spread is by electrotonic spread or two cells where the spread is a synapse producing an EPSP, which is the generator potential. Here the depolarization where the action potential is initiated is the generator potential (this sentence is referring to the one cell). Depending on the size of the generator potential, it requires more or less time for the sodium channels to recover from their refractory state, so you will get action potentials produced at different frequencies. And the action potential frequency produces, carries the information to your brain about what the strength of the stimulus is. Now there is just one other thing here, suppose you apply a stimulus and this leads to a receptor potential which leads to a generator potential. Looking at the receptor potential. And here the receptor potential is the depolarization of this transducer cell. So in either one cell or two cell transducers, the more stimulus you give, the more permeability change you get and you get a receptor potential that starts out going right through the origin because zero produces zero, but then it levels off because after all youre never going to reach +60 certainly in terms of the membrane potential. And therefore it obviously has to asymptotically approach that level, so this is as sort of a hyperbole and thats for one cells and two cells. But suppose you want to look at the stimulus versus the generator potential. Which is not the receptor potential. In the one cell transducer, generator potential is a fixed fraction of the receptor potential. So the generator potential will have the same shaped curve, except it wont be as large, it sort of levels off. It approaches asymptotically some level. In the two cell transducer, a little depolarization and a little more depolarization wont get you to -40 to release transmitter because you know you need to reach -40 to open calcium channels. So here you are going to have a range of stimuli that dont produce any action potential at all, or any EPSP because they dont realease any transmitter. So the generator potential will start out like that and then eventually level off. This is the two cell. And similarly the action potential frequency produced by a stimulus will for a certain range of generator potentials. Theres a certain range of depolarization where the signal is subliminal because the generator potential is less than up to -55. You need like 15mv of depolarization to get from -70 to -55 so in that certain range you arent going to get any action potentials and then you get action potentials but that sort of levels off as the generator potential levels off. And here with the synapse, same sort of thing. Theres a range thats subliminal and this goes even further because you might get subliminal EPSP or generator potnetials, and then you have this curve that levels off asymptotically. Okay. Why dont we take a break here.