Clinical Neurobiology Fall 2024 Course Outline PDF

Clinical Neurobiology: Fall 2024 146:447:01, Tues. & Thurs. 5:40 –7:00 PM; Tillett Hall 232, Livingston Campus September 3, 2024 Professors: Grumet & Young Introduction to Course and Neurobiology 1...

Clinical Neurobiology: Fall 2024 146:447:01, Tues. & Thurs. 5:40 –7:00 PM; Tillett Hall 232, Livingston Campus September 3, 2024 Professors: Grumet & Young Introduction to Course and Neurobiology 1 Which arrow paralyzed the lion? 2 3 North Palace of Nineveh, circa 645-635 BC  Clinical Neurobiology Research Experience of the Instructors – Martin Grumet– Course Organizer Stem Cells, Spinal cord injury and glioblastoma – Wise Young Spinal cord injury, repair, clinical trails and stem cells Course consists of 4 modules.  Module 1: CNS Development & Stem Cells Instructor: Grumet 9/3: Course Introduction, and Intro to Neurobiology 9/5: Embryo Development to Neural Cells 9/10: CNS and Neuronal Development 9/12: Neural stem cells, Lineage and Induced Cells 9/17: Effects of Zika virus and COVID in the CNS 9/19: Immunological Basis of Neural Disorders 9/24: Cancer Stem Cells and Review for Exam 1 9/26: Exam Module 1  Module 2: SCI Regeneration and Neurogenesis Instructor: Young 10/1: Debunking SCI Dogmas 10/3: Walking Recovery after SCI (spinal cord injury) 10/8: Neuro Regeneration 10/10: Spinal Cord Regeneration 10/15: Lithium Treatment of Down Syndrome and Severe Neuropathic Pain 10/17: Regeneration vs. Neurogenesis and Review for Exam 2 10/22: Exam on Module 2  Module 3: CNS Disorders and Therapies Instructor: Young 10/24: Clinical Trial Ethics 10/29: Umbilical Cord Blood Exosomes Therapy 10/31: Glaucoma & Macular Degeneration 11/5: Traumatic Brain Injury 11/7: What are prions and what do they do? 11/12: Prion diseases of the brain and eye, and review for Exam 3 11/14: Exam on Module 3  Module 4: Neural Diseases & Disorders Instructor: Grumet 11/19: Intracellular Transport Mechanisms in Normal Neurons and Disease 11/21: ALS is a Neurodegenerative Disease 11/26: Stem Cells and Spinal Cord Injury 12/3: Alzheimer’s Disease 12/5: Parkinson’s Disease and Stem cells 12/10: Huntington’s Disease and Review for Final Exam Final: TBD Human Neurological Diseases & Disorders Genetic & Environmental Injuries & Insults Myelinating Diseases Spinal Cord Injury (SCI) o Multiple Sclerosis (MS) Traumatic Brain Injury (TBI) o Guillane Barre Amyotrophic lateral sclerosis (ALS) Stroke Alzheimer’s Disease (AD) Parkinson’s Disease (PD) Infections Huntington’s Disease (HD) Zika Brain Tumors o Glioblastoma (GBM) COVID-19 o Medulloblastoma Prions Down syndrome Macular Degeneration 7  Clinical Neurobiology 4 Exams & Grading o Each exam = 1/4 of the grade o Exams consist of multiple choice and T/F o Papers will be assigned in each module. o Highly discourage makeups, need to arrange in advance with justification. Contacts o Grumet: [email protected] o Young: [email protected] Student support hours in Nelson D251 o Tuesdays from 12:10 PM – 1:10 PM o Thursdays from 2:00 PM – 3:00 PM  Clinical Neurobiology No Textbook assigned Study Guides as a source for background o ESSENTIAL CELL BIOLOGY 6th Edition by Bruce Alberts, ISBN 9781324033394 o NEUROSCIENCE 6th Edition by Dale Purves, ISBN-13: 978-1605353807 Papers o Discussed at Student support sessions on: Tuesdays from 12:10 PM – 1:10 PM or Thursdays from 2:00 PM – 3:00 PM Lectures o Slides will be posted on Canvas before lecture o Lectures will be recorded Exams o There will be a review before each exam o Study lecture notes and papers for exam  Clinical Neurobiology Papers Two papers related to the lectures will be discussed in each Module. You will be provided on the Canvas Homepage with the papers along with Study Guides for each one prior to discussion sessions. Your assignment is to read relevant parts of the papers using the guides so that you will be prepared to discuss the papers in the student support sessions. There will be two sessions for each paper. The same material will be presented at both sessions, so there is no need to attend both sessions; one is sufficient to learn key elements of the papers. Each paper will relate to one question in the exam for that Module. All student support sessions will take place in Nelson D251 Conference Room on Busch Campus.  Clinical Neurobiology Papers Module 1 Papers Lecture: Thurs 9/5 lecture will introduce the glymphatic system. Paper 1: “Glymphatic failure as a final common pathway to dementia” By Maiken Nedergaard and Steven A. Goldman Review sessions: Tues 9/10: Student support session 12:10 - 1:10 PM Thurs 9/12: Student support session 2:00 - 3:00 PM  Clinical Neurobiology Review & Sample Questions Which tissue shares a developmental origin with brain? A. Skull B. Skin C. Intestine D. Muscle E. Kidney Answer: skin Both are derivatives of the embryonic ectoderm  Review & Sample Questions: Best Answer Which neural cells do not normally proliferate in the adult CNS? A. Neurons B. Astrocytes C. Oligodendrocytes D. Neurons and Oligodendrocytes E. Neurons and Astrocytes Review & Sample Questions: Best Answer Which neural cells do not normally proliferate in the adults CNS? A. Neurons B. Astrocytes C. Oligodendrocytes D. Neurons and Oligodendrocytes E. Neurons and Astrocytes Best Answer: D Neurons and Oligodendrocytes. Both are post-mitotic cells. These are polarized cells with complex structures, they often die when stimulated to proliferate.  Review & Sample Questions: Best Answer Which of the following is a type of neuronal cell death? A. Excitotoxicity B. Apoptosis C. Necrosis D. Anoikis E. All of the above Best Answer: E All of the above They all are different types of cell death.  Review & Sample Questions: Best Answer Which of these is a neurotrophin? A. Serotonin B. Acetylcholine C. BDNF D. IL-1 E. Insulin  Review & Sample Questions: Best Answer Which of these is a neurotrophin? A. Serotonin B. Acetyl choline C. ANSWER = BDNF (brain derived neurotrophic factor) D. IL-1 E. Insulin What is a neurotrophin? – ANSWER: a molecule that nourishes, protects and/or guides a neuron or its processes. Which of the remaining choices are arguably neurotrophins?  Review & Sample Questions: Best Answer Which of the remaining choices are arguably neurotrophins? A. Serotonin: promotes survival of adult neurons B. Acetyl choline C. BDNF D. IL-1 E. Insulin: promotes survival of neurons in development & adult  Clinical Neurobiology Course materials including lecture notes are available in Canvas on the Home Page. General Questions About the Course?  Introduction to Neurobiology: Nomenclature What is a Nerve? A Nerve is bundle of axons that contains glial cells. Astrocytes and Oligodendrocytes in the CNS. Example: Optic nerve contains axons and glia but no neuron cell bodies. Schwann cells in the PNS. Example: Sciatic nerve axons are myelinated by Schwann cells What are Nerve Cells? They should be called neural cells, which includes both Neurons (neuronal cells) single nerve cell Glia (glial cells: astrocytes and oligodendrocytes)  Historical Overview and Refresher Diverse Neuronal Morphologies (Historical Perspective) o Golgi silver stain (1900) o Electron microscopy (1930) Use of Fluorescence to detect molecules & cells (1960’s) Brain Imaging: Computerized Tomography & MRI (1970’s) Proteins and antibodies (Mab) (1960’s) Genes & the Nervous System (1980’s) Molecular genetics (PCR, transgenics, CRISPR…) Visualizing Neural Cells 19th-21st Century Golgi Silver Stain (~1900) Cortical Neurons Purkinje Cells Silver (black) is taken up only by a small subset of cells in tissues, but it gets distributed throughout the entire cell including in axons and dendrites. Shows detailed images of individual cells within complex neural tissue. Used by Ramon y Cajal for his pioneering research in neuroanatomy.  Neuron Doctrine: Nervous system made up of discrete cells Golgi Silver Stain of Cerebral Cortical Neurons (~1900) Detection of Neuron Cell Bodies and Their Processes They did not have cameras, they drew diagrams. Golgi Silver Stain of Purkinje Cells in Cerebellum: Drawings based on Golgi Stains (~1900) Neuron Doctrine: Nervous system made up of discrete cells Drawing During development neuronal complexity develops through sequential stages of interactions among cells within tissues. Purkinje cells in cerebellum = have highly branched dendrites. Purkinje cell axons project to deep cerebellar nuclei.  Retinal Ganglion Cells Project Signals to the Brain via the Optic Nerve Receive visual information from Regeneration of retinal neurons occurs in photoreceptors via bipolar cells Zebrafish but not in mammals. & transmit visual information via What are signals for regeneration in Zebrafish? the optic nerve to the brain for Can they be recapitulated in mammals? processing images. cell body > Axos > - - optic newve Optic nerve Contains axons and glia  Historical and Technical Overview Diverse Neuronal Morphologies (Historical Perspective) necions and their structure Visualize Individual o Golgi stain (~1900)- detail and their structures in seen as cell body , dendrites, o Electron microscopy (~1930) revealed cell structures and axon. Use of Fluorescence to detect molecules & cells (~1960s) Brain Imaging: Computerized Tomography & MRI (~1970s) Genes & the Nervous System  Major Structures in Neurons Visualized with Electron Microscopy B Axuns. So few C. Golgi D Azens. I Gegisterin. E. Dendrite. Election 2 microscopy F Nucleus. G. Node of Revier Focus on Myelin D. Transverse section through a myelinated nerve. G. Node of Ranvier axon Compact Myelin on Central Nervous System Axons Cross section of axons Psuedo Colored Compact Myelin winds around each axon axon Oligodendrocyte Microtubules Cell body, cytoplasm & nucleus in axons  Node of Ranvier in Gap Between Myelin Sheaths Paramodel loops Longitudinal view of axon with Node of Ranvier specializedregis are at Myelin Oligodendrocyte processes where the myevir terminate as paranodal loops at Sheeth crapseround the Node of Ranvier. the exus. axon They serve to cluster Na+ channels at the Node. paranode K+ channels are in paranodes paranodal loops node Na+ channels are clustered at the Node of Ranvier. Structure Suggests Function at Synapses Electrophysiology discovered quantal activity at synapses. Terminal Electron microscopy demonstrated - boutons - synaptic vesicles, providing an explanation for a quantal mechanism of neurotransmission. Synaptic vesicles  Overview: Fluorescence Diverse Neuronal Morphologies (Historical Perspective) o Golgi silver stain (~1900). Visualization of individual cells in - tissue ~ o Electron microscopy (~1930) shows fine structure of cells. Use of Fluorescence to detect molecules & cells (~1960) Brain Imaging: Computerized Tomography & MRI (~1970s) Genes & the Nervous System  Proteins Involved in Propagation of Action Potentials Cluster at Nodes of Ranvier Immunofluorescence with specific antibodies to identify proteins. Paranode Myelin K+ channels Paranode (K+ channels) Na+ Channels Cluster at the node. Plasma membrane depolarization above threshold levels opens Na+ channels, which allow influx of Na+ Node of and propagation of action potentials Ranvier that move anterograde. Outflow of K+ through K+ channels in Paranode hyperpolarizes the membrane preventing retrograde backflow of action potentials. Time Action Potential Resting potential  Fluorescence Microtubule Cytoskeleton in Neurons Tubulin in cell body, axons and dendrites detected by antibodies that bind to tubulin (immunofluorescence). Microtubules play important roles in axonal transport. Intracellular Injection of Dye into Live Retinal Neurons Fills Cell Bodies and Penetrates into Dendrites Fluorescent dye micro- injected into neurons. dendrites Microinjection of fluorescent dyes into single cells, illuminate cell bodies, axons and dendrites in live cells. axon  Overview: Brain Imaging Diverse Neuronal Morphologies (Historical Perspective) o Golgi stain (~1900) o Electron microscopy (~1930) Use of Fluorescence to detect molecules & cells (~1960s) Brain Imaging: Computerized Tomography & MRI (~1970s) Genes & the Nervous System  Computerized Tomography (CT Scan) X-ray source and detector are moved around the individual’s head to obtain 2-D images of planes through the brain. Computerized analysis of Multiple 2-D scans are used to create 3-D images. Computerized axial tomography (CAT) Tomography – slice recording cross sectional of recording the brevd - Altered CT scan patterns showing differences in cell densities indicate damage or tumor growth. CT Scan of Tumor in Adult Brain tumor CT X-ray scans are very useful in detecting brain lesions that have - different tissue densities than the surrounding brain tissue. White area shows a brain tumor and the skull. However, CT uses X-rays, which can damage tissues.  Magnetic Resonance Imaging (MRI) grey matter white matter Ventricle CSF Pulses of radio waves excite the nuclear spin of hydrogen atoms and magnetic field gradients localize the relaxation signal in space. Rapid relaxation of hydrogen (protons) occurs in water (black) but relaxation is very slow in lipids (white). Ventricles filled with cerebrospinal fluid (CSF) are black. Gray matter is colored gray, and white matter rich in lipid membranes are white. Excellent for visualizing myelin and fluids in the brain. -  Overview Diverse Neuronal Morphologies (Historical Perspective) o Golgi stain (~1900) o Electron microscopy (~1930) Use of Fluorescence to detect molecules & cells (~1960s) Brain Imaging: Computerized Tomography & MRI (~1970s) Genes & the Nervous System  Many Genes are Selectively Expressed in the Nervous System Of ~20,000 human genes, ~8,000 are expressed in all cells. There are about ~6,000 genes expressed selectively in the nervous system and a similar number in the rest of the body. Venn diagram of the human genome. A very large fraction of our genes are specifically expressed in the nervous system. In this course we will focus on a subset of genes that play critical roles in normal nervous system function and in disorders.  Example: Mutations Cause Disease Point mutation in ASPM (Abnormal Spindle-like Microcephaly- associated protein) results in microcephaly (small brain). Mutation in ASPM normal Causes Microcephaly Proper development and orientation of the mitotic spindle is critical for generation of new neurons. Disruption by mutation in ASPM results in fewer neurons born during development. Abnormal Spindle-like Microcephaly · Infection with the Zika virus also causes microcephaly. Reasons to Understand CNS Development It’s the blueprint for building and repairing the CNS. Try to fix a car without a manual. Factors that control cell development and fate (e.g., TF) are often involved in disease. Studying development will help: o To recapitulate cell and tissue development with a view towards regeneration and therapeutics. o To identify disease mechanisms as abnormal changes in developmental genes and factors. o To modify the extracellular environment (e.g., ECM, fate- determining and growth factors) to enable migration, integration and differentiation of transplanted stem cells.  Take Home Messages Neuroanatomy Neuron Doctrine. Structure provides clues to function. Markers and Imaging tools are critical to study cells and tissues. Genetics provides tools to study normal CNS function and disease. Questions 44