Before we talk about the response of the brain to direct injury of itself let's just touch briefly on the mechanisms by which peripheral nerves respond to injury. Well this is the good news part of the story of regeneration of nervous tissue. With damage to a peripheral nerve, the axon that has been injured has a significant capacity to regenerate. And to reestablish a functional connection with the target of that axon. So typically this is a process that unfolds in a sequence. following an injury to a nerve, so for example we imagined there may be some kind of surgical or traumatic injury to a peripheral nerve. be it a spinal nerve or a cranial nerve. And what we see is a degeneration of the distal portion of the axon. However, the entire nerve typically is not lost. Rather the macrphages invade the region and consume the debris in the wake of the injury. but the schwann cells then, will proliferate. And the proliferation of these schwann cells basically establishes a channel, through which a regenerating axon might locate it's target. And reestablish a functional connection. But along the way the schwann cells really are the key mediators of regeneration and regrowth of this injured axon. Because the schwann cells begin to produce growth promoting substances. These growth promoting substances can influence the expression of growth related genes in the cell body of these neurons. And that can then induce the formation of a growth cone. Which can then respond to local signals that are produced by the schwann cells and laid into the extracellular matrix. And thereby a growth cone can be reestablished, it could become modal, and it could recognize adhesion molecules. And it could respond to other kinds of inductive signals that are produced by these schwann cells that are now proliferating. And reestablishing this channel through which this growth cone can eventually find it's peripheral target. Now once the growth cone does make it to the target. Be it a muscle fiber or a ganglionic neuron in the case of preganglionic visceral motor neuron for example. we have the capacity to reestablish a synaptic connection. Now, this typically is not done with perfect fidelity, so that the connections are never 100% of what was there previously. And often the rules that shape the connections, in the developing embryo, are recapitulated. But perhaps not with the, uh,exact degree of precision, that was once possible. So, as a consequence, one typically doesn't see full functional recovery with peripheral nerve injury. I know in my case I have had some return of sensation in the cutaneous surfaces. but I remain somewhat impaired in certain motor functions involving the lower right regions of my face. So at least following my injury to the mandibula division of trigeminal in some branches of the facial motor nerve. I'm still awaiting the restoration of, of full function of course, doing everything I can to rehabilitate this process. But nevertheless, I think the realistic expectation is that the process of re-innovation at best will be incomplete. Now, we are talking about the changing brain across the lifespan. And, unfortunately, as we age, the likelihood that we will encounter some kind of an injury. That, changes the, the structure, or the integrity and the function of the nervous system, is, is increasing. So, we're going to turn out attention now to the way that the central nervous system responds to injury. And as we'll see despite its best attempts to do so There are active mechanisms that limit the regenerative capacity of the brain and the spinal cord following injury or disease. Well, there are essentially three ways that the central nervous system can be injured. They can be injured through trauma, they can be injured through hypoxia or ischemia. That denies the brain of the oxygen or the blood flow that's necessary for full neural functioning. And the brain can degenerate, under the conditions that are consistent with a neurodegenerative disease. In each if these three categories of central injury, there is often the acute risk of the loss of neurons, right at the time of injury. And this happens basically because of, of two considerations. the first is excitotoxicity. And as you may remember from unit two in the course, excitotoxicity refers to the destruction of neurons due to the release of glutamate. And the interaction of glutamate with its receptors that set off a sequence of events that leads to the lysis of cell. So neurons can be excited to death by an elevated concentration of glutamate in the extracellular fluids. Well, this can happen during acute injury to the nervous system Because as brain tissue is damaged the glutamate that 's found within cells is now released to the extracellular fluids. But also there is typically an increase in electrical activity, which leads to an increase in the synaptic release of glutamate. So the direct release of glutamate from damaged cells, together with the synaptic release of glutamate. Elevates this neurotransmitter to levels that interact with the receptors on surviving neurons To the point where dangerously high levels of intracellular calcium can become establish in the postsynaptic neurons. And with dramatically high levels of intracellular calcium, well beyond what is physiological for inducing long-term potentiation for example. These pathologically high levels of calcium can trigger a sequence of events that leads to the programmed cell death of neurons. This is a phenomenon that we call Apoptosis. And we know more now about what these pathways are. So as calcium enters through typically NMDA receptors for glutamate as well as other signalling molecules related to damage to cells, to hypoxia, to stress. even to the withdrawal of growth factors following injury. these factors can interrupt the normal function of this signal called Bcl-2. So when Bcl-2 is blocked, this allows a sequence of events to unfold. That lead to the activation of this important enzyme, Caspase-3. Caspase-3 is what can trigger this downstream set of mechanisms that leads to program cell death. This involves the condensation of chromosome, the fragmentation of DNA, and the destruction of nuclear membranes. Now, lets consider what happens to these neurons that are just on the margins of the injury. So we can consider this to be like the shadowy margins of the infarcted brain tissue, following lets say a stroke of traumatic brain injury. In fact we sometimes call this region of tissue the pernumbra. So the penumbra means shadow. The penumbra is a region of brain that has been stressed by the injury. But these neurons have not necessarily been pushed into excitoxicity or apoptosis, program cell death. So these neurons will survive but perhaps many of their axons have been severed. And the question is what will happen to this neurons? Do they have capacity to regenerate new connections and restore some functional capacity. Well, there is a mixed answer to this question that we're beginning to understand. And part of the reason why the answer to the question is mixed is that, it may depend upon where the axons are growing. The axons that are trying to grow back through white matter have a much more difficult time with regrowth and regeneration. Than do the axons that are spreading out in the horizontal dimension within gray matter itself, such as the cerebral cortex. So let's first consider what's going on within the white matter. Where the axons that might have supplied a long pathway such as, the corpus callosum, or the corticospinal tract. Are going to have a very limited capacity, to regenerate, and regrow, a normal axonal connection. So let's think about why that might be the case. So imagine that we have, some neurons in the cerebral cortex, that are extending axons into some white matter structure. And if there's some region of injury now, that affects these cells, so there's some injury to neurons within this region. One of the most dramatic reactions that will happen around the margins of this infarcted tissue, is proliferation of glial cells. In fact, the proliferation is so intense that this local volume of brain becomes congested by these glial cells and their processes. And it's not just a physical congestion. But it's also an exuberant production of chemical signals that have a negative effect on the growth potential of their surviving neurons. Indeed if we look at what happens following an injury within a white matter structure of the brain or the spinal cord. What we see is a rather dramatic reaction. first involving the infiltration of microglia that will phagocytize the cellular debris. Astrocytes become activated, and might likewise migrate into the area, and then the oligodendrocytes themselves will proliferate. And together these glial cells will form a scar of tissue. That continues to produce substances that have a suppressive effect on the development of a modal growth cone in the activation of growth promoting programs by this injured neuron. So there are a variety of molecules that are expressed by these glial, some of which are especially important and are expressed by the oligodendrocytes themselves. And among these molecules are integral membrane proteins such as this molecule right here, this OMgp. Which stands for Oligodendrocyte-myelin glycoprotein. And this integral membrane protein, MAG, Myelin-associated glycoprotein. And then this intriguing protein that you can read about in the textbook if you like called Nogo-A. And what these integral membrane proteins seem to be doing, is inhibiting the expression of growth promoting programs by injured neurons. Now, in addition to these Integral membrane proteins. There are secreted ligands that will interact with a variety of receptors, that are expressed on the membranes of the axon. And a growth cone that may be attempting to regenerate. And these Ligands interacting with their receptors, seem to promote the collapse of that growth count, and, and active inhibition of growth. So one of the problems for the central regeneration of axons within compact white matter within the brain and spinal cord is this active suppression of growth. That's mediated via the signals that are expressed on the surface of glial cells. So, once might imagine a variety of strategies to try to overcome this. Either by suppressing these signals through immunotherapy, or other kinds of pharmacological, therapy. One might imagine providing a permissive environment. That would provide a route for the regenerating axon to avoid this plethora of signals that will actively suppress the growth and elongation of a regenerating axon. Well, there are a variety of strategies that have showed some limited success in animal models. Unfortunately, we have yet to see dramatic success in any human studies. But with ongoing study and ongoing discovery I think there is potential to develop strategic interventions. That will overcome these intrinsic limits on the capacity of central axons to regenerate.
