>> Hello everyone. Today, we're going to begin a series of tutorials in which we will consider the basis of neural signaling. And to begin, I'd like to give you just a broad overview of different types of electrical signals that are generated by. Neurons. I got two learning objectives for you today. I would like for you to be able to differentiate the resting membrane potential from the action potential. And I would like for you to consider the actual potential and describe one means for encoding information in the activity of neurons. So let's begin. Well perhaps the most important thing I'll have to say to you today is that electrical signaling is the fundamental neuronal process that underlies all aspects of brain function. So if we want to understand how the brain does it's job of processing information, then we need to know about the basis of electrical signaling. Well, this brings us to neurons and their unique properties. However, we've got a bit of a problem. And that is that neurons are intrinsically poor generators of electricity. That is, they just don't conduct electricity very well being made of biological material. However, neurons. Have evolved really fascinating mechanisms overcome this limitation and those mechanisms involve the generation of electrical signals through the flow of ions across the neuronal plasma membrane. So Much of what we're going to be discussing in this unit of the course, has to do with understanding how ions move across the neuronal plasma membrane. Okay. Well, let's begin by considering an experiment. I want you to be the neuroscientist. And I want you to have at your disposal a neuron for experimentation. This can be a neuron grown in culture, perhaps it's a neuron living in a natural brain in an experimental animal model system that we have at our disposal. Or perhaps it's a computer simulation. That will, give us a chance to prob the behavior of an actual neuron, based on previous recordings of real neurons. Well, whatever the case, we have a neuron in front of us and we've got the ability to manipulate this neuron and then to record the electrical behavior this neuron generates. So, we have two micro-electrodes, we have a stimulating electrode. Which we can use to pass current into the cell and we can either inject negative current or positive current and effect the electrical behavior of the nerve. Well we can record that behavior with a second microelectrode. Now lets begin the experiment by first putting that stimulating Electrode in place. And then, just leaving it alone, we'll come back to that in just a moment. And meanwhile we'll approach the neuronal plasma membrane with the recording micro-electrode. And let's use some graphs, and follow the behavior of this experiment as we go forward in time. So time will be progressing on the x axis. In this direction, so there's time. And, on the top, and what's labeled panel b at the top here. We're going to record the current that's passed through our stimulating micro electrode number 1. But we're not using it just yet. So, the current is just, zero. So, we're not doing anything there. So, we'll ignore that for the time being. What I want us to focus on is the recording microelectrode. Now we begin to approach that microelectrode and we're recording 0 potential. That means that there is no electrical potential between the tip of the microelectrode. And a reference wire because their both essentially in the same medium that is the solution that is bathing this neuron. As soon as we insert this microelectrode into this neuron, we see that there is a sharp fall in the recorded membrane potential, which is to say we are recording a potential between the inside of the cell and the outside. With the inside of the cell being negative relative to the outside and the magnitude of that negativity, at least in this experiment, is on the order of about minus 65 millivolts. So, we call this the resting membrane potential. Now, the resting membrane potential can vary from one neuron to the next. Based on a variety of parameters it's usually between about minus 40 and minus 90 millivolts. So it's a small potential, but it's significant and it is measurable and predictable. So we're going to expand upon those ideas as we go through the next few tutorials. But so for note that the inside of the cell is negative relative to the outside and order of about minus 65 millivolts. Now, we begin to use electrode number 1. And we can stimulate this cell with either positive or negative charge. So let's see what happens. As we pass a little bit of negative current into the cell, we can record some. Passive responses of that membrane. That is, the membrane becomes even more negative, relative to the outside reference electrode, when we pass in this negative current. Now, we call that hyperpolarization. Which is to say, the membrane potential's becoming even more polarized than it is when that neuron is just at rest. Before we did any experimentation to it. Now we can also pass positive current into the cell and we see a decrease in the amount of polarization. We call that depolarization. So polarization refers to the magnitude of the potential and if it's greater than rest, we call that hyperpolarization. And if that potential is less than at rest we call that depolarization. Now let's provide an even stronger positive current into the cell. And we know that, with these steps to higher and higher positive current values, you're passing this up and notice what happens. We no longer just see passive responses. What we see something looks quite different. We call this an active response. And these, explosive, sudden depolarizations of the membrane that look like these spikes, are called action potentials. In fact, sometimes we call them spikes for short, for the reason that in a typical time base like what we are seeing here, they do in fact look like very sharp spikes. So what we found here is that with some Injection of inward current beyond some threshold. There is a sudden explosive depolarizing event that can occur. In fact, the depolarization can even exceed our. Zero membrane potential level, meaning that for a very brief period of time, the inside of the cell actually becomes more positive than the solutions that are bathing it on the outside. Okay, let's consider a few other aspects of this action potential before we wrap up this brief tutorial. First, note that there is some kind of a threshold. And in this experiment, that threshold is around minus 50 millivolts. If we inject a positive current that depolarizes this membrane, beyond about minus 50 millivolts. Then, we trigger the generation of an action potential. So minus 50 millivolts is what we'll call our threshold. And this generation of an action potential beyond threshold is indicative of the all or none nature of the action potential. And we say this because it either occurs or doesn't, and if it occurs, we see it at full amplitude. Now notice what happens as we go from a current step that elicits an action potential to an even stronger current step. One might have imagined that pherhaps you'd get a bigger and bigger action potential. But that's not what happens. What we see is an increase in the number of action potentials and this is a very important point. Essentially what we have here is a stimulus that's getting stronger and stronger and stronger. And the way that stimulus strength is encoded by the activity of this neuron is by generating more and more action potentials. So at least at first approximation in this simple experiment the numbers of action potentials is in some sense proportional to the strength of the stimulus. And this begins to give us some insight as to how information might be encoded in the nervous system. A rapid barrage of action potentials Could mean, the presence of a stronger stimulus, compared to a briefer train of action potentials with fewer individual events. Okay, so, this is just a picture of what we might see when we record the electrical activity of a neuron. Action potentials could be generated. Action potentials could propagate along an axon. That is going to grow out from a neuron like this, so we can imagine there being a series of action potentials being propagated that eventually might come to the terminal where we the, the synaptic junction. And there through a set of processes that we'll describe at a later tutorial, a chemical neurotransmitter might be released that might have an effect on the neurons that are connected with this One particular neuron in question. And so that gets us into the whole topic of symmetric transmission and we will have a great time talking about that. All right, well, let's conclude this tutorial by considering what are the mechanisms that make all this possible. We have to explain the resting membrane potential, we have to explain concept like threshold and why is the extra potential an all or nothing event. So in order to explain these phenomenon we need to consider two basic molecular mechanisms that account for neural signaling. And they are the establishment of a concentration grade of a permeate ion and Then, a flow of that ion down its concentration gradient through some kind of mechanism that allows for permeability through the plasma membrane. So, these two mechanisms map roughly onto two different kinds of proteins that are found in the neuronal plasma membrane. On the left hand side of this figure, we see the mechanism for generating ion gradients. And these gradients are formed by active transporters that bind ions and transport them. Upstream if you will against their concentration gradient. So I've got this large arrow here to the left indicating that we're transporting ions from one side of the membrane to the other building up a concentration gradient. Well that concentration gradient. Is a means of storing energy that can then be dissipated if that gradient is allowed to discharge. And that gets us to the second mechanism that we have illustrated here in this slide, and that is the presence of ion channels. That allow ions to diffuse through an aqueous pore created in the center of that channel that allows for the passage of an ion across the plasma membrane. Now recall that ions are charged molecules so they are not going to pass through a lipid bilayer very easily. There needs to be some kind of aqueous pore created that allows that ion to flow and that's exactly what the ion channel does. So, ion channels provide a means for dissipating the gradients that are stored by the action of ion pumps. So we've got two mechanisms here. We've got ion pumps and ion channels. The pumps establish concentration gradients. The channels explain the selective permeability of the neuronal plasma membrane to particular ions. So, let me leave you with one concluding thought and that is ion pumps establish the concentration gradients that provide the driving force for the diffusion of ions across the normal neuron paths of the brain. In this way, pump set the stage for the movement of ions through those channels that generates electrical signals. Okay, this wraps up today's tutorial we will break down these various mechanisms over the next several sessions, we'll talk in more depth, and more quantitative terms about the basis of the resting membrane potential. As well as the action potential. And then eventually, we'll move into mechanisms and synaptic transmission, neurotransmitters and their receptors, and then the means by which synaptic strength can be changed through experience. This is the fascinating topic of Synaptic Plasticity. So that's where we're going in Unit 1. Thanks for beginning the journey with me. And I look forward to having you with me next time.
