Biological Foundations of Mental Health Week 1 PDF

Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 1 Overview of CNS development - Part 1 of 3 Professor Sarah Guthrie Professor of of Developmental Neurobiology Lecture transcript Slide 2 Neural Development. We can think of neural development as taking place...

Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 1 Overview of CNS development - Part 1 of 3 Professor Sarah Guthrie Professor of of Developmental Neurobiology Lecture transcript Slide 2 Neural Development. We can think of neural development as taking place on two levels, namely, a ‘systems’ level and a cellular level. In this topic, we will first consider the systems level, looking at the changes in size and shape that occur during the embryonic development of the nervous system. This process is called morphogenesis. Next, we will describe changes at the cellular level that allow cells to change from dividing progenitors into mature neurons with complex morphologies, interconnected in circuits. This process is called differentiation. In the final section we will show the relevance of each stage of neural development to mental health by outlining the disorders that can result from defects that arise in specific developmental events, with examples. Slide 3 Levels of Neural Development. In humans, development begins with fertilisation of the egg, which cleaves to give rise to a ball of cells called a blastocyst. Implantation of the embryo into the uterine wall occurs at the end of the first week. And further development generates a two-layered embryonic disc, consisting of hypoblast and an epiblast. At the end of the second week, the process of gastrulation transforms this disc into a three-layered structure consisting of three so-called ‘germ’ layers-- the ectoderm, mesoderm, and endoderm-- which give rise to all the tissues of the body. Slide 4 By the end of the third week, the process of neurulation begins, which creates the embryonic nervous system. Amazingly, in weeks 4-5, the embryo starts to be recognisable, with a head, tail, and some of the embryonic structures that will be present in the adult, such as the limb buds, which grow into the limbs. This stage is often called the ‘tailbud’ stage. In humans, the second month of gestation is referred to as the embryonic period, during which the major organ systems start to form. And months three to nine is the foetal period, which is mainly concerned with growth. Large amounts of cell proliferation take place, a process which is particularly important for the brain. Slide 5 Further development of the nervous system involves the ectoderm, which develops under the Transcripts by 3Playmedia Week 1 © King’s College London 2019 1. influence of signals from the underlying mesoderm, a process called neural induction. During this process, a portion of the ectodermal germ layer is induced to become neural tissue, which will form the nervous system. As the tissue becomes neural, it also undergoes morphogenetic changes in shape, called neurulation. Slide 6 We will now look at neurulation in more detail, visualising the process of neurulation in a surface view, a transverse view, and in scanning electron micrographs of a human embryo. Early neurulation, at three weeks. The surface view is shown with the anterior, or cranial, end of the embryo at the top of the picture and the posterior, or caudal, end at the bottom of the picture. The arrow shows the level of the surface view at which the transverse section is taken. In the transverse section, at 19 and 20 days, we can see that the embryo consists of three germ layers. The ectoderm lies on top, and the medial part will give rise to the nervous system, with the more lateral regions giving rise to the epidermis of the skin. The medial part forms the neural plate, which has started to thicken. Underneath it lies the mesoderm, consisting of the notochord, medially, and two other blocks of mesoderm, laterally. Underneath this lies the endoderm. We can see that between 19 and 20 days, the neural folds rise up on either side of the midline and form a v-shape. Somites form from some of the mesoderm underneath these folds, which will later form the axial muscles. In the surface view, the somites can also be seen to form small blocks of tissue, and the embryonic disc to lengthen further. In the surface view, we can see how the neural folds form first at one axial level. In the scanning electron micrograph of the human embryo, the neural tube looks somewhat striated because of the somite blocks beneath it. Slide 7 During later neurulation, at 22 to 23 days, looking first at the transverse section, the neural folds can be seen to approach each other, and the somites to have expanded. Eventually, the neural tube closes and becomes enclosed and separated from the layer of ectoderm which forms over the top. In the surface view, it is clear that one region of the neural tube has started to fuse. This is typically the neck region. At the later stage we can see that the neural tube starts to zip up, towards the anterior and the posterior ends, and the nervous system starts to be subdivided, with the spinal cord posteriorly, and the brain vesicles, or subdivisions, more anteriorly. The scanning electron micrograph of the human embryo is very similar to the diagram, but the embryo is attached to extra embryonic membranes which will later cover it. Slide 8 By the tailbud stage, which is at four to five weeks of gestation, cranial and caudal folding has occurred, arching the body to give it what has sometimes been referred to as a ‘comma’ shape. Lateral folding has also occurred to enclose all forming internal organs in a covering of ectoderm, which will become the skin. We can see that the embryo has acquired a more recognisable appearance, with a head and tail somite blocks, and structures called branchial, or pharyngeal, arches, which will form elements of the lower jaw and neck. At a later stage of human development shown, you can also see the limb buds, outpocketings of tissue which will eventually grow into the limbs. The diagram highlights the developing eye, and the otic vesicle, which will give rise to the inner ear. In this way, the major structures of the developing embryo are already formed by four to five weeks. Transcripts by 3Playmedia Week 1 © King’s College London 2019 2. Slide 9 Surprisingly, the embryo of a human looks extremely similar to that of other animal groups at this stage. These beautiful drawings by the 19th century embryologist, Haeckel, show that at the tailbud stage, all the essential features of the body plan are present and look similar, even though the eventual body plan of these different organisms is rather different. Haeckel may have exaggerated the similarities somewhat, for effect, but the basic idea is correct. This also brings home the point of why we can study a variety of different experimental organisms in order to understand more about human development. Slide 10 Looking now at the further development of the neural tube without the other tissues, we can see that the cranial to caudal folding of the tube has taken place in concert with the folding of the rest of the embryo. Several subdivisions now appear in the tube. Whereas the region of the developing spinal cord remains with a small diameter, the forebrain, midbrain, and hindbrain, also termed the prosencephalon, mesencephalon, and rhombencephalon, have started to expand. The prosencephalon is divided into the telencephalon more cranially, and the diencephalon more caudally. The telencephalon is later destined to give rise to most of the cerebral hemispheres via an extensive folding process. The diencephalon will give rise to some of the important collections of neurons, such as the thalamus. These sorts of collections of neurons are termed nuclei. The folding of the neural tube which occurs involves the formation of flexures. In this way, convex flexures at the midbrain, and at the level of the junction between the spinal cord and the hindbrain, create the more mature morphology. A third, concave flexure also appears in the hindbrain, which means that the cranial part of the hindbrain, called the pons, becomes separated from the more caudal region, the medulla. Transcripts by 3Playmedia Week 1 © King’s College London 2019 3. Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 1 Overview of CNS development - Part 2 of 3 Professor Sarah Guthrie Professor of of Developmental Neurobiology Lecture transcript Slide 2 Now we will consider neural development as it applies to the individual cell level. During development, individual cells go through a process of differentiation. We can broadly think of development as a process where cells progress from a ‘multipotent’ population, capable of producing a range of cellular derivatives, to cells of particular, specialised identities, or ‘fates’. The embryologist, Waddington, nicely represented this as a ball rolling down a hill-- the epigenetic landscape-- and then rolling into one of a number of channels. Which channel the ball ends up in is not random, however. It depends on a number of events which take place in development, especially external influences and interactions between groups of cells, which instruct cells on their next developmental step. The process of neural induction is an example of this, in which the neural plate is influenced by the mesoderm to develop into the nervous system. We can thus see cell differentiation as a decision tree, which will eventually lead to cells assuming one of a number of fates. Slide 3 There are various different aspects of neuronal differentiation. One is the appearance, or morphology, of individual cells, shown here using the examples of a Purkinje neuron and a pyramidal neuron. The Purkinje neuron resides in the cerebellum and has an extremely elaborate dendritic tree, whereas the pyramidal neuron resides in the cerebral cortex and is less elaborate, with an apical dendrite and some branches. Both neurons have an axon which extends downwards in the diagram, exiting the cerebellum or cortex to project to other parts of the brain. Other aspects of neuronal differentiation are the gene expression profile, neurotransmitter type, and connectivity to other neurons in the nervous system. Together, all of these features make up the individual characteristic of differentiated neuronal types. Slide 4 Now I will explain the developmental steps which lead to differentiation in more detail. These steps are neurogenesis, during which cell division occurs to generate neurons; cell migration, when young neurons migrate away from the ventricular zone; axonogenesis, when the neuron starts to develop processes, including an axon which grows out towards targets; synaptogensis, when axons make contact with their target neurons or other structures; cell death or pruning, when regressive events often occur, leading to the formation of the mature neuron. Transcripts by 3Playmedia Week 1 © King’s College London 2019 1. Slide 5 The neural tube is divided into a ventricular zone, adjacent to the ventricle, which contains the cerebrospinal fluid, and a mantle zone, adjacent to the pial surface covered by the meninges. Radial glial cells are elongated cells with a long process or endfoot on each surface. These are the progenitor cells of the nervous system. Radial glial cells undergo cell divisions repeatedly to expand the progenitor cell population, and some of these divisions give rise to a neuron shown by the shaded cell in the cartoon. The cell divisions themselves, of the cell body, occur adjacent to the ventricular surface of the neurepithelium. Once the neuron is generated in such a cell division, it will migrate along the radial glial cell, using it as a guide towards the mantle zone. There, further differentiation of the neuron will take place, including extension of an axon. Slide 6 Neurons frequently have to migrate long distances towards their final position in the developing nervous system. There are two main types of migration-- radial migration and tangential migration. We have already dealt with one type of migration in the previous section using the example of the spinal cord, in which progenitors of cells migrate radially from the inside to the outside of the neural tube to generate neurons. This type of radial migration also occurs in the telencephalon, or forebrain, and is shown here in a transverse section of the developing telencephalon in a mouse, which will later form the cerebral hemispheres. Cells which migrate radially, along radial glia, give rise predominantly to the neurons with long axons that project to other regions of the nervous system, and that use the neurotransmitter glutamate, called excitatory projection neurons. The other type of migration which occurs in the telencephalon is called a tangential migration, in which neurons migrate orthogonal to the radial axis. Neuronal progenitors migrate from the ventral telencephalon into the dorsal telencephalon, the developing cerebral cortex, and intermingle with the neurons which have undergone radial migrations. These neurons, which have migrated tangentially, give rise to neurons with short axons, which use the neurotransmitter GABA, called inhibitory interneurons. Our third example of a neuronal migration concerns cells that split off from the ectoderm while neurulation is underway. These are the neural crest cells. Shown in a transverse section of the developing spinal cord, neural crest cells migrate away from the forming neural tube to form elements of the peripheral nervous system. In particular, these are the dorsal root ganglia and sympathetic ganglia in the trunk, and the cranial ganglia of the head. Slide 7 As neurons move into the mantle zone and start to differentiate, they start to develop an axon. This process of axonogenesis can be beautifully visualised in hippocampal neurons growing in vitro, as shown by this example from the lab of Gary Banker. Here you see the different identified stages of axonogenesis and neural development at the single cell level. At Stage 1, neurons are initially round blobs. At Stage 2, neurons look radially symmetrical, with several neurites, or processes. At Stage 3, one of these neurites becomes selected as an axon in a process of symmetry breaking. This axon will go on to grow out and extend towards its targets. At Stage 4, the axon continues to grow and the dendrites start to grow out from the cell body. At Stage 5, the dendritic tree becomes more elaborate with small protrusions, or dendritic spines, forming on the dendrites. In vitro, the neurons can be seen to form a network. Transcripts by 3Playmedia Week 1 © King’s College London 2019 2. Slide 8 Development of the axon and the dendrites proceed in parallel. Growing axons are guided by molecules in their environment to their targets. Axons eventually make contact with their targets, whether that is a neuron, as in this case, a gland, or a muscle. In the case of neuron-neuron synapses, these are most frequently made on dendrites, and in fact, the dendritic spines. Synapses are sometimes made on the neuronal cell body itself-- axosomatic-- or on an axon-axoaxonic. Just to make this clear, in the diagram, the synapse is formed by the growing tip of the neuron to the left on the neuron on the right. Thus, the neuron to the left is the presynaptic part, and the neuron to the right, the postsynaptic part. Slide 9 Once the growth cone has reached its target cell, synapse formation is initiated between the presynaptic axon and the postsynaptic dendrite, soma, or axon. There are many stages to synaptogenesis. Various molecules, including cell adhesion molecules, contact dependent, and diffusible molecules play a role in synapse formation. Neuroligins and neurexins are families of transmembrane proteins that are expressed by the postsynaptic and the presynaptic neuron, respectively, and that are important in the process of synaptogenesis. They bind the pre- and postsynaptic parts of the synapse together, and serve as a focus for other proteins to cluster together to form the synapse. Different members of the neuroligin group are enriched in excitatory and inhibitory synapses, and are involved in specifying these different synaptic types. Molecules such as cadherins and SynCAMs help to consolidate synapse formation. The neurexins and neuroligins then help to recruit specialised groups of proteins into the presynaptic active zones, containing the neurotransmitter vesicles in the presynaptic terminal. They also coordinate the assembly of the postsynaptic densities, which contains so-called scaffolding proteins and neurotransmitter receptors. Overall, the process of synaptogenesis is a very complex and coordinated process. Slide 10 The nervous system forms not only by growth and elaboration of axons and dendrites, but also by sculpting of neuronal architecture and by cell death. Cell death is a surprisingly common phenomenon in the nervous system. It’s estimated that around 50 per cent of motor neurons, for example, die during later development. These regressive events may thus involve either the elimination of whole cells, or parts of cells, axons, synapses, or dendrites. In the examples shown of the developing cortex from humans, the complexity of the brain can initially be seen to increase, in terms of the density and numbers of neurons, up to two years of age, with increasing synapse formation. From four years to six years, however, a process of synapse pruning and consolidation takes place, and some decrease in the complexity of the brain landscape occurs. Pruning can occur to axons and to dendrites, which disintegrate and the debris is then cleared away. Cell death and pruning may eliminate unwanted neurons or connections, match numbers of pre- and postsynaptic cells, and ensure that synaptic transmission and circuit function is optimised. It’s not completely clear why these events occur, but it may be to ensure that there are matching numbers of pre- and postsynaptic cells. In addition, the removal of any aberrant or unwanted connections may occur, and the fidelity of connections in terms of structure and function may be improved. Transcripts by 3Playmedia Week 1 © King’s College London 2019 3. Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 1 Overview of CNS development - Part 3 of 3 Professor Sarah Guthrie Professor of of Developmental Neurobiology Lecture transcript Slide 2 Examples of human disorders which can be caused by defective developmental processes are autistic spectrum disorder, schizophrenia, childhood onset epilepsy, and X-linked mental retardation. In this section, we will highlight certain developmental aspects of ASD and schizophrenia. Understanding the developmental processes I have described in this subtopic is extremely important, as this can give insight into neurodevelopmental disorders in humans. Large-scale human genetic screenings and experiments in animal models have started to uncover some of the principles that underlie these disorders. We now know some of the genes that are mutated in humans with these disorders. Developmental neuroscientists are trying to understand the mechanisms that underlie the changes caused by these mutations. It’s emerged in recent years in particular that dendrite and synapse development are often affected by these gene mutations. Many aspects of development can be perturbed to lead to such disorders, such as axon growth, guidance, neuronal migration, synapse formation, and function. Slide 3 Autistic spectrum disorder, ASD, is an umbrella term for a disorder which can take on multiple forms and have multiple causes. Nevertheless, it is clear that ASD is a neurodevelopmental disorder and that some forms of ASD are genetically based. In humans, it has been shown that mutations in several genes including neuroligin-4 are linked to autistic spectrum disorder. Neuroligin-4 is involved in synapse development. Studies using mice, which are deficient in the neuroligin-4 gene, called knockout mice, have shown that markers of inhibitory synapses are reduced in some areas of the hippocampus, pointing to a developmental defect. In the figure, you can see the white staining representing immunofluorescence for two markers of inhibitory synapses-- gephyrin and a GABA A receptor subunit. Compared to the wild-type panels to the left, there’s a reduction in the staining in the neuroligin for KO, or knockout, mouse. In addition, neuroligin for knockout mice showed behavioural changes reminiscent of ASD. It’s perhaps surprising that it’s been possible to model some of the behavioural aspects of ASD in mice using assays of, for example, social interaction or vocalisation. These experiments have shown that neuroligin for knockout mice showed impairments in social interaction and communication, as well as repetitive behaviours and interests. Some of these features are characteristic of humans with ASD. Whereas the process of synaptogenesis and its link to behaviour is extremely complex, these Transcripts by 3Playmedia Week 1 © King’s College London 2019 1. studies give us hope that ASD can be modelled using the mouse as an experimental system. Slide 4 As well as changes in the numbers of synapses, there may be changes in the structural features of dendrites and dendritic spines which are key to synapse formation. There is a large amount of evidence now to show that the numbers, shape, and development of dendritic spines change in some individuals with schizophrenia or ASD including X-linked mental retardation, Fragile-X, which has features of ASD. The number of dendritic spines is reduced in the dorsolateral prefrontal cortex of some schizophrenia subjects. You can see this in the figure where the black line with the blobs on it represents a dendrite and the dendritic spines in a normal subject. In the two schizophrenia subjects shown, you can see that the number of dendritic spines looks to be reduced. This may reflect defects in either the process of dendrite development and/or pruning. Mice lacking the Fragile-X mental retardation protein have more immature, thin spines, and there is evidence for a similar change in humans with Fragile-X. You can see this in the figure comparing a dendrite from the wild-type animal with a mouse used as a model for Fragile-X and lacking the FMRP protein. Knowledge about the genes and proteins which are involved in dendritic spine development and testing their role using animal models will be key to understanding the link between spine development, function, and mental health. It’s worth bearing in mind, however, that there are a large variety of studies on issues such as dendritic spine development, density, and maturation. Some of the results from these studies are conflicting, and much further work will be required before we can draw general conclusions from this work. Slide 5 We can conclude that understanding development in detail can unlock many of the secrets of the way the nervous system is built and how it later functions. Research in developmental neuroscience will help us understand neurodevelopmental disorders and mental health and vice versa, Many of the techniques currently being used and under development will play an essential role in the next decades in unravelling these principles. For example, live imaging in vivo using the mouse and zebrafish can now tell us much about the dynamic events that occur during dendrite development, pruning, and plasticity. Behavioural tests in the mouse are also beginning to give us insight into the effect of particular genes and proteins on behaviour at the organism level. Genetic screens in humans can then reveal the genes whose function can be tested in animals, while genes shown to be important in development through basic science studies can be screened in the human population. This interplay will be the foundation of future discoveries in development and mental health. Transcripts by 3Playmedia Week 1 © King’s College London 2019 2. Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 2 Neuroanatomy, neural systems and brain function - Part 1 of 3 Dr John Pizzey Teaching Fellow - Biosciences Education Lecture transcript Slide 1 Hello. My name is John Pizzey. I’m an anatomist here at King’s College London, and in this lecture, I’ll be telling you about the ways in which the nervous system is put together, some of the classifications that we use to divide it up. We’ll also look at some of the component parts and how they’re connected. Slide 2 By the end of the lecture, you should be able to recognise some of the two main ways in which we divide the nervous system up. We divide it up by function, and we can divide it up by the anatomy of the parts of the central nervous system. We’ll be speaking about the differences between the central nervous system and the peripheral nervous system as we go along. We’ll also be looking at the ways in which these parts are wired together-- not in great detail, but in general terms so that you can appreciate how we can derive a large huge amount of complex circuitry and computing power from the ways in which we wire up the different component parts. Slide 3 To start with, let’s think about what the starting material is. We have about 100 billion neurons in the adult human brain. Now, this equates to up to 100,000 trillion synapses. That’s a vast amount of potential given that each of these is effectively a binary unit that contributes to the computing power of the brain. But that is only a part of the story. The greatest complexity comes, not so much from these big numbers, but from some of their properties that we’ll look at now. Slide 4 The first is convergence. This is the ability of many different cells to send their inputs to one target cell. That is, the single cell receiving the inputs is receiving it from multiple sources. In fact, the average neuron in the human brain receives 10,000 different inputs-- not necessarily from 10,000 different cells, but there will be 10,000 different synapses on it. Slide 5 The other side of the coin from convergence is divergence, and here, this is the ability of a single cell to project to multiple cells. Here again, we’re looking at large numbers, maybe up to 1,000 different axon terminals from one single neuron. So we have the ability of the cell to receive multiple signals as well as to send out multiple signals. This creates what we know as neural networks. Transcripts by 3Playmedia Week 1 © King’s College London 2019 1. Slide 6 Now, these neural networks are not the same as neural networks that you might be familiar with in computing terms, but they’re genuinely networks of neuronal origin, and this is the key to the complexity of the nervous system. This means that a cell here can target a cell here in multiple different ways, going from the front of the brain via the back of the brain or directly in a more sensible route, if you like, a shorter route. But it can recruit different cells along the way. Slide 7 If we think of this in terms of a tube map, now, how many different ways could we get, for example, from Bayswater to Arsenal, over here. There’s clearly a quickest way, maybe this route, but there are alternatives, via this route for example. But in addition to these two we could take a very extreme route out via North West London coming back in again, maybe going down to South London and then arriving at Arsenal. So we have multiple ways of which we can get from one station to another, not necessarily the quickest way but how many different ways could we do it? Now of if you think of this in terms of the nervous system you can see, you can start to appreciate, how you can build up a great amount of complexity within the system. So I don’t know how many ways you can get from Bayswater to Arsenal, if you can work it out, well done, but if you think of that multiplied by how many ways could you get from any one station on the London tube map to another you would soon realise you are dealing with very big numbers indeed. Now if you apply this to the nervous system, where each of these stations, each station, is effectively a single neuron and each station instead of recieving just one or two or three lines coming in you’re now dealing with a hundred thousand lines coming in, 300 billion neurons, 300 billion stations, a hundred thousand lines coming in and a thousand lines going out you can see that you can genreate huge possibilities for the routes in which circuits can be made and it has been estimated that there are more possibilities for routing through the brain than there are atoms in the known universe. Slide 7 Let’s look now at some of the ways the nervous system can be divided up. What you can see here is one of the commonest ways, in which the nervous system is divided into the central nervous system and the peripheral nervous system. For now what I want you to look at is the fact the central nervous system is typically divided into the brain and spinal cord. Now this has limitations we’ll come to later. The peripheral nervous system includes the autonomic, which is the component that we are not aware of-- maintaining our heart rate, maintaining our breathing rate, maintaining gut peristalsis for example-- and the somatic nervous system, things we are consciously aware of-- things like movement, things like feeling temperature or fine touch or vibration. But this scheme, although you will see it a lot, has serious limitations. Slide 8 First of all, let’s have a look at the autonomic nervous system. Now, you might be familiar with this as often described as being divided into the parasympathetic component, and its complement, the sympathetic component. These are often referred to as ‘rest and digest’ or ‘fight and flight’ divisions. I would encourage you not to think along those lines as there are too many exceptions to these rules. For example, the parasympathetic nervous system via the action of one of the cranial nerves-- in fact, the third cranial nerve, the ocular motor nerve-- is responsible for constriction of the pupil in bright light. The complement via the sympathetic nervous system is to dilate the pupil in dim light. It’s not really related to ‘rest and digest’ or ‘fight and flight.’ And there are a large number of exceptions to these. But generally, they do work in opposite ways. They work against each other. Dilation or constriction is a common feature of the two nervous systems. Transcripts by 3Playmedia Week 1 © King’s College London 2019 2. But the important point here is that although they send peripheral branches, they’re not restricted to the periphery alone. So in the brain, there will be pathways that are wholly concerned with either parasympathetic or sympathetic function. Therefore, the earlier description of the parasympathetic and sympathetic nervous system not being related to the brain is probably not ideal. Slide 10 I would think of the nervous system as being divided up into central nervous system where we have this definition whereby a neuron is a member of the central nervous system if it’s wholly contained within the brain or spinal cord. So this means it might be within the brain, within the spinal cord, or travel between the brain and spinal cord. But no part of it-- not the cell body, not the dendrites, not the axons-- project outside of those two structures. If any part of it does, then it’s a peripheral nervous system neuron. And that’s the way I would suggest you think about these terms. Transcripts by 3Playmedia Week 1 © King’s College London 2019 3. Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 2 Neuroanatomy, neural systems and brain function - Part 2 of 3 Dr John Pizzey Teaching Fellow - Biosciences Education Lecture transcript Slide 2 Now, let’s think about dividing the nervous system up anatomically. The problem here, before we start, is to make sure you understand the axes and planes involved. This isn’t as straightforward as it might sound, and it arises because of our evolutionary change from fish and quadrupeds to bipeds. For a fish or a mouse, for example, it’s very simple. The part coming towards you is the anterior end, and the part furthest away is the posterior. As soon as we stand up, we have a problem because the part coming toward you now is the anterior end, but also it’s the belly, and the part furthest away is the posterior end, but it’s also the back. Before, these were orthogonally arranged. So we have anterior and posterior is not the same as the belly and the back. So what you will come across a lot in topographical anatomy generally, but neuroanatomy in this context, is the terms ‘ventral’ and ‘anterior’ on the one hand, and ‘dorsal’ and ‘posterior’ on the other, become synonymous. I’ll be using them interchangeably throughout the course of this lecture, and you will find in textbooks and reference papers them also being used interchangeably. There is one other degree of complexity that’s introduced, in terms of axes and plane terminology as far as the nervous system is concerned, and this is because of something called cranial flexion. What this means is the long axis of the spinal cord is approximately at right angles to the long axis of the brain. And this occurs during embryological development. So what this means is, if we are describing the front of the spinal cord, we can refer to it, for example, as the ventral surface. This would be this surface of the spinal cord. But because of cranial flexion, the ventral surface of the brain now becomes the underside of the brain. Similarly, the dorsal surface of the spinal cord is continuous with the dorsal surface, which now is the top, the superior surface of the brain. So pay attention to these terms, because it might not be immediately obvious. If people are talking about the dorsal aspects of the brain, they’re really talking about the top, and if they’re talking about the ventral surface of the brain, they’re really talking about the inferior, lower surface because of this cervical flexion, or cranial flexion, that occurs during development. And lastly, be familiar with the main three planes that are used to describe sections through the brain: horizontal, which is effectively transverse sections; sagittal, which runs through the midline, from Sagittarius the archer, the stance an archer would take; and coronal, or a frontal, section, parallel with the plane of the face. Corona is Latin for a crown. So it’s imagining putting a crown on Transcripts by 3Playmedia Week 1 © King’s College London 2019 1. your head. So these terms will be used a lot in the lectures that you’ll be coming across. So do pay attention to what they mean - sagittal, horizontal, and coronal, the three main planes to divide up the brain. Now with this in mind, we can start looking at the anatomical divisions of the brain in a little more detail. Slide 3 So this is the commonest way to anatomically divide the brain, into four main parts: the spinal cord, which ends approximately at the level of the foramen magnum, the large hole in the base of the skull; which is then continuous with the hindbrain, which is made up of these three parts we’ll meet in a little bit more detail later, the medulla, the cerebellum, and the pons; and above that, this region called the midbrain; and above this, the much bigger area, which represents the cerebral hemispheres of the forebrain. And we’ll be looking briefly at each of these. Slide 4 Let’s start with the spinal cord. These should be familiar to most of you already, so I don’t want to say too much about this. It’s just to remind you of two things, really. The first is the white matter, composed of axons, is largely on the outside of the spinal cord. This is the opposite arrangement to the brain, where on the outside, it’s mainly the grey matter, which is the cell bodies. The grey matter in the spinal cord sits in the middle. The exact shape will change according to where you are in the spinal cord. But it’s roughly the shape of the letter ‘H’ no matter where you are. The other thing to note is that the nerves associated with the spinal cord are mixed. So this nerve that’s going out to the periphery will have both sensory neurons within it, they’re bringing information in with cell bodies in the dorsal root ganglia, projecting their information into the cord, as well as axons projecting their information out to skeletal muscle. So each of the spinal nerves is mixed - has both sensory and motor information. They enter and leave the cord as a series of rootlets, multiple entry and exit points for each spinal nerve. Slide 5 We have 31 spinal nerves, most individuals do. A few exceptions, where some have one or more, one fewer or one more. But the vast majority of people have 31, of which there are 8 cervical, 12 thoracic, 5 lumbar, 5 sacral. And if there’s any variation, it comes in the coccygeal nerves, but most of us only have one. They exit through holes - foramina - between the vertebra, the intervertebral foramina. Now the spinal cord isn’t as big as the vertebral column. In fact, it’s only about 2/3 of the length of the vertebral column. It stops growing at the same rate by about the end of the first trimester. After that, the vertebral column is growing faster. Now that has important consequences, some of which are exploited clinically. What this means is that the spinal cord is ending at about the level of the intervertebral disc between L1 and L2. But because each spinal nerve exits through a corresponding intervertebral foramen, it means that any nerve below L1 and L2 has to travel down the spinal cord until it finds its corresponding intervertebral foramen and exits. S1, for example, segment S1 of the spinal cord is here, but the first sacral vertebra is here. So this nerve has to project down through a space below the level of the cord before it exits. This means that you have a group of nerves at the base of the spinal cord where there’s no neural tissue, no cell bodies involved. This gives the name to this structure, the cauda equina, the horse’s tail, because that’s exactly how it appears in a fresh specimen. And clinically this is important, because it means a needle can be put into the spinal cord below the Transcripts by 3Playmedia Week 1 © King’s College London 2019 2. level of L1, L2 - for example, to drain cerebrospinal fluid diagnostically, or if build up of pressure knowing that you’re going below the level of the spinal cord itself and therefore won’t damage it. And this, of course, is done in lumbar punctures. Slide 6 Let’s move up a little higher. The spinal cord, as I mentioned, ends at the intervertebral foramen, and above that, we come to the region of the hindbrain, the medulla, the cerebellum, and the pons. The medulla is the oldest part of the hindbrain in evolutionary terms, and in fact, it’s the oldest part of the brain in all. It contains life-supporting centres - this is the part of the brain that keeps you alive on a minute-to-minute basis. Slide 7 Above the hindbrain is a relatively smaller area, the midbrain, separated by a small channel. Small, but an important area of the brain. Amongst other things, it’s a very important relay between activity in the forebrain above and the hindbrain below. Slide 8 Sitting on top of the midbrain is a structure called the thalamus, and we’ll meet this again later. This is a part of the brain called the diencephalon, And it’s a very important relay. Virtually all sensory information, whether it’s special sensory, such as taste or vision or hearing, go through the thalamus. Or somatosensation, fine touch, coarse touch, vibration, pain, temperature, go through the thalamus. And it’s also, as we’ll see, an important relay for descending information, motor information as well. You will find that there are some texts that include the thalamus in the brain stem, and there are evolutionary reasons why you might do so. There’s functional reasons why you might do so. But in general, in the UK, we tend to regard the thalamus as a separate structure to the rest of the brain stem. In American texts, the tendency is to include it with the brainstem. Slide 9 Let’s think about the brainstem. That area shown in red on the rotating skull here is the most important part of the brain. It’s the reason why brainstem activity is used as a clinical descriptor of life. I’m sure you’ve heard of the term ‘brainstem death’, which is used to clinically define whether somebody is capable of independent life or not. And it’s complicated because there’s a lot going on. There are ascending, somatosensory, and descending motor pathways going through it. Also, there are lateral connections between the stem of the brainstem and the cerebellum dorsal to it. A lot of the cranial nerve nuclei-- remember you have 12 pairs of cranial nerve nuclei-- most of those are contained within it. it’s an important centre for chemo reception, as well as a number of cranial reflexes, such as salivation, mastication, swallowing. We could also include the gag reflex and suckling in infants amongst these. It’s important for a number of vital life-supporting roles, which we’ve already mentioned the cardiovascular and respiratory ones sitting in the medulla. But there are others as well, not least those concerned in arousal - arousal as wakefulness, keeping you out of a comatose state. All of these are important activities of the reticular formation, which runs throughout the brainstem. Finally, there are three important nuclear groups: the raphe, the locus coeruleus, and the substantia nigra, which also reside in the brainstem. These are the sites of very important monoaminergic pathways within the brain. The raphe, for example, is the centre for all the serotonergic pathways within the brain. If you use serotonin as your neurotransmitter, they originate from a site within the brainstem. The locus coeruleus is the site of all the adrenergic pathways - pathways that use adrenaline, Transcripts by 3Playmedia Week 1 © King’s College London 2019 3. noradrenaline, as the neurotransmitter, originates from the locus coeruleus. And the substantia nigra is the important centre for dopaminergic neurons within the brain, very important in movement control. Parkinson’s disease is the loss of the dopaminergic neurons from one part of the substantia nigra. So the brainstem is responsible for a very large range of important functions to keep us alive. Slide 10 If we move up to the forebrain, the first thing you notice is that it’s large and thrown into a large number of folds. The folds increase the surface area of the brain, so we can fit more neuronal tissue into the cranium, and the ridges are known as a gyrus. This, for example, is the middle temporal gyrus, plural gyri. And the grooves, here we have the central sulcus, plural sulci. There are bigger divisions too. Here, for example, is the lateral fissure. Separating the cerebellum from the cerebrum, we have a transverse, or horizontal, fissure. Slide 11 Now we can divide the brain up into lobes, as I’m sure you know, and the lobes are named after the associated bone of the cranium. So normally, the brain is described as having four lobes, an occipital lobe, parietal lobe, frontal lobe, and temporal lobe. You may also see some texts that include a limbic lobe, which is a part of the brain concerned with determining your emotional state, and that’s buried deep within the brain. But that’s less common. It’s much more common to refer to these four. What’s important to note here is that no single function of the body is concerned with any one lobe. So if we look at the frontal lobe here, for example, this has many functions. But one of the main ones is movement, since much of the motor cortex resides within the frontal lobe. But for effective movement control, you also need the activity of other lobes. For example, the parietal lobe is very important in receiving feedback from the rest of the body, or the skeletal musculature of the body, to perform effective motor functions. So motor functions can be regarded as spread over both of these lobes. Similarly, the parietal lobe has important roles in determining your interpretation of what you see. So that indicates that the parietal lobe has multiple functions. The occipital lobe also is important in vision, houses the primary visual cortex. So the take-home message here is that you cannot allocate a single function to any one lobe, and no one lobe has just one function. Slide 12 When we look at the outside of the brain, we’re looking at the cortex, the outer layer. But there’s more to the cerebral hemispheres than the cortex. Buried deep within it are other structures, and we refer to groups of cell bodies within the nervous system as nuclei. Now this has nothing to do with the term used to house your genetic material within a cell. In neuroanatomy, a nucleus is just a group of cell bodies of similar function, and buried deep within the cerebral cortex, we have a number of nuclei. Some here, for example, are nuclei of the basal ganglia, a very important group of cells involved in movement control. There are also various small nuclei dotted around that aren’t shown on this figure, but also associated with the basal ganglia and other parts of the brain. In particular, the one that’s not shown here is the hippocampus. That would be sitting deep in the temporal lobe. We can’t really see that. That’s an important nucleus, concerned, amongst other things, with memory. Transcripts by 3Playmedia Week 1 © King’s College London 2019 4. In addition to these nuclei, at the top of the brain stem is the diencephalon, a group of nuclei of great range of functions. This one you’ve met already. This is the thalamus. I mentioned that that was important for motor and sensory relay. Below it is the hypothalamus, under the thalamus. The hypothalamus, an important structure, amongst other things, concerned with autonomic control such as reproductive behaviour, thirst, measuring glucose levels, a number of other important homeostatic functions. Transcripts by 3Playmedia Week 1 © King’s College London 2019 5. Module: Biological foundations of mental health Week 1 Introduction to brain anatomy Topic 2 Neuroanatomy, neural systems and brain function - Part 3 of 3 Dr John Pizzey Teaching Fellow - Biosciences Education Lecture transcript Slide 2 Now the connections to the cortex are many. Firstly, we have ascending connections. Sensory connections. These are coming up, largely, from the thalamus. Remember its important role as a relay. So, sensory information from the body enters the spinal cord, and is then transferred via the thalamus to parts of the cortex, in particular, the parts of the cortex responsible for processing sensory information, the somatosensory cortex. In addition, the special senses I mentioned also go through various components of the thalamus - all of them, in fact, except smell. Smell - olfaction - is the most primitive of all our senses, and this goes directly into the olfactory cortex, and it’s the only sense which doesn’t go through the thalamus. There is a component that goes through the thalamus, but that’s just to tell us whether we like or don’t like the particular odour. It doesn’t tell us what that odour is. This route directly into the olfactory cortex with very little processing reflects the very primitive nature of olfactory senses. Slide 3 As well as the ascending connections to the cortex, there are descending connections from it. Now these are mainly motor, to the spinal cord, largely through the corticospinal tract, and to nuclei within the brain stem. If they the terminate on the nuclei of cranial nerves, motorcranial nerves, to innervate facial muscles - muscles of the head and neck - they will be going via the corticobulbar tract. There are also pathways concerned with higher levels of motor control, and go to the basal ganglia and the cerebellum. And finally, there’s projections to the limbic system. This is the part of the brain concerned with determining our emotional states, and there are large areas of the cortex that impact on this. What you can see will have an impact on emotional state, so there’s projections from the visual cortex to the limbic system. What you’re physically doing can have an impact on your emotional state, so you’ll have projections from the motor cortex to the limbic system. In fact, there are multiple cortical projections to the limbic system in determining our emotional state and emotional behaviour. Now importantly, there are also connections within the cerebral cortex. If they occur on the same side, the same cerebral hemisphere, we refer to them as association files. So for example, this can link parts of the auditory cortex with the visual cortex to help us determine what we’re seeing and how we recognise what it is. We might be getting visual as well as auditory clues, for example. Or, connecting taste and smell senses in appreciating exactly the nature of something that we’re eating. Transcripts by 3Playmedia Week 1 © King’s College London 2017 1. We also have connections between the hemispheres. So between, for example, the somatosensory cortex on one side of the brain with the somatosensory cortex on the other. This is via tracts called commissures-- commissures are just the names for pathways that connect one side of the brain with the other, and the most prominent of these that you may have come across is the corpus callosum, the large band of white matter that you can see in a hemisection of the brain. Slide 4 So let’s just have a little look at these, and they are shown here. The association fibres are shown in blue, and you can see them linking different parts of the brain on one side. The commissures cross the midline. Here, for example, is the big commissure of the corpus callosum. Although it’s only showing a little bit of it here, it will be radiating out, such that equivalent areas of the cortex on one side are connected to equivalent areas on the other, literally letting one side of the brain know what the other side is thinking or is doing. Inferiorly, we have another commissure, the anterior commissure, which does very similar things, but for the more ventral parts of the brain. Here they’re shown connecting the two temporal lobes. In addition to the association and commissural neurons, we also have projection neurons, and these are neurons that extend, typically, long distances, and frequently connect structures from the brain to the spinal cord, or to the spinal cord from the brain. These are shown in red. Here, they’re running through a structure called the internal capsule, which is the main pathway that some major ascending and descending axons make. So these projection fibres will include motor fibres that are descending from the motor cortex down to the spinal cord, and will also include ascending somatosensory fibres that are bringing information in from the spinal cord and taking it to the cortex. So these are three of the major classes of neurons that we will find connecting cortical structures to other parts of the brain: association, commissural, and projection neurons. Slide 5 Now a great deal of advances have been made recently in neuroimaging, and one of the major advances is in the field of tractography. This has really helped us understand much more about the ways in which parts of the brain are connected to another, and in particular, a technique called diffusion tensor tractography-- it’s a type of magnetic resonance imaging, a type of MRI-- that relies on looking at the ways in which water diffuses through structures. It’s particularly useful in enabling us to image myelin. So we can plot individual pathways. Here, the socalled seed point-- part has been labelled-- in the right frontal lobe-- and we can follow the axons that are present here as they enter the corpus callosum. Remember, this is a commissural neuron that crosses the midline-- and here are the extensions of these axons from the right frontal lobe across to the left frontal cortex. And you can see them ramifying out, very beautifully. Multiple pathways can be labelled in this way, and then imaged, using computer graphics to build up a pattern of tracts within the brain. Slide 6 This is an example of computer-enhanced diffusion tensor imaging, where a large number of pathways have been labelled. You can see some which are crossing from one side to the other. Commissural neurons, commissural axons and others, which are coming down here, entering the pons - and in fact, if we follow these purple ones down, we’d see them going below. Examples of projection neurons here. This approach has been used both in surgical planning, and in understanding, increasingly, how different parts of the brain are speaking to each other. They’re helping us greatly understand how the brain is connected, how the parts of the brain are connected, and therefore giving us bigger clues into how it’s functioning. Transcripts by 3Playmedia Week 1 © King’s College London 2017 2. Slide 7 So let’s summarise. What have we seen? We’ve seen that we can divide the nervous system by functional and anatomical criteria. We have learned that the CNS and PNS can be divided up, and that a good definition of the CNS is an axon or a neuron which is wholly contained within it, and that’s perhaps a better one than simply saying a brain or spinal cord neuron. We’ve seen that the CNS can be divided up into the hindbrain, midbrain, and forebrain, with the spinal cord below also being a part of the peripheral nervous system. We’ve seen that the hindbrain consists of the pons, medulla, and cerebellum. We’ve seen that we can derive a large amount of the very complex circuitry in the brain by means of neural networks, and this is a property of both the very large numbers of neurons we are dealing with, together with the properties of convergence, whereby a neuron can receive multiple signals, as well as divergence, whereby a single neuron can innovate and form synapse with multiple other neurons. And finally, we’ve seen that we’re starting to learn more about how these structures are put together with some recent advances in neuroimaging. Thank you. Transcripts by 3Playmedia Week 1 © King’s College London 2017 3. Module: Biological Foundations of Mental Health Week 1 Introduction to brain anatomy Topic 3 Microanatomy of the nervous system - Part 1 of 3 Dr Sarah Mizielinska Lecturer in Dementia and Related Neurodegenerative Disorders, Basic and Clinical Neuroscience, King’s College London Slide 1 Hi, my name is Dr Sarah Mizielinska, and I specialise in the neuronal cell biology of dementia. In this topic, we will be delving into the microanatomy of the nervous system. Slide 3 Part 1, neurons and glia. Slide 4 In 1906, Ramóny Cajal and Camillo Golgi were jointly awarded the Nobel Prize in physiology and medicine for their discovery that the brain is not a single continuous entity but composed of individual cellular units. We now know that during development, the cells of the nervous system differentiate into two major cell types: neurons – the cells responsible for fast communication along large networks – and the supporting glial subtypes. Slide 5 Neurons communicate by passing electrical signals along their elongated form and they’re converting this into a chemical signal to activate an electrical signal in the next neural network. Information travels at different speeds in different neurons, ranging from 1 mile per hour, the speed of a tortoise, to 268 miles an hour, which is faster than most Formula 1 racing cars. Slide 6 Neurons are not homogeneous, they come in many forms specialised for their particular function within the nervous system. On the left, we have a classical neuron which both receives signals from and sends signals to other neurons and has a long, extended shape. However, some neurons can both receive signals and send signals Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 1. to other cell types. For example, sensory neurons can be activated by changes in the skin cells, and lower motor neurons can stimulate muscle movement. Some neurons, such as interneurons, can actually send and receive signals with multiple other neurons. Slide 7 Even within brain regions, neurons can vary widely. For example, in the cerebellum, the brain region that primarily coordinates movement, there is a dense lobe structure. The dense layer in these lobes is generated by millions of small granule cell neurons, which feed into one of the largest types of neuron in the brain, the Purkinje cells, with other interspersed basket and Golgi neurons. Slide 8 But neurons do not function in isolation, they are supported by multiple types of glia. Those that directly interact with neurons – oligodendrocytes, astrocytes, microglia – and ependymal cells, who line the ventricles of the brain and the central canal of the spinal cord (similar to epithelial/skin cells). We will now go through each of these cell types one by one. Slide 9 Astrocytes have many known functions, including distribution of nutrients from the blood supply to neurons, maintenance of extracellular ionic balance and tissue repair. They can also regulate synaptic activity by direct contact with synapses, in what is known as the 'tripartite synapse', and signal between each other independently of neurons via gap junctions – small gaps in the cell membrane that leak charged ions. For further reading, you can see Santello et al. (2019) Nature Neuroscience. Slide 10 Microglia, as inferred by the name, are smaller than astrocytes and function as the resident immune cells of the brain. In this function, they clear debris, recruit other cells to sites of damage and aid in tissue repair. In addition to debris clearance, they can also degrade synapses – which is essential for synaptic pruning during development but may make matters worse by preventing recovery when neurons undergo chronic stress during disease. For further reading for this, you can see Lannes et al. (2017) Oncotarget. Slide 11 The next type of glia, oligodendrocytes, play the same role in the brain as Schwann cells in the periphery. They wrap their processes around neuronal axons secreting the lipid myelin, generating a protective myelin sheath. This sheath also increases the speed of neuronal signalling by insulating the passing of electrical charge along the axon, in a process called saltatory conduction. Recent data also shows that oligodendrocytes also provide metabolic support to neurons, aided by their proximity. Demyelinating diseases, like multiple sclerosis, cause degeneration of the myelin sheath, preventing the brain communicating adequately with the body. Slide 12 We have now seen that many different cell types contribute to the proper functioning of the brain and, therefore, it is not surprising that dysfunction of any of these cell types can lead to disease. Neurons and glia cohabit in a very delicate balance. Neuroinflammation is the activation of glia within a nervous system. This neuroinflammation Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 2. may initially be a defence response to threat, to protect neurons. But chronic activation can lead to the over or aberrant activation of astrocytes and microglia and toxicity to neurons. Altered function of astrocytes and oligodendrocytes can also directly disturb synaptic transmission. Therefore, these changes can result in vulnerability of neurons both in neurodevelopmental and neurodegenerative diseases. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 3. Module: Biological Foundations of Mental Health Week 1 Introduction to brain anatomy Topic 3 Microanatomy of the nervous system - Part 2 of 3 Dr Sarah Mizielinska Lecturer in Dementia and Related Neurodegenerative Disorders, Basic and Clinical Neuroscience, King’s College London Slide 2 In Part 2, we'll be learning about cell structures and function. Slide 3 Neuronal morphology, or shape, is refined during development to fit the function of neurons and is, therefore, highly variable. The extent of dendritic arborisation, or branching, reflects the level of input that a neuron requires – as dendrites are the main sites of neuronal input. For example, cerebellar Purkinje cells are highly branched, as they receive many inputs and are the only input of the entire cerebellar cortex. Slide 4 Axonal length can also vary widely, determining the distance of output in the network. The longest axon in the body is from the lower motor neurons, which is one meter in length, which is quite incredible for a single cell. To give you an equivalent – if the cell body was the size of a ping pong ball, the axon would be 380 meters long, just under four football fields in length. Slide 5 Neurons also have microstructures called dendritic spines. These are small protrusions from dendrites which form the postsynaptic side of a synapse with axon tunnels from other neurons. Dendritic spines come in different forms, from long and thin to mushroom shaped. Their shape and size will affect how they receive and transmit input. Those with a larger surface area provide more space capacity for neurotransmitter receptors and, thus, generally form stronger, more stable synapses rather than the more transient, filopodial types. Spines are also plastic and can increase in size during learning and memory. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 1. Slide 6 Glial cells also vary in morphology. Here, microglia change morphology when they become activated, or 'reactive', with increasing numbers of processes and progressively become more round and phagocytic. Reactive microglial release more cytokines to attract more microglia to the site of a perceived injury. In phagocytic mode, they engulf any perceived debris, which can include synapses. Thus, microglial morphology can be used to score and infer neuroinflammation. Here, we show an example of the scoring system in a mouse brain from a model of frontotemporal dementia stained with a microglial marker, 'Iba1'. You can see the scoring system goes from '1', ramified – which is normal; through '2', reactive; '3', ameboid; to '4', phagocytic. This has then been used to show progressive neuroinflammation in this model, compared to a non-transgenic mouse control. Slide 7 Astrocytic morphology is highly heterogeneous even under normal conditions. Therefore, instead of morphology, activation is often inferred from increased numbers of cells in a given location – this is often called 'astrocytosis'. An increased number of cells may be due to local recruitment or enhanced proliferation of astrocytes. In the same mouse model of frontotemporal dementia as before, an increase in the number of astrocytes is quantified by the percentage of the total area that is stained for the astrocytic marker, 'GFAP'. In this case, progressive astrocytosis is observed from 12 months of age, panel 'E', and quantification below. Slide 8 Inside a neuron, the majority of specialised organelles are very similar to a standard eukaryotic cell, including the following: the nucleus – where all genetic information is stored; the endoplasmic reticulum – where some new proteins are produced, sorted and processed for delivery to their required location; the Golgi apparatus – where additional sorting and processing occurs; mitochondria – are the energy generator of the cell and also have key roles in calcium buffering and cell signaling; lysosomes – are enzyme-filled vesicles for the degradation of proteins and other organelles when faulty; and the cell membrane – is a lipid bilayer containing receptors for cellular communication. You can see a great video introduction to some of these concepts with this link provided [https://www.youtube.com/watch?v=URUJD5NEXC8]. Slide 9 Neurons do, however, have some unique features that relate to their highly specialised function. The first of these is that they have an unusually high energy demand. In a human, the brain comprises only 2% of body mass yet it uses about 20% of the oxygen consumed by the rest of the body. The majority of this is used to maintain the electrical equilibrium of the neuronal cell membrane by the sodium-potassium ATP pump which, as its name suggests, consumes ATP. Other main energy demands include the recycling of neurotransmitters and calcium buffering. Slide 10 Due to their extended morphology, including both axons and dendrites, neurons also need to transport cargo along very long distances. Although some proteins are made locally, the vast majority of proteins – and mitochondria – are produced next to the nucleus. But they are often required at distant sites, such as synapses. Cargo, therefore, needs to be transported out to synapses and back to the soma for recycling or signalling. Cargo is mainly transported along microtubules, one of the key cytoskeletal components of the cell. This can be away from the nucleus – 'anterograde' – or towards the nucleus – 'retrograde'. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 2. Slide 11 As for the majority of processes in neurons, neuronal transport lies in a delicate balance – where even a slight imbalance can lead to dysfunction. This is notable in most neurons, probably due to their really long axons. For example, a slight impairment in retrograde transport can lead to a build-up of dysfunctional components at synapses and a reduction in the supply of recycled components, blocking normal synaptic function. Slide 12 The last key feature of a neuron is due to the fact that we have limited capacity to generate new neurons during adulthood and that neurons are post-mitotic and cannot undergo cell division for growth or repair. Thus, neurons become vulnerable with age – as cell components deteriorate and, thus, have a reduced resistance to cell stress. The key processes that often become dysfunctional with ageing are protein clearance, DNA repair and mitochondrial function. Selective neuronal vulnerability in disease is probably due to the varying vulnerability of specific neuronal populations to different cell and networks stresses. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 3. Module: Biological Foundations of Mental Health Week 1 Introduction to brain anatomy Topic 3 Microanatomy of the nervous system - Part 3 of 3 Dr Sarah Mizielinska Lecturer in Dementia and Related Neurodegenerative Disorders, Basic and Clinical Neuroscience, King’s College London Slide 2 In the final part of the topic, we're going to be talking about gene expression. Slide 4 Compared to other cells and organisms, neurons have a particularly high protein and lipid content due to their specialisation and elongated form. Renewing the protein content of a neuron is essential for maintaining neuronal cell health and plasticity, a key feature of neurons. By plasticity, we mean the ability of a neuron to adapt to stimuli, such as the growth of existing or new synapses during memory formation. Renewal of proteins can occur by protein synthesis or the recycling of existing proteins. Slide 5 Gene expression is the process by which a gene is used to synthesise the product it encodes. This is most commonly protein but can also include functional RNAs, such as transfer RNA and ribosomal RNA. Protein synthesis is how gene expression results in the generation of new proteins from the genetic code. For those of you that are already familiar with this process, I hope this serves as a succinct refresher course. Slide 6 Gene expression occurs via two key steps: transcription – the photocopying of DNA into messenger RNA. This is a clever evolutionary step that keeps the DNA in the nucleus where it can be protected from damage. The second step is translation – the literal translation of the genetic code on the mRNA photocopy into protein. These processes are highly regulated so that proteins are only made when they are needed. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 1. Slide 7 Transcription occurs by the enzyme RNA polymerase moving along the DNA, copying it from the DNA code ('A', 'G', 'C' and 'T') into messenger RNA ('A', 'G', 'C' and 'U'). Note the changing of 'T's to 'U's from DNA to RNA. DNA is normally kept in a condensed structure, which needs to be relaxed so that transcription factors can bind and initiate transcription. Epigenetic factors, such as DNA methylation, can control when the DNA structure can be relaxed. Slide 8 Before being ready for translation, RNA undergoes several processing steps, including RNA splicing. The splicing machinery chops out non-coding regions – 'introns' – of the messenger RNA, thus leading only protein-coding regions. Alternative splicing can chop out different regions, producing different mature RNA transcripts, which encode different proteins, which may have different functions within a cell. This is a way in which the genetic code can increase the number of potential proteins it makes. This mature RNA is then exported from the nucleus to the cytoplasm for translation into protein. Gene expression is often assessed at the mRNA level by 'RNA sequencing'. This informs which genes are being actively transcribed and how they are spliced. Slide 9 In the cytoplasm, ribosomes read mRNA code and translate this into protein. The ribosome recognises a 3 basepair code on the mRNA and brings in a transfer RNA carrying the appropriate amino acid. It binds sequential amino acids together to form a polypeptide which, when folded into the correct structure, becomes a functional protein. Translation begins at the start code of an mRNA, which is AUG – or ATG on DNA – encoding the amino acid ‘methionine’. Translation normally occurs close to the nucleus, where the RNA is made, but in neurons this also occurs at sites with high protein demand, such as synapses. This is called local translation. Slide 10 Processing of proteins is essential for their correct folding and cellular targeting. Protein folding occurs as soon as a protein is made and then undergoes quality control to ensure it is correct. Thus, misfolded proteins can be targeted quickly and efficiently for degradation. Proteins also often have post-translational modifications that modulate their folding (such as phosphorylation), again, greatly increasing the diversity of protein functionality. This can allow different protein activity during different cellular activities. Protein misfolding is a major cause of disease, especially in neurodegenerative disorders. This can be due to genetic mutations, cellular stress or impairment of clearance mechanisms and often leads to a build-up of aggregated protein in the brain. Slide 11 In summary, I hope this topic has guided your understanding into the foundations of the complex microanatomy of the nervous system. In Part 1, we learned how the nervous system is comprised of neurons and glia which come in many different forms with specific functions. In Part 2, we explored how neurons and glia have specialised morphologies which enable them to carry out their function and that neurons share many substructures with a standard eukaryotic cell, but also have their unique features and demands. And, finally, in Part 3, we delved into the totally critical cellular process of protein expression. Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content. Week 1 @ King’s College London 2.