Well now, we come to the final of our three tutorials on synaptic plasticity, and in this session I would like to talk to you about Hebb's postulate. Again we are talking about content that pertains to 3 of our core concepts in the field of neuroscience. We continue to talk about how neurons communicate through electrical and chemical signals and we're elaborating on a new theme for us and that is how life experiences Can change the structure and function of the nervous system. And as I've commented on in the previous two tutorials, I think this is a tremendously important and exciting field within neuroscience because what we are now capable of discovering are the very mechanisms that we can harness and use to promote healthy living and the treatment of disease and the rehabilitation from neurological dysfunction and disability. Well, my learning objectives for you in this session are again to relate. Our discussion to general cellular mechanisms of synaptic change. And I want you to be able to state Hebb's postulate and discuss its relevance for neural plasticity. Ok, we've gone through this a few times already and we'll do it again very briefly just to remind you of our cellular mechanisms of synaptic plasticity. Well, this begins with neural activity, triggering the activation of postsynaptic second messenger systems. The trigger is typically an alteration in the level of intracellular calcium that's free in the pseudoplasm of the postsynaptic process. That is critically important because The amount of calcium in that intracellular process is going to activate calcium dependent second messenger systems. And these second messenger systems generally alter two categories of enzymes that are present within the postsynaptic cell. Either protein kinases. Which tend to turn on target proteins through phosphorylation. Or protein phosphatases. That tend to inactivate target proteins through dephosphorylation. So this alteration in protein phosphorylation is very important in mediating the early stages of long term plasticity. Because what is happening here doesn't involve the generation of new proteins, just the alteration in the structural and functional competency of existing proteins. But to get to the long-term stages of synaptic plasticity, There needs to be a means for altering gene expression. Though that, so that's the basic scenario by which synaptic plasticity has both short- and long-term consequences on the structure and function of neuronal connections. So now, I want us to consider a very powerful postulate that's been with us in the field of neuroscience for, well, more than 60 years now. But it's been especially in the last 20 to 30 years that this postulate has really proved to be formative in understanding cellular and synaptic mechanisms of synaptic change. Well, this is a postulate that was proposed by the Canadian psychologist Donald, Donald Hebb, who passed away in 1985. And the usual form of this postulate that is often reproduced and quoted is from a very important work of Dr. Hebb's, Published in 1949 called, The Organization of Behavior. And I know many of you will be interested to learn about Donald Hebb than I'll have to say and, there's some excellent compilation of information found in Wikipedia. I don't normally recommend Wikipedia but, This is a good starting place for someone just trying to gather some resources concerning the life and the work of Donald Hebb. Well, that brings us to the principles of the postulate. What Hebb's postulate stated in principle, I'm not going to give you the verbatim text, but in principle Is that coordination of activity or coordinated activity of a presynaptic terminal and a postsynaptic cell would lead to the strengthening of that synaptic connection between them. And conversely, uncoordinated activity between synaptic partners would weaken their synaptic connections. Now, a colleague of mine from Duke University who, who sadly was take far too early and with great heartache for, for his family and his friends who, who knew him well Dr. Larry Catz. Dr. Catz Encapsulated these principles quite insightfully as he was known to do in the following phrase. Neurons that fire together, wire together. The firing together captures beautifully the heavier notion of coordinated activity and the wiring together speaks powerfully about the consequences of coordinated activity. For not only synaptic strength but also the long term consequences that require the building up of new synaptic connections. Now Hebb's postulate really is not a departure from what we've been talking about so far in our tutorials on synaptic plasticity. The changes in synaptic strength that Hebb could only imagine in his day and now we come to speak of in these terms are long-term potentiation and long-term depression. So LTP and LTD would be the logical consequences of the coordination or incoordination of activity that Hebb postulated. Now, how does spike-timing dependent plasticity fit in? Well again, spike-timing dependent plasticity explains how Synaptic change can occur one post-synaptic spike at a time under normal physiological conditions that are found in real neural networks with ongoing activity. So spike timing dependent plasticity has been a framework that has been based upon data Such as what we've seen previously here reproduced in figure 8.18. Here in this figure, we see that when pre-synaptic activity comes before post-synaptic activity, within a fairly short interval of about 20 milliseconds or so, then we see long term potentiation. So pre before post leads to long term potentiation. Conversely, if we see postsynaptic activity presumably driven by some other input to a neuron than the one that we have command of, when that postsynaptic activity comes before. Presynaptic activity then that's a regime that favors long-term depression. So now, to put these data in the context of heavy inplasticity or Hebb's postulate, we might say that pre before a post is equivalent to the kind of coordination of firing across a synaptic connection that would be consistent with the strengthening of that connection. Where as the post before pre regime, might be a picture of what in-coordination of activity might mean. At least for the synaptic connection under study. Presumably there's coordination at some of the other synapses to this postsynaptic neuron, otherwise it wouldn't be firing an action potential. But in this particular isolated synapse that's under study here, it doesn't appear as though. The presynaptic element is really what's driving the activity of that postsynaptic neuron. Hence the incoordination, at least at that one synaptic junction. Okay. So, again, Hebb's Postulate Is captured by this phrase neurons that fire together wired together. And understanding plasticity at this level begins to take us from one synapse to the compounding impact across an entire set of connections that builds up neural circuits and even neural systems. So again, change at the synaptic level can produce change in wiring patterns of entire neural circuits. This is why I love this phrase from Larry about wiring together. Because it really points to the long term and broader consequences. Of a change in activity that occurs at the synaptic level. And so, this synaptic change accumulates throughout a network of interconnected neurons, and the net effect of firing or misfiring Maybe wholesale change in the structure and function of network properties. Well, this is the briefest of our tutorials that I prepared for you so far. But only in terms of my participation with you here. I hope that this tutorial continues in the discussion forum, as you consider the study question that I will leave you with. And it's a question that is reproduced for you at the, The bottom of your tutorial. As I've been mentioning, my former colleague here at Duke, Dr. Larry Katz, proposed the aphorism neurons that fire together, wire together. Well, this is a wonderful phrase to take away from this tutorial and perhaps it sounds familiar to an aphorism that you may know, that aphorism is use it or lose it. And this might appear to be a valid restatement of Hebb's Postulate, but this is the question I want you to consider and perhaps even kick it into the discussion forum and share your thoughts about it. So, here's my question that I leave you with today. Is use it or use it an accurate expression that reflects a synaptic mechanisms of neural plasticity? Maybe you have a definitive yes or no, or maybe you have a definitive no one knows. So go ahead and think about it and, let's see what kind of discussion we can generate around this question.
