Welcome back to this next tutorial in our series on the changing brain. Today we're going to talk about the construction of neural circuits. And this topic will pertain to three of our core concepts in the field of neuroscience. Again, we're going to be talking about a different kind of Neuronal communication communication that is mediated chemically. But in this session, we're going to begin to introduce the concept of building synaptic connections. And that will enable both chemical and electrical communication to be possible in developing neural circuits. So we're going to see the genesis of this very important core concept in the field of neuroscience today as we consider the construction of circuitry. We're going to talk about circuits that are in large meder, measure genetically determined, circuits that provide the foundation for behavior. such as the ability to detect potentially painful and damaging stimuli in our skin surfaces. And then lastly, we'll set the stage for a more rich discussion that I hope to have with you in our next tutorial about how life experiences can modify the structure and function of the central nervous system. And I'd like to introduce a hypothesis really that will allow us to understand how can chemical signals that have the ability to change the course of neural development be modulated by activity? And this hypothesis will then help us understand how life experience can change the structure and function of the brain. Okay, well lets consider the learning objectives that I have for you in this tutorial. I want you to be able to understand what is a principal organelle that is responsible for pathfinding in developing axons. As well as the, growth of dendritic arbors. And this structure is called a growth cone. So I want you to be able to characterize the structure and function of growth cones. I want you to be able to discuss the major classes of signaling molecules. That guide axonal growth in the developing brain. And I want you to be able to have a cogent discussion of neural trophins. And I want you to be able to discuss the mechanisms of neural trophin signaling. Well hopefully all of these topics will make sense to you after spending a little time with me in this tutorial. So let's jump right into it. Well, I would remind you of our broad framework for understanding the forces that influence the developing brain. we talked, quite a bit in our last tutorial about the concept of nature in brain development. That is, the lineage-derived signals that result from the expression of particular genes. And so this influence in brain development can be considered genetic specification. Well, today we're going to talk about the construction of neural circuits, which begins to engage our two other major sets of factors that influence the finally shape and structure and function of neural circuits. Well, if indeed there is ever a final shape to them. What I have in mind is self-organization. Self-organization is mediated via activity based Mechanisms that play out as cells acquire the capacity to generate electrical signals. And that begins to shape the expression of a varierty of [UNKNOWN] types that circuits begin to acquire as they build otu their connections. Well as the developing embryo, fetus, and then to post natal life, developing infant begns to interact with the environment. Then, sensory motor experience becomes an important shaper of circuitry in an ongoing phase of circuit construction that continues into post-natal life. So, the story of the construction of neural circuits begins in utero. It begins at a, relatively, later stage in embryonic development in the third trimester. But it will continue, well into post natal life. So many of the mechanisms we'll be talking about today reflect nature. That is, genetic specification. However we will begin to describe some of those factors that play an important role in mediating the influence of nurture. And again that's going to be more primarily the topic of the next tutorial in this series. Okay. Well. With that as a broad introduction, let's talk about some of these mechanisms that pertain to genetic specification and self-organization in early brain development. Mechanisms that will shape the growth and the viability of neurons and their connections in the developing central nervous system. Well the first set of mechanisms that play out establish polarity in the developing neuroblast. Now, you'll recall that the neuroblast is derived from epithelium and all epithelial cells acquire a polarity, that is there's an epithelium, surface and a basal surface to their cells. And, this process plays out in developing neuroblasts, although their apical and basal surfaces are increasingly difficult to recognize, because increasingly these cells no longer resemble the columnar epithelium that first established the neuroectoderm. Nevertheless, theer os the establsihment of polarity such that from the apical surface, of the developing neuroBlack, an axon will emerge and from a basal surface, dendritic branches will begin to grow out. Now initially, with the out growth of these processes, we really can't. Tell whether they are destined to become axon or dendrite, we simply call them neurites. But as development progresses, a single axon becomes recognizable and differentiated from the apical aspect of the neuroblasts, and that axon begins to acquire a distinctive organelle. At the growing tip of that axon. That's a structure that we call the growth cone. Let's spend some time together thinking about the growth cone, and what makes it such an important structure in the finding of axonal pathways in the developing brain. Well, if one were to look at the tip of an axon that is emerging let's say from a cell body somewhere in this direction. One would find that there is a large, flattened structure that begins to develop as that axon begins to differentiate from just a neurite that might be extending away from this neuroblast. So this structure, is what we call the growth cone. And its charecterized by a fairly flat laminar type of appearance. We call this a lamella podium or a sheet foot, that's one way to understand that term. And then from that lamellipodium extend these long finger like processes called filopodia. Now what we're seeing in this figure is an illustration zooming in just on one portion of the growth cone looking at a filopodia. And this allows us to understand just a little bit about the dynamics that shape this growth cone as it interacts with the environment of the developing embryo. So what we find in this labella podium is a rich supply of mitochondria to supply the energy that's necessary for the activity of the growth cone. We also find a variety of filaments. We find actin filaments that assemble in the philopodium, and this allows that philopodium to have a highly dynamic behavior as actin polymers are assembled. From the monomeric elements. So, the assembly of those filaments is responsible for the protusion of a phyllopodium. And then the disassembly of those filaments allows for the retraction of a phyllopodium. Meanwhile, microtubules are being assembled and disassembled in the lamellipodium. So, all of the machinery that's necessary for the construction and deconstruction of these filaments, needs to be synthesized and then localized to this growth cone. Now, these processes are responding to signals in the environment through which this growth cone is exploring. And those signals are tranduced via a variety of receptors that are present within the leading edge of this growth cone. So for example, one can find a variety of channels, including our transcient receptor potential channels that can mediate the interaction of this growth cone with chemical signals in the environment. There are other means by which calcium can enter this lamellipodium. And as you know calcium is a very important second messenger system within all cells, and in particular within developing neurons. So calcium becomes a key mediator of the events that are detected at the plasma membrane of the growth cone which then are transduced into changes in the structure and growth patterns of this growth cone. So, this entire growth cone is a highly modeled structure, so this growth cone can explore the environment. Within which this axon might be proceeding. It can decide that it needs to change directions. Perhaps retract from growth in one direction, and begin to extend growth in a different direction, perhaps an othoganal direction to the original pattern of growth. So there is a tremendous amount of dinamism associated with this growth cone as it actively explores the environment responding to chemical signals. And sometimes there is an important point of decision, is there not? There are what we might call forks in the road. For a developing axon that's pioneering a pathway. We think of these forks in a, in the road in particular at the midline of the developing embryo. Where a variety of exonal projections must make a choice. To cross the midline or not to cross the midline. Well, I thought this might be a helpful point to insert a study question to challenge you to review some of what you know about anatomical pathways. mainly those that you learned in unit 3 of the course. So, let's just pause for a moment here, and take on the following study question.
