Systems Neuroscience Fundamentals (MEDI3300) PDF

Systems Neuroscience Fundamentals MEDI3300 INTRODUCTION Welcome MEDI3300 UNIT OUTLINE MEDI3300 UNIT OUTLINE (ILEARN) Peter Burke MEDI3300 Unit convenor Macquarie Medical School Email: p...

Systems Neuroscience Fundamentals MEDI3300 INTRODUCTION Welcome MEDI3300 UNIT OUTLINE MEDI3300 UNIT OUTLINE (ILEARN) Peter Burke MEDI3300 Unit convenor Macquarie Medical School Email: [email protected] Qualifications BSc (Hons) Physiology, Sydney University PhD Neuroscience, Macquarie University Fields of Research Autonomic neuroscience Oromotor & respiratory motor control Obstructive Sleep Apnoea pathophysiology MEDI3300 ASSUMED KNOWLEDGE MEDI3300 builds on prior neuroscience units, like MEDI2300 (neuroscience I) and it is assumed that you can build upon you prior neuroscience knowledge. From the start, please remind yourself of the general anatomical structures of the nervous system and the fundamentals of neurophysiology (i.e. resting potential, action potential, synaptic transmission and various neurotransmitters). Test your current knowledge with these questions: 1. How is the nervous system organised? 2. What cells make up the nervous system and what are their individual roles? 3. What different types of neurons are there, and how do they communicate with each other? 4. What are the main factors that contribute to the membrane potential? 5. What are EPSPs and IPSPs? How are action potentials generated and propagated? 6. What is the difference between ionotropic and metabotropic receptors? 7. Describe the different classes of neurotransmitters ? (Glutamate, GABA, Serotonin, Acetylcholine, etc). 8. What types of receptors do they signal via, and what effect does this have on the post-synaptic neuron? Systems Neuroscience MEDI3300 LEARNING OUTCOMES Systems neuroscience: A discipline of neuroscience that studies the structure and function of neural circuits and systems MEDI3300 Learning outcomes 1. Understand how the nervous system encodes sensation, regulates homeostasis, and creates complex behaviours, including perception, movement, emotion and cognition 2. Provide the foundation for understanding the impairments of sensation, movement, homeostasis and cognition that accompany injury, disease, dysfunction in the central nervous system. 3. Critique the role of discovery in advancing the field of neuroscience in both a clinical and medical research setting.  Systems Neuroscience Fundamentals CORE CONCEPTS WE WILL EXPLORE IN MEDI3300 To understand how the billions of individual cells in the nervous system encode sensation of our internal and external environments, regulate homeostasis, enable movement in our environment, and produce emotion and cognitive. As a first step, we need to understand the building blocks - the electrical properties of neurons and their connections to other cells - and the organisation of the nervous system from supporting cells to neural circuits. We will focus on five fundamental features of the nervous system: 1. The structural components the nervous system and of individual cells within 2. The mechanisms by which neurons produce signals within themselves and between each other 3. The patterns of connection between neurons, or between neurons and their effector (e.g. muscles, glands) 4. The relationship of different patterns of interconnection to different types of behavior 5. How neurons and their connections are modified by experience Further readings: Chapters 1,4, Principals of Neural Science. Kandel, Schwartz & Jessell 1. Organisation of the nervous system THE BRAIN HAS DISTINCT FUNCTIONAL REGIONS The central nervous system is a bilateral and largely symmetrical structure with two main parts, the spinal cord and the brain. The brain comprises six major structures: the medulla oblongata, pons, cerebellum, midbrain, diencephalon, and cerebrum. Each of these in turn comprise distinct groups of neurons with distinctive connectivity and developmental origin.  1. Organisation of the nervous system FUNCTIONAL COMPARTMENTALISATION The organisation within structures or nuclei is highly compartmentalised  1. Organisation of the nervous system A HISTORICAL PERSPECTIVE Our first appreciation of the organisation of the nervous system came from clinical pathological correlation: Destruction of a particular brain region will impair a particular function. Stimulation mapping: Stimulating a particular brain region induces a particular functional outcome.  1. Organisation of the nervous system NEUROANATOMICAL TERMS OF NAVIGATION Location and orientation of components of the central nervous system within the body are described with reference to three axes: the rostral-caudal, dorsal-ventral, and medial-lateral axes. 1. Neurons THE SIGNALLING UNITS OF THE NERVOUS SYSTEM A typical neuron has four morphologically defined regions: (1) the cell body, (2) dendrites, (3) an axon, and (4) presynaptic terminals Action potentials are the electrical signals generated by neurons. These signals are how the brain receives, analyses, and conveys information. Intracellular recording of an action These signals are highly stereotyped throughout potential. Hodgkin & Huxley, 1939 the nervous system. How action potentials are initiated by different neurons to encode our internal and external environment and behavior will be a thematic we will study across all topics in MEDI3300. 1. Glia GLIAL CELLS SUPPORT NEURONS Glial cells greatly outnumber neurons—it is estimated that glia outnumber neurons 10 to 1. They are clearly important for brain function, and we will briefly explore their role for homeostatic functions (week 3), sleep (week 11). 2. Neuron signalling NEURONAL SIGNALLING IS THE SAME FOR ALL NEURONS Four functional regions define neuronal signalling: The input, integrative, and conductive signals are all electrical and intrinsic properties of the cell. The output signal is a chemical substance ejected by the cell into the synaptic cleft.  3. Neuron signalling NEURONAL ACTIVITY ENCODE STIMULUS A muscle stretch receptor The input signal (stretch) is graded in amplitude and duration; the sensory neuron translates this stimuli into action potentials coded by the firing frequency and duration of firing. The chemical output of the neuron is proportional to the stimuli and action potentials generated. neuron sensory amplitude andduration intimidation firingternary coded by firing duration as and 4. Neurons THE BUILDING BLOCKS OF NEURONAL CIRCUITS Interconnected neurons comprise neuronal circuits, and neuronal circuits underpin behavior. 5. Neuron signalling MODIFIED BY EXPERIENCE Anatomical reorganisation Dendritic structures (spines) Axonal sprouting or pruning https://www.sciencedirect.com/science/article/pii/S0012160622000896#fig1 5. Neuron signalling MODIFIED BY EXPERIENCE Neuroplasticity Long term potentiation (LTP) Long term Depression (LTD) Final Message SUMMARY Modern neuroscience aspires to explain mental processes like consciousness and cognition that are far more complex than reflexes. However, a natural starting point is to understand the ways that neuronal circuits are formed, how they function, and how they elaborate reflexes and sensory-motor control. We can learn a great deal about how the nervous system produces complex behaviors by focusing on five fundamental features of the nervous system: 1. The structural components the nervous system and of individual cells within 2. The mechanisms by which neurons produce signals within themselves and between each other 3. The patterns of connection between neurons, or between neurons and their effector (e.g. muscles, glands) 4. The relationship of different patterns of interconnection to different types of behavior 5. How neurons and their connections are modified by experience We hope that you will find this unit of Neuroscience stimulating and rewarding, and that it ignites in you a life-long scholarly and research-based interest in Neuroscience. OFFICE | FACULTY | DEPARTMENT 17 Developmental Neurobiology – Establishing regional identity MEDI3300 – Neuroscience II – Bowen Dempsey – Faculty of Medicine Health and Human Sciences Support materials: “Principals of Neural Science” (6th Ed, Chapter 45) “https://archive.org/details/podcast_hhmis-holiday-lectures-on-sci_2008-neuroscience-lecture- 2_1000053919613” [email protected] 1 Hello, my name is Bowen Dempsey, I am a researcher in the Faculty of Medicine Health and Human Sciences at Macquarie. Welcome to the first topic lecture of MEDI3300 – which I have titled “establishing regional identity”. Today we will dive into developmental neurobiology and cover the early processes that establish complexity within the developing nervous system. This mechanisms that guide brain development are still being actively being researched in laboratories all around the world, including here at Macquarie Today I will cover some of the basic principals that have been established over the past century. These principals are derived almost entirely from research on experimental animal models which will feature heavily throughout this lecture. What I cover today can be found in chapter 45 of Principals of Neural Science, a great neuroscience textbook you find worth getting your hands on. This lecture will also feature material from a talk given by one of the pioneers in the field developmental neurbiology, Thomas Jessell back in 2008 as part of the Howard Hughes holidays lectures series. I also recommend watching this talk in full. 1 Establishing regional identity – MEDI 3300 LEARNING OBJECTIVES - By the end of this lecture you will be able to describe the processes by which: Different brain regions are established during development -the regional segmentation of the early brain -role of transcription factors -role of morphogen gradients -anterior-posterior patterning Bowen [email protected] | FHMMS 2 The objective of this lecture is to introduce you to the mechanisms that guide the specification of the developing brain into the different regions that will eventually give rise to the mature brain. This will include becoming familiar with the morphology and segmentation of the early brain and the mechanisms that drive these morphological changes - which are transcription factors, morphogen gradients and how position along the anterior-posterior axis of the developing nervous system influences cell fate and the overall patterning of the brain for its future development. In this lecture you will hear the names of many different genes and signaling molecules. The point of this lecture is to understand the mechanisms served by these genes and signals, not to remember each individually. 2  How do brains work?– Does structure inform function? Brain: Difficult to predict Heart: gross structural function from gross features suggest function structure as pump e.g. valves and chambers made of a heterogenous subunit – made of a homogenous ”neuron” features: highly specialised subunit – “cardiac myocyte” cell, >5000 types varying across features: contractile regions, form intercommunicating myofilaments, intercalated networks “circuits” discs allowing depolarisation and contraction of adjacent Gray's Illustrations, Radiopaedia.org, rID: 36255 cells. DOI: 10.1172/JCI19448 DOI: fnana-10-00038 Because of the brains key role in most aspects of human life, understanding how it works is an important goal for medical science. It is difficult to solve brain disease and dysfunction with out first understanding the basic biological principals that govern its function. When we want to understand how something works, we usually begin by looking at its structure. The relationship between structure and function has informed a lot of what we know about other vital organs in the body. When we look at the heart for example, it gross structure gives us key insights into what it is and what it might do. We can see that it is regionalized into chambers and valves and when we look at its microscopic structure we see it is composed of a homo geneous subunit, the cardiac myocyte, which communicate with each other and contract. Taken all together we know we are dealing with a pump, that can contract and direct flow into two directions. However when we look the brain, we can see that it has complex regionalisation at the gross scale but this doesn’t really provide much information about what it does. This quote from wilder penfield captures the profound potential of the brain as the driver of human destiny, but this does not come from a structural assessment. At the microscopic scale we see that the brains structure only become more complex, being primarly built upon by hetero geneous subunits - neurons - which are themselves highly specialized, withover 5000 different types, and being arranged into intercommunicating networks that span across the entire nervous system. 3  Function is regionalised within the brain Clinical pathological correlation: Destruction of a particular brain region will impair a particular function Wilder Penfield – Stimulation mapping Fundamentals of Cognitive Neuroscience A Beginner's Guide Pierre-Paul Broca – Expressive aphasia (speech production) https://doi.org/10.3171/jns.1991.75.5.0812 Stimulation mapping: Stimulating a particular brain region induces a particular functional outcome e.g. motor response or sensory perception Because of the brain’s complexity, structure alone is insufficient to develop an understanding of its function. However we do know that particularfunctions are served by particular brain regions. This insight was established through clinical pathological correlation, which showed that destruction of a particular brain region will impair a particular function. An early example of this was the discovery of Broca’s area, lesion of this particular region of the cortex induces a form of aphasia, where speech production is impaired. Furthermore, stimulating different regions of the cortex in conscious patients provided the opportunity to map out the he discrete regions that perform the sensory integration or motor control for different parts of the body. In this lecture we will examine the processes in early development that will eventually give rise to the functionally regionalized brain. 4  How does the brain become regionalised 1x cell 1x10^10 (new fertilized born human) egg 1x10^11 (adult human) >5000 different cell types This process is the transformation from a single fertilized egg, into a structure that consists of over 10 billion neurons, specialized into over 5000 different cell types. 5 https://opentextbc.ca/biology/chapter/13-2-development-and-organogenesis/ “Becoming” Jan van IJken Here we see the first stages of development of a fertilized salamander egg. One cell will become many as it repeatedly divides. Eventually an inner cavity will form establishing the three germ layers that will give rise to all future tissues of the body. The innermost endoderm, the outermost ectoderm and the mesoderm sandwiched between them. 6  Anatomy of the Human Body (Gray) Principals of Neural Science The tissues of the nervous system arise from the out ectodermal layer. A portion of the ectoderm will thicken to become the neural plate, a long grove will form along the anterior-posterior axis of this plate. The dorsal edges formed by this grove will come together to forming a tube with a hollow centre. This structured called the neural will give rise to the brain and spinal cord. Even at these early stages, days after fertilization, the developing nervous system already exhibits regional specification that will give rise to the mature structures of the brain. Todays lecture will largely focus on the processes that guide the early specialization of the nervous system. 7  Position determines identity Neurulation Principals of Neural Science Principals of Neural Science (Chapter 52) Anatomy of the Human Body (Gray) The ectoderm that will give rise to the neural plate also referred to as the neuro epithelium, will exhibit region specific changes in morphology as the neural tube forms. Viewed from above, we can see that one end of the tube is clearly different from the other. This polarity will determine which parts of the neural tube give rise to the brain or the spinal cord. The anterior end, located near the oral pharyngeal membrane will form the brain and the posterior end located near the primitive node will form the spinal cord. These morphological changes will eventually give rise to the anatomical contours of the mature brain. Early in this process we see 3 swellings or vesicles at the anterior pole. The proencephalon, mesencephalon and rhombencephalon. When viewed sagitally we can see that anterior – posterior boundaries between 2 of these divisions occur at major flexures of the neural tube. The anterior most vesicle will then give rise to two morphologically distinct regions, the telencephalon and diencephalon. The Rhombencephalon will develop a dorsal flexure subdividing it into the metaencephalon and myelencephalon 8 Early regionalisation of the brain OpenStax Anatomy and Physiology This slide summarizes the early regionalization that occurs along the anterior – posterior axis of the developing neural tube, from the 3 vesicle stage to the 5 vesicle stage. On the right hand side are the mature structures these morphologically distinct regions are destined to form. 9 Early regionalisation of the brain http://dx.doi.org/10.1016/B978-0-12-801238-3.05440-4 Here we can see the differentiation of the neural tube in regions as tree of branching events. Here can see the 3 vesicle stage, followed by the 5 vesicle stage. As we move from left to right the number of structures increases and through this process of existing structures seeding new structures the regional divisions of the brain will be eventually be established. 10 Regionalisation is driven by the differential expression of genes neonate FoxG1 adult DOI: 10.1016/j.ydbio.2016.02.011 DOI: https://doi.org/10.1101/2020.02.05.935189 FoxG1 DOI:10.1242/dev.121.12.3923 The force that drives these regional changes is the differential expression of genes. A particular region of the neural tube will express a particular set of genes setting their regional fate for future development. I have highlighted the cells located within the prosencephalon in blue. This morphological feature is delimited by the expression of a gene called foxg1. We can see the actual expression pattern of this gene below, by looking at the distribution of its mRNA in a mouse embryo at day 10 of development. As the embryo continues to develop, now shown at day 13, these regions undergo further morphological differentiation, giving rise the cortex and forebrain. Furthermore we can see in these cross sectional images that gene expression actually sets the regional boundaries these mature neuroanatomical structures. Note the sharp transition between blue foxg1 expressing neurons of the forebrain (shown in blue) and the adjacent unlabeled neurons of the thalamus. 11 Transcription factors define regional fate in the early brain Transcription factors: Proteins that regulate the expression of specific genes Transcription factor – gene expression – cellular identity / cellular fate Genes that set regional fate, like foxg1, are a special class of genes called transcription factors. These genes drive the expression of proteins that then interact with DNA, binding to the enhancer or promoter regions of a specific gene to regulate its expression. In this way, the presence of absence of a particular transcription factor will determine the fate of a cell by regulating which genes are turned on or turned off. These will includes genes important to defining cellular identity, including growth factors, surface ligands and receptors and neurotransmitters and receptors. Here we can see a transcription factor (shown in pink) binding DNA. In this schematic we can see how gene expression is regulated by transcription factor binding. In this example, the process of gene expression can only proceed after transcription factor binding to its upstream promotor region. Only in the presence of transcription factor binding to the promotor region can the down stream coding region be transcribed to produce mRNA. During development, transcription factor expression is the driving force that ensures that the correct cell types…. form in the correct locations. 12 Transcription factors define regional fate in the early brain https://doi.org/10.1016/C2014-0-01601-2 After regional identity is established through transcription factor expression, the developmental potential of regionally specified cells becomes restricted, locking in their future identity. Even cells that are transplanted from one region to another will continue to develop along their previously specified trajectory. In this example, regionally specified cells of the metencephalon will continue to develop into cerebellar neurons despite being relocated to the prosencephalon early in development. Here we can see the formation of an ectopic cerebellum between cortex and midbrain in the mature brain of a chicken, as a result of this relocation earlier in development. 13  Position determines transcription factor identity via morphogen gradients Early regionalisation of the brain reflects the differential expression of transcription factors, that begin to make cells different in a way that anticipates the regional functions of the brain BMP inhibitors “organiser” “organiser” https://doi.org/10.10 16/j.ydbio.2016.12.0 23 neural BMP skin BMP inhibitor https://opentextbc.ca/biology/chapter/13-2-development-and-organogenesis/ So far we have established that the early regionalization of the brain reflects the differential expression of transcription factors and that these genes begin to make cells in these regions different in a way that can anticipate the regional functions of the brain. We will now discuss the processes by which these regions gain distinct genetic identities. Here we have a frog embryo. The process of neural induction has just begun, we can distinguish the neural plate from the surrounding ectoderm by their morphology and differential expression of the transcription factor sox2. So why are these cells different, what has caused them to under go this change. Something in the embryo has signaled to this patch of ectoderm to undergo neural induction. To understand this process we will go back to our simple three layer embryo. Generally speaking, ectodermal cells will either turn into neural cells or skin cells. Interestingly, their default preference is the neural trajectory. However this blocked by the presence of a signaling peptide called bone morphogenic peptide -4 or BMP-4. Which prevents neural induction allowing the ectoderm to form skin. If bmp signalling is blocked by a BMP inhibitor, neural induction can then proceed. Signals that inhibit BMP emanate from a group of cells located at the dorsal lip of the blastopore, exposing some ectodermal cells to sufficient concentration to allow neural induction. So the parts of the embryonic ectoderm that have formed the neural plate are those influenced by BMP inhibition shown in red. Those continually suppressed by 14 BMP shown in blue will form the skin. So, the signals emitted from this region, we call the organizer allows the ectodermal cells closest to it to become the neural plate and futhurmore the neural tube. The influence of these signals is so potent, that if we transplant a secondary organizer region, from a donor embryo, it will induce the formation of a secondary neural axis and secondary neurvous system. 14  Position determines identity via morphogen gradients https://studylib.net/doc/5453430/induction Neural induction is driven by morphogen exposure Principals of Neural Science Morphogens: Signaling molecules that emanate from a restricted region. This signaling pathway called neural induction, is summarized on the left. In short, the ectoderm that is influenced by BMP inhibition will form the neural plate and gain differential expression of transcription factors. The key concept here is that cells can become different as a result of exposure to signaling molecules. These signalling molecules are proteins called morphogens. These morphogen signals are synthesized by cells located within a spatially defined region of the developing embryo, which in this case the organizer region. Morphogen signals will emanate from this region, having a greater influence on those cells within its immediate proximity. Therefore position relative to the source of these signals is critical in determining regional identity in the developing brain. Futhurmore, exposure to different levels of morphogen concentration will induce differential transcription factor expression. Here we can see that cells located across a decreasing concentration gradient gain different transcriptional identities represented as differences in colour. In this way cells located closer to region X will become different to those located closer to the source of the morphogen signal by the induction of different transcription factors. The mechanism underlying this process will be discussed in more detail in later slides. 15 Position determines identity via morphogen gradients https://doi.org/10.1016/C2014-0-01601-2 The brain will eventually gain its regional identity through sequential exposure to multiple morphogen signalling events. Secondary to neural induction, an anterior posterior gradient of the morphogen WNT1 is established. The posterior paraxial mesoderm shown here in blue and denoted by the letter will release Wnt signals and the anterior paraxial mesoderm shown here in red will release WNT inhibitors. The perceived levels of wnt signalling experienced by the overlying neural plate shown here in blue will be strongest at the posterior end and weakest at the anterior end. The cells interpret this gradient with high wnt signalling giving rise to posterior brain structures, the rhombencepalong /hindbrain and spinal cord, and low wnt signalling giving rise to the mescencephalon/midbrain and prosencephalon/forebrain. We can see this anterior posterior polarity expressed by two different transcription factors. Otx2 in the anterior and Gbx2, the transition between representing the future hindbrain/midbrain boundary at the cephalic flexure. Just after 2 rounds of morphogen gradient exposure, the polarity and gross morphological features of early neural tube are established. 16  How do cells interpret morphogen gradients “https://archive.org/details/podcast_hhmis-holiday-lectures-on-sci_2008-neuroscience-lecture- 2_1000053919613” https://doi.org/10.1016/C2014-0-01601-2 How does morphogen concentration differentially influence the expression of genes? We have established that position is important for determining the domains of transcription factor expression across the developing nervous system and that these patterns of gene expression will determine the future regional identities of the brain. In the previous example, the anterior and posterior parts of the neural plate gained distinct transcriptional identities (express different transcription factors) as a result of being exposed to different morphogen concentrations. The ability for cells to convert their position across a morphogen gradient to a genetic identity is the fundamental principal that drives regional specification. The question still remains as to how these signals are differentially interpreted to induce these genetic changes. I am going to play video detailing the molecular mechanisms that underlie this process. This is an excerpt of a talk given by the late Thomas Jessell in 2008 called “Building Brains: The Molecular Logic of Neural Circuits”, which can be viewed in its entirety using the link below the video. 17 The right place at the right time determines regional identity Morphogen exposure will induce transcription factor expression which will subsequently regulate the expression of target genes. These genes can themselves be morphogens driving subsequent signaling events. A limited number of signaling molecules generate variation temporal and spatial contexts. https://studylib.net/doc/5453430/induction As the developing nervous system changes and new regional identities emerge, additional sites of morphogen signalling will be established. Because of this a small number of initial regions can give rise to broad regional diversity over time. In this scheme when have two regions, A and B. A Morphogen signal emanating from B will induce the formation of a new regional identity, C, from the most proximate cells of region A. A secondary morphogen signalling event from the newly formed region C (shown in red) will induce the formation of 2 new regions from the proximate most cells of regions A and B. Because A and B have different developmental contexts (i.e. they have different genes), exposure to the same signal from region C will drive different developmental response, giving rise to two distinct regional identities, D and E. In this way, a limited amount of cells types and a limited number of signalling molecules can produce a great amount of diversity, depending on when and where they are located. 18  The right place at the right time determines regional identity The same signalling molecules can have different effects in different places at different times! FoxG1 En1 DOI:10.1242/dev.121.12.3923 DOI:10.1242/dev.000620 With this principal in mind we will return to the developing neural tube to look at how regional identity is further refined through additional signalling events. When we left, Wnt1 signalling had established anterior – posterior polarity with the anterior and posteriors regions acquiring distinct genetic identities and establishing a boundary between the midbrain and hindbrain. Here highlighted in purple are two new sites of morphogen signalling that influence the regional development of the surrounding neural tube. These are the anterior neural ridge at the anterior most pole of the neural tube and the isthmic organiser which forms at the midbrain hindbrain boundary. Here wnt1 will be recycled, in a new temporal and spatial context, wnt1 (shown in blue) will emanate from the isthmic organiser to establish the regional identity of the dorsal midbrain. Furthermore, these two regions will use the same morphogen signalling molecule, FGF8, shown in green to establish different regional identities. FGF8 expressed at the anterior neural ridge will drive foxg1 expression in the nearby cells that will form the telencephalon and subsequent cortex, which I showed in early slides. FGF8 expressed at the midbrain hindbrain boundary will drive expression the expression of an entirely different set of transcription factors. One of these is engrailed-1 or En1, which will play a role in establishing the identity of the dorsal midbrain to form the tectum and the anterior dorsal part of the hindbrain to form the cerebellum. establish boundary b w anterior and posterior regions midbrain andhindbrain Wnt 1 anteriothridge anteriormost pole as neural tube ismic purple hindbrain and midbrain boundaries organiser joins context from ismic organises_ tempered and spacial Watt 19  regard anterior read ridge telephonyscavenges FGF 8 IGF8 midbrain hindbrain bonday It idummitygfm.de tatump The right place at the right time determines andsteadiness cerebellum regional identity http://dx.doi.org/10.1016/B978-0-12-801238-3.05440-4 Now with these insights when we look at this branching schematic of the developing nervous system we can appreciate that each of these branching points that produce new regional identities are in fact the result of differential morphogen exposure and the subsequent induction of transcription factor expression. Here I have expanded the schematic to include all of the events we have covered so far in the lecture, with morphogen exposure events represented by colour grandients and transcription factor expression represented by grey text. Here we can see clearly that through a very limited set of signalling molecules, rich regional diversity is established even in the very early stages of neural development and through this continued process will produce the complex regionality of the mature brain. 20 Transcription factors specify anterior - posterior position Early regionalisation of the brain reflects the differential expression of transcription factors, that begin to make cells different in a way that anticipates the regional functions of the brain https://doi.org/10.1016/C2014-0-01601-2 https://doi.org/10.1002/1096-9861(20000814)424:1%3C47::AID- CNE4%3E3.0.CO;2-5 r1 r2 r3 r4 r5 r6 r7 r8 Earlier in the lecture we established that transcription factor expression drives the regional differences in the early nervous system. Transcription factor expression will trigger a cascade of gene regulation within regionally specified cells, changing them in a way that allows them to anticipate the future functions of the brain regions they will go on to form. An example I provided earlier in the lecture demonstrated that regionally specified cells of the mesencephalon, destined to become the cerebellum will continue down that developmental directory even when moved to a different location in the brain. You can see from this example that it is important for the right populations of cells to stay in the right place during development to ensure that the brain forms correctly. In the following slides I am going explain some of the mechanisms by which transcription factors first endow cells with regional identity and then ensure they are able to maintain their correct position. The principals that govern the anterior-posterior organization of the hindbrain have been studied extensively, we will focus the ways in which transcription factors direct positional identity in this brain region. As the hindbrain forms it acquires further regionalization along its anterior – posterior axis, forming morphologically distinct segmental units. These segments called rhombomeres, are shown here numbered 1-8. You can seem them here in an embryonic fish, with the boundaries separating each rhombomere stained blue. Each of these segments will go on to produce functionally distinct pools of neurons that will form the pons and medulla, however the rhombmeres 21 themselves are only transient structures, they will disappear leaving no trace of their original boundaries. 21  Transcription factors specify rhombomere position r1 r2 r3 r4 r5 r6 r7 r8 mouse chicken Transcription factors exhibit an alternating expression pattern across sequential rhombomeres. frog fish DOI: 10.1126/science.274.5290.1109 DOI: 10.1002/dvdy.10086 The Rhombomeres positions are specified by a large set of transcription factors that have been studied in detail. Here is the hindbrain at a slightly oblique angle, presenting it as a long segmented tube. The alternating pattern of blue and green represent the odd and even numbered rhombomere segments. Below we can see an inexhaustive list of transcription factors expressed across these segments. Bold colouring underneath a rhombomere representing the presence of a gene indicated by that row. What is immediately obvious when we view transcription factor expression across the rhombomeres this way, is that many of the transcription factors are expressed across multiple segments in an alternating pattern, either exclusively in odd or even rhombomeres. If we look at the expression of one of these genes krox20, which is expressed in r3 and r5, we see that its expression pattern, shown in black, sharply delimits these segments, forming a stripe pattern just like we see in the table. I’ve shown the krox20 expression pattern across multiple species just to emphasis how fundamentally conserved these genes as well as their organizational logic are for development of the vertebrate brain. 22 Transcription factors specify and maintain rhombomere position DOI: 10.1126/science.274.5290.1109 Mutual repression forces the expression of one r3 r5 Krox-20 transcription factor and the suppression of another. r4 Hoxb-1 Ephrin surface signaling creates repulsion, forcing cells away from those expressing the complimentary signal. Now we are going to see how these transcription factors establish and maintain these boundaries. We are going to look at 2 adjacently expressed transcription factors, krox-20 which we already know is expressed in r3 and r5, and Hoxb1 which is expressed in r4. We are going to focus specifically on the boundary between r4 and r5. Initially hoxb1 and krox20 expression are established by a gradient of the morphogen retinoic acid. Cells located at the anterior end gain expression of Hoxb1 shown in blue and cells located at the posterior end gain expression of krox20 shown in orange. However those that lie at the intermediate concentration range shown here in green will form a “fuzzy” boundary of interspersed hoxb1 and krox20 expressing cells. These cells will then migrate to their correctly specified rhombomere positions, creating a sharp boundary. So how does this arrangement of intermediately exposed cells happen. There are 2 repressive mechanisms that drive this. First, Hoxb1 and Krox20 mutually repress each others expression, meaning that the first of these transcription factors to be established in a cell, will stop the expression of the other by binding to its promotor region. At the intermediate morphogen gradient this is equally likely to happen for either gene, resulting in the intermingled pattern we see in the schematic. This intermingling is rectified by the expression of a set of surface recognition signaling molecules. Called EphA4 and ephrinB3. These two proteins bind to each other, leading to transmission of a repulsive signal that pushes hoxb1 and krox20 cells aways from each other. This force which maintains the rhombomere border is a product of the transcriptional regulation driven by this two transcription 23 factors. It should now clear why krox20 is expressed in alternating segments. It is because ephrinA can only create repulsion against cells expressing the complimentary surface molecule, ephrin B3, which are generated in the intermediate hoxb1 expressing territory R4. alternating segments ephrin A Knox 20 repulsion again cells expensis inflates BB estressis sugar ephrin tarites RA HoxB 23 The right place at the right time determines regional identity http://dx.doi.org/10.1016/B978-0-12-801238-3.05440-4 To conclude I will return to this slide, that summarises the core principals that drive regional development. These are, that position and timing are what establish regional differences throughout out the developing nervous system. Differential exposure to morphogens converts position to a distinct regional identity through the expression of transcription factors. In turn these transcription factors change the transcriptional identity of regionally defined cells changing them in ways that will anticipate future specification through sequential morphogen exposure events, leading to the regional diversity that constitutes the mature brain. 24 The visceral nervous system MEDI3300 – NEUROSCIENCE II – BOWEN DEMPSEY [email protected] “The Heart” (1950) Hello, My name is Bowen Dempsey, I am researcher in the faculty of medicine health and human sciences at macquarie university Today’s lecture will serve as introduction to the visceral nervous system. We will first talk about the functional and anatomical criteria used to define visceral behaviours, followed by a detailed description of the nerves and ganglia that make up the visceral nervous system. 1 Learning Objectives THE VISCERAL NERVOUS SYSTEM I 1. Define visceral behaviours and how they differ from somatic behaviours 2. Identify and describe the parts of the peripheral nervous system that serve visceral behaviours Autonomic Efferents Special Visceral Efferents Visceral Afferents Enteric Neurons OFFICE | FACULTY | DEPARTMENT 2 By the end of this lecture you will be able to define what makes a behaviour visceral and how visceral behaviours differ from somatic behaviours. And You will also be able to identify and describe the parts of the peripheral nervous system that serve visceral behaviours. Including the specific branches of the visceral nervous system 2 What are visceral behaviours THE VISCERAL NERVOUS SYSTEM I What are visceral behaviours? -automatic / reflex responses -innate, well developed at birth -visceral / homeostatic behaviours - maintaining metabolism - digestion, respiration, thermogenesis and blood flow + metabolite constitution Visceral behaviours are how the brain interacts with the internal environment OFFICE | FACULTY | DEPARTMENT 3 The behaviours served by the visceral nervous system are automatic reflex responses that are performed involuntarily. They are executed by the brainstem or occur entirely within the periphery without any conscious effort. These behaviours are are well developed at birth and mostly serve to maintain bodily homeostasis and meet metabolic demands. These behaviours mostly fall under the following catagories the ingestion and digestion of food and drink, respiration, controlling body temperature, regulating the metabolite constitution of the blood. As shown the right here one of the major roles of the visceral nervous system to regulate the flow of blood throughout the body. When the brain is interacting with the internal environment, it is almost always through a visceral behaviour. 3 Visceral vs Somatic Behaviours THE VISCERAL NERVOUS SYSTEM I Visceral = Automatic processes, concerning the internal environment (e.g. digestion) - action upon smooth muscle and glands Somatic = Volitional behaviours, concerning interactions with the external environment (e.g. locomotion) – action upon striated muscles (somatic muscles) https://commons.wikimedia.org/wiki/File:Gray19_with_color.png Image Credits: Hudson Garcia, Caters News Agency OFFICE | FACULTY | DEPARTMENT 4 The internal or external actions of the brain set a major thematic and anatomical division for behaviour. As we established in the previous slide, visceral behaviours are automatic processes concerned with the internal environment. Visceral behaviours can also be defined by the types of tissue upon which they act. For the most part visceral actions are served by smooth muscle and glands. This is in opposition to somatic behaviours which are performed volitionally, involve interactions with the external environment, which for the most part are locomotor behaviours and are executed via striated muscles. A major distinction between these two behavioural modalities are the developmental origins of their effector tissues. The striated muscles that serve somatic behaviours arise from the paired somites located along the posterior neural tube. Whereas the tissues that constitute the visceral effectors, like smooth and cardiac muscles arise from other paraxial mesoderm sources. 4 Visceral vs Somatic Anatomy THE VISCERAL NERVOUS SYSTEM I Somatic/Visceral mostly an anatomical distinction. Romer AS. The vertebrate as dual animal - somatic and visceral. Evol Biol. 1972;6:121–156. Image Credits: Hudson Garcia, Caters News Agency OFFICE | FACULTY | DEPARTMENT 5 Using these themes we can break the body down into distinct anatomical divisions. The visceral which regulate the internal environment, example breathing, eating and blood flow, and the somatic, which are those concerned with moving. We can see this clear divisions across the vertebrate body plan here, in these drawings of a tadpole and a shark. The visceral circled in blue respresenting the respiratory and gastrointestinal systems and the somatic circled in red representing the muscles used to swim. 5  Visceral vs Somatic nervous systems THE VISCERAL NERVOUS SYSTEM I Sensorimotor circuits: sensory neurons detect changes and motor neurons respond to these changes. sensory “contract” motor “blood pressure” “swim” “wetness” Somatic - sense the environment and respond by shaping bodily motions. Visceral - sense the interior milieu and respond by Image Credits: Hudson Garcia, Caters News Agency regulating vital functions (homeostatic). OFFICE | FACULTY | DEPARTMENT 6 The way the brain controls different parts of the body through sensorimotor circuits. In the simplest form, these circuits have sensory componenet that can detect changes and motor component that can respond to these changes. In the case of our frog here we can detect a visceral change like a drop in blood pressure and generate a visceral motor response, which would be to contract the blood vessels to increase blood pressure back to its normal range. Or the frog can detect an external change, as he plunges into the water he feels wet, and he responds by kicking his legs and swimming away. As we have established before, the big difference when it comes to somatic and visceral behaviours is interaction with the external vs the internal. 6 Visceral vs Somatic nervous system THE VISCERAL NERVOUS SYSTEM I The nervous system has distinct divisions or Somatic - sense the environment and respond by shaping branches for visceral and somatic bodily motions. sensorimotor behaviours. Visceral - sense the interior milieu and respond by The are located in different parts of the regulating vital functions (homeostatic). nervous system and express different genes. OFFICE | FACULTY | DEPARTMENT 7 The difference is also represented in the nervous system. It is organized in a way where the parts that regulate the internal environment are located in different places and express different genes from those parts that interact with the external environment. Todays lecture will cover the visceral part of the nervous system and focus on how it is arranged in space. 7 Visceral vs Somatic Origins THE VISCERAL NERVOUS SYSTEM I mollusca (invertebrates) abdominal ganglion (Phox2) Visceral and somatic duality was established early in the evolution of the nervous system. Visceral neurons have distinct ontogenetic origins to somatic neurons abdominal + buccal + Viseral and Somatic duality in the nervous pleural ganglia (visceral) system is based in the differential pedal ganglion (somatic) expression of genes DOI: 10.1186/1741-7007-11-54 pedal ganglion (Brn3) Phox2 transcription factor homologues “make” neurons become visceral during development OFFICE | FACULTY | DEPARTMENT 8 The visceral and somatic divisions of the body are controlled by distinct branches of the nervous system that were established long before the evolution of the vertebrate body plan. When we look at the nervous system of distantly related animals like mollusks, we can see a clear division in the parts of the nervous system that participate in visceral sensorimotor circuits and somatic sensorimotor circuits. The neurons in the pleural, buccal and abdominal ganglia that control feeding, respiration and regulation internal organs, shown in blue are spatially distinct from those that control locomotion located in the pedal ganglion shown in red. This spatial division is made even clearer when we lay the nervous system out flat. More importantly these ganglia also display differences in the types of genes they express. The pedal ganglion that serve locomotion express Brn3 which we can see here in black and the abdominal ganglion the regulates the internal organs express Phox2 shown here in black. These two genes are transcription factors which we established in the development lecture are important in deciding the fate or specification of neurons during development. We know that this transcription factor Phox2 as well as its homologues is very important in specifying the neurons that will participate in visceral sensorimotor circuits. These genes, in particular phox2, remain an important feature for the development of the complex nervous systems of vertebrates whose closest common ancestor to the snail lies over 600 million years in the past. The take home message of this slide is that the visceral and somatic divisions of the nervous system were established before the evolution of complex nervous systems and that Somatic and visceral neurons have a distinct developmental and evolutionary 8 origins, which are founded in the expression of different genes. 8 Visceral vs Somatic Origins THE VISCERAL NERVOUS SYSTEM I Invertebrate chordates, live separate somatic and visceral lives. Somatic: lecithotrophic (non-feeding), free “sea squirt” swimming larva https://commons.wikimedia.org/wiki/File:Uroc004b_Jon.png DOI: (10.1111/j.1440-169X.2012.01343.x) Visceral: Sessile (stationary) adult. https://commons.wikimedia.org/wiki/Fil https://commons.wikimedia.org/w/index.php?curid e:Uroc005b.png =5633976 DOI 10.3389/978-2-88976-053-4 OFFICE | FACULTY | DEPARTMENT 9 Our more closely related invertebrate chordate ancestors like this “sea squirt” lived almost entirely visceral or somatic life styles over the different stages of their life. First as a free swimming, non feeding larva and then after permanently affixing itself to a rock, transitioning to a sessile adult that feeds through sucking in and expelling water. 9 Visceral vs Somatic Origins THE VISCERAL NERVOUS SYSTEM I “sea squirt” (urochordate) Somatic: Lecithotrophic “sea squirt” (non-feeding), free (urochordate) swimming larva Visceral: Sessile (stationary) adult. “tadpole” (vertebrate) dual visceral and somatic animal OFFICE | FACULTY | DEPARTMENT 10 We can see these 2 different life stages or lifestyles represented in the body plan of modern vertebrates shown here via this tadpole. A visceral part for breathing and feeding and a somatic part for moving around. The point of all this is to say that vertebrates have inherited a nervous system that has treated somatic and visceral behaviours as two very distinct entities in the past which, we have established in previous slides is consequence of expressing different genes. These ontogenetic differences emphasize that the division between the somatic and visceral branches of the nervous system are more than mere anatomical demarcation but a consequence of different genetic and evolutionary processes. 10 Visceral vs Somatic Origins THE VISCERAL NERVOUS SYSTEM I “sea squirt” “mouse” -vertebrate Visceral: Sessile https://doi.org/10.1073/pnas.0600805103 Phox2 (stationary) adult. Phox2b OFFICE | FACULTY | DEPARTMENT 11 I mentioned earlier that the Phox2 is important genetic factor for visceral neurons. In green we can see Phox expression in the visceral neurons of the sea squirt that control its respiratory and feeding behaviours, driving the bellowing action that pumps sea water in and out of its internal cavity. This genetic coding for visceral neurons is persistent, specifying the neurons in the vertebrate nervous system that perform visceral functions. In green we can see the expression of the Phox2b, a mammalian homologue of Phox2 in a mouse embryo, in neurons that perform functionally analogous behaviours to those in the sea squirt. These motor neurons help control the muscles of the head and neck during feeding and breathing. We viscend photos 11 Visceral vs Somatic Origins THE VISCERAL NERVOUS SYSTEM I “sea squirt” “mouse” -vertebrate Visceral: Sessile https://doi.org/10.1073/pnas.0600805103 Phox2 (stationary) adult. Phox2b OFFICE | FACULTY | DEPARTMENT 12 12 What is the visceral nervous system THE VISCERAL NERVOUS SYSTEM I What is the VNS? A series of interconnected ganglia, nerves and brain centres that: sense changes in the internal environment and generate appropriate responses to these environmental changes to ensure internal stability (homeostasis). are recruited to meet the physical and metabolic demands of behaviour. Sensory organs (afferent) → Processing centres →Effector organs (efferent) OFFICE | FACULTY | DEPARTMENT 13 The visceral nervous system is a network of interconnected nerves, ganglia and brain centres that regulate internal bodily state. In this schematic on the right we can see a summary of the circuit formed by the different branches of the VNS shown in red. On the left are the afferent branches that relay sensory information to the brainstem, the brain centres in the medulla that integrate and process this information to produce appropriate responses that will then be executed by the efferent nerves to the visceral organs. 13 Visceral Nervous System (Peripheral Overview) THE VISCERAL NERVOUS SYSTEM I Visceral Nervous System (VNS) = nerves, ganglia and brain nuclei that support internal state. Anatomical Divisions: -Visceral Afferents (Sensory) -Special Visceral Efferents (Motor) -Autonomic Nervous System (Motor) https://commons.wikimedia.org/wiki/File:Gray698.png -Sympathetic -Parasympathetic -Enteric DOI: 10.4199/C00039ED1V01Y201107ISP026 OFFICE | FACULTY | DEPARTMENT 14 In this lecture we will focus on the peripheral aspects of the visceral nervous system. These can be divided into anatomically distinct branches. The visceral afferents, the special visceral efferents and lastly the autonomic nervous system which can be further divided into its sympathetic, parasympathetic and enteric divisions. 14 Visceral Nervous System (Peripheral Overview) THE VISCERAL NERVOUS SYSTEM I Visceral Nervous System (VNS) = nerves, ganglia and brain nuclei that support internal state. Anatomical Divisions: -Visceral Afferents (Sensory) -Special Visceral Efferents (Motor) -Autonomic Nervous System (Motor) https://commons.wikimedia.org/wiki/File:Gray698.png -Sympathetic -Parasympathetic -Enteric OFFICE | FACULTY | DEPARTMENT 15 We will begin with the visceral afferents 15 Visceral Nervous System (Sensory - Afferents) THE VISCERAL NERVOUS SYSTEM I Visceral Sensory Ganglia Unifying Features Geniculate (VII) – Taste (SV) – anterior 2/3 tongue Convey interoceptive sensory information Petrosal (IX) – Taste (SV) – posterior 1/3 tongue Pseudo-unipolar sensory – Chemo (GV) – neurons – Mechano (GV) – Located within the head carotid bifrication Terminate within the brainstem at the nucleus of the solitary tract (NTS) doi: 10.1007/s11906-020-1024-x Nodose (X) – Chemo (GV) – – Mechano (GV) – visceral organs https://commons.wikimedia.org/wiki/File:Gray698.png OFFICE | FACULTY | DEPARTMENT 16 The visceral afferents consist of 3 distinct sensory ganglia located in the head. These ganglia contain pseudo-unipolar sensory neurons that innervate different visceral organs and convey interoceptive sensory information from the body to the brainstem. The geniculate ganglion conveys special visceral information regarding taste from the anterior 2/3rds of the tongue and travels via cranial nerve 7, the facial nerve. The petrosal ganglion conveys both special visceral taste information from the posterior 3rd of the tongue and general visceral information from chemoreceptors and mechanoreceptors located in the carotid bifrication and travels via the 9th cranial nerve, the glossopharyngeal nerve. The nodose travels via cranial nerve 10, the vagus nerves and provides the general visceral sensory innervation for the rest of the body. 16 Visceral Nervous System (Visceral Efferents) THE VISCERAL NERVOUS SYSTEM I Cranial (Efferents) Mesencephalic outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the eye (cranial nerve III) Medullary outflow – 7 9 10 Parasympathetic preganglionic nerves – Parasympathetic ganglia of the head, neck and body (cranial nerves VII, IX and X) Branchiomotor nerves (special visceral) – Branchial Muscles of the head and neck (cranial nerves V, VII, IX, X, XI) Spinal (Efferents) 5791011 Thoracic/Lumbar outflow – Sympathetic preganglionic nerves – Para + Pre-vertebral ganglia Sacral outflow – Parasympathetic preganglionic nerves – Pelvic ganglia OFFICE | FACULTY | DEPARTMENT 17 On this slide we have an overview of the different efferent projections of the visceral nervous system. The schematic on the left shows the vertebrate nervous system truncated at the mesencephalon. The autonomic nerves and ganglia and the special visceral efferents are shown in blue. Generally, the parasympathetic preganglionic neurons and special visceral efferent neurons are located in the brain and innervate their targets via the cranial nerves. Sympathetic preganglionic neurons are located in the thorasic and lumbar regions of the spinal cord and innervate sympathetic ganglia via short nerves. Lastly, the parasympathetic preganglionic neurons that control the pelvic organs are located at sacral end of the spinal cord 17  Visceral Nervous System (Peripheral Autonomic) THE VISCERAL NERVOUS SYSTEM I Cranial (Efferents) Mesencephalic outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the eye (cranial nerve III) Medullary outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the head neck and body (cranial nerves VII, IX and X) Branchiomotor nerves (special visceral) – Branchial Muscles of the head and neck Spinal (Efferents) Thoracic/Lumbar outflow – Sympathetic preganglionic nerves – Para + Pre-vertebral ganglia Sacral outflow – Parasympathetic preganglionic nerves – Pelvic ganglia https://commons.wikimedia.or g/wiki/File:Gray839.png OFFICE | FACULTY | DEPARTMENT 18 We will now cover the sympathetic and parasympathetic divisions of the autonomic nervous system. 18  Visceral Nervous System (Sympathetic) THE VISCERAL NERVOUS SYSTEM I Cranial (Efferents) Mesencephalic outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the eye (cranial nerve III) Medullary outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the head neck and body (cranial nerves VII, IX and X) Branchiomotor nerves (special visceral) – Branchial Muscles of the head and neck Spinal (Efferents) Thoracic/Lumbar outflow – Sympathetic preganglionic nerves – Para + Pre-vertebral ganglia Sacral outflow – Parasympathetic preganglionic nerves – Pelvic ganglia https://commons.wikimedia.or g/wiki/File:Gray839.png OFFICE | FACULTY | DEPARTMENT 19 19  Visceral Nervous System (Sympathetic) THE VISCERAL NERVOUS SYSTEM I Spinal (Efferents) Cholinergic preganglionic neurons located in the intermediolateral cell column (IML) (T1-L2) project to nor-adrenergic ganglionic neurons located in the sympathetic chain (para-vertebral) and pre-aortic ganglia (pre-vertebral). Choline acetyltransferase Tyrosine hydroxylase https://commons.wikimedia.or g/wiki/File:Gray839.png DOI: 10.1016/j.jns.2012.08.026 doi: 10.1111/nyas.14119. OFFICE | FACULTY | DEPARTMENT 20 Sympathetic preganglionic neurons are cholinergic and are located in the intermediolateral cell column (IML) from the (T1-L2) segments of the spinal cord. They project to ganglionic neurons located outside of the spinal cord, in the sympathetic chain or pre-aortic ganglia. These ganglionic neurons synthesise the transmitter, nor- adrenaline and enzymes like tyrosine hydroxylase. 20 Visceral Nervous System (Sympathetic) THE VISCERAL NERVOUS SYSTEM I Sympathetic Ganglia Cervical (Chain) Superior Cervical Middle Cervical Stellate Thoracic (Chain) Pre-aortic – innervated by the splanchnic nerves Celiac Superior mesenteric Inferior mesenteric Adrenal Gland –innervated directly by splanchnic nerves ISBN : 9786611021115 OFFICE | FACULTY | DEPARTMENT 21 The anterior most part of the sympathetic chain runs parallel to the cervical spinal cord and are referred to as the cervical sympathetic ganglia. There are usually between 2- 3 cervical ganglia in humans, the superior cervical, the middle cervical and the stellate, which provide the sympathetic innervation of the head, the heart and the lungs. The rest of the sympathetic chain runs parallel to the thoracic spinal cord and provides sympathetic innervation to the body There are 3 sympathetic ganglia that are located outside of the sympathetic chain, located ventral to the spinal. These are called the pre-aortic ganglia or pre-vertebral ganglia. These ganglia are innervated by the splanchnic nerves that emerge from the spinal cord and travel through the chain ganglia. These are the celiac, superior mesenteric and inferior mesenteric which provide sympathetic innervation to gut. Lastly, the adrenal gland receives no ganglionic innervation and is innervated directly from the spinal cord via splanchnic nerves. 21 Visceral Nervous System (Sympathetic) THE VISCERAL NERVOUS SYSTEM I Sympathetic Ganglia Sympathetic chain (paravertebral chain) Cervical Superior Cervical Middle Cervical Stellate Thoracic Pre-aortic (pre-vertebral) innervated by the splanchnic nerves Celiac Superior mesenteric Inferior mesenteric Adrenal Gland –innervated directly by splanchnic nerves ISBN : 9786611021115 OFFICE | FACULTY | DEPARTMENT 22 Now looking from a coronal view we can get a better idea of how the sympathetic chain and pre-aortic ganglia are positioned relative to the spinal cord and to each other. The spinal cord is surrounded by a vertebral bone represented here by this green line. The sympathetic chain runs parallel to the vertebrae, hence the alternative name for this ganglion, the paravertebral ganglion. Again this includes both the cervical and thoracic parts of the chain. The pre aortic ganglia, are located ventral to the vertebrae and below the aorta, hence the name pre-aortic or pre-vertebral ganglia. This is represented by the purple line. We can also see that these more distant ganglia are innervated by sympathetic nerves called splanchnic nerves that first travel travel through the chain. This is highlighted in red. 22 Visceral Nervous System (Sympathetic) THE VISCERAL NERVOUS SYSTEM I Example: The celiac ganglion (pre-aortic) provides sympathetic innervation of the pancreas. Sympathetic nerves release adrenaline onto beta cells within the islet, blocking insulin secretion. DOI: 10.1007/s00125-017-4409-x OFFICE | FACULTY | DEPARTMENT 23 Sympathetic ganglia are located far way from their targets. In this example sympathetic ganglionic neurons located in the celiac ganglion travel all the way to the pancreas to innervate their targets in the pancreatic islets. On the left we can see the axons and terminals of sympathetic ganglionic neurons shown in white, as they enter the pancreatic islets and wrap around the beta cells shown in red. The activation of these sympathetic fibres will release adrenaline onto the beta cells, binding to adrenergic receptors and blocking the secretion of insulin. wrap around pancreas celiac ganglion pan beta cells to target Sympathenngions creatine islets sympatti theatre onto bite cells gaffer binding receptors insulin beating jaction as 23  Visceral Nervous System (Parasympathetic) THE VISCERAL NERVOUS SYSTEM I Cranial (Efferents) Mesencephalic outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the eye (cranial nerve III) Medullary outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the head neck and body (cranial nerves VII, IX and X) Branchiomotor nerves (special visceral) – Branchial Muscles of the head and neck Spinal (Efferents) Thoracic/Lumbar outflow – Sympathetic preganglionic nerves – Para + Pre-vertebral ganglia Sacral outflow – Parasympathetic preganglionic nerves – Pelvic ganglia https://commons.wikimedia.or g/wiki/File:Gray839.png OFFICE | FACULTY | DEPARTMENT 24 Now we will cover the parasympathetic nervous system. Starting the with the parasympathetic preganglion neurons of the mesencephalon. 24 Visceral Nervous System (Parasympathetic) THE VISCERAL NERVOUS SYSTEM I Parasympathetic Mesencephalic outflow – Midbrain Preganglionic neurons (cholinergic) located within the Edinger-Westphal nucleus – project through CN III (inferior branch) – ciliary ganglion (cholinergic) – innervate the iris and ciliary body (lens) Pupillary reflex and accommodation on cit ay ganglion neurons CN 11 cigar cholinergic Preganglionic Westphal branch innervate theftp.andy located in Edinger body OFFICE | FACULTY | DEPARTMENT 25 nucleus These neurons are cholinergic and are located within part of the midbrain, called the oculomotor complex, which contains the motor neurons that innervate most of the extrinsic eye muscles. The pre-ganglionic neurons are located within a specific part of the oculomotor complex called the Edinger-Westphal nucleus. The preganglionic neurons project via the 3rd cranial nerve, the oculomotor nerve, specifically its inferior branch and innervate a small cluster of parasympathetic ganglionic neurons located at the back of the eye, called the ciliary ganglion. The ciliary ganglion neurons are also cholinergic and innervate the muscles of the ciliary body and the iris. Parasympathetic innervation of these structures are important for the pupillary reflex in response to different levels of light as well as accommodation of the lens to focus near or distant light onto the retina. Jo 25 Visceral Nervous System (Parasympathetic) THE VISCERAL NERVOUS SYSTEM I Pontine/medullary outflow – VII and IX Pontine nuclei 7 9 Superior salivatory nucleus (cholinergic) – via VII – Pterygopalatine (Sphenopalatine) ganglion (cholinergic) – Lacrimal gland / nasal mucosa / palate – via VII – Submandibular (Submaxillary) ganglion) ganglion (cholinergic) – Submandibular and Sublingual salivary glands / oral mucosa Inferior salivatory nucleus (cholinergic) – via IX – Otic ganglion (cholinergic) – Parotid gland OFFICE | FACULTY | DEPARTMENT 26 Moving on from the midbrain we will cover the parasympathetic preganglionic populations of the brainstem. The first 2 are located in the pons. They are the superior salivatory nucleus and the inferior salivatory nucleus. These preganglionic neurons are cholinergic and innervate parasympathetic ganglia located in the head and neck. The superior salivatory nucleus innervates the pterygopalatine ganglion and submandibular ganglion, via the facial nerve. These ganglia contain cholinergic neurons that innervate the lacrimal glands, the salivary glands and the oral, nasal and palatal muscosa. The inferior salivatory nucleus innervates the otic ganglion via the glossopharyngeal nerve. The otic ganglion contains cholinergic neurons that innervate the parotid gland. 26 Visceral Nervous System (Parasympathetic) THE VISCERAL NERVOUS SYSTEM I Medullary outflow – X Dorsal Motor Nucleus of the Vagus / Nucleus Ambiguus (cholinergic) – via X – “the rest of the body” small ganglia located within target organs e.g. heart and lungs and directly with the enteric plexus DOI: 10.1007/s00125-017-4409-x Parasympathetic – insulin release OFFICE | FACULTY | DEPARTMENT 27 The last population of cranial parasympathetic pre-ganglionic neurons are those located in the medulla. They are distributed across two closely located nuclei, the dorsal motor nucleus of the vagus and the nucleus ambiguous. Again these pre-ganglionic neurons are cholinergic. They project via the vagus nerve and provide the efferent parasympathetic innervation to small parasympathetic ganglia located close to or embedded within the visceral organs of the body. Using the pancreas as an example we can see the parasympathetic preganglionics shown in cyan project all the way into the pancreas to innervate the target ganglion, located right next to the pancreatic islet shown in red. The cholinergic neurons in the ganglion then project over a short distance to the islet, where they can release acetyle choline, driving insulin release from beta cells. 27 Visceral Nervous System (Pelvic) THE VISCERAL NERVOUS SYSTEM I Cranial (Efferents) Mesencephalic outflow – Parasympathetic preganglionic nerves – Parasympathetic ganglia of the eye (cranial nerve III) Medullary outflow –