7/26/10 Pan W

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7/26/10 Pan W

  1. 1. Introduction to Neurobiology of Disease <ul><li>Overview of neurological disorders </li></ul><ul><li>Common mechanisms </li></ul><ul><li>Animal models </li></ul><ul><li>Integration of basic and clinical perspectives </li></ul>
  2. 2. Approaches to neurological diseases <ul><li>1. Localization in the neuraxis </li></ul><ul><li>Focal vs multifocal vs diffuse </li></ul><ul><li>CNS – cerebrum, WM, BG, thalamus, hypothalamus, cerebellum, CNI-II, BS, SC </li></ul><ul><li>PNS – CNIII-XII, cauda equina, roots, plexuses, peripheral nerves, NMJ </li></ul><ul><li>Muscle </li></ul>
  3. 3. Approaches to neurological diseases <ul><li>2. Categorization – nature of the lesion </li></ul><ul><ul><li>Congenital or developmental </li></ul></ul><ul><ul><li>Vascular </li></ul></ul><ul><ul><li>Neoplastic </li></ul></ul><ul><ul><li>Traumatic </li></ul></ul><ul><ul><li>Systemic – toxic </li></ul></ul><ul><ul><li>Degenerative </li></ul></ul><ul><ul><li>Infectious </li></ul></ul><ul><ul><li>Inflammatory, autoimmune, or demyelinative </li></ul></ul><ul><ul><li>Epileptic </li></ul></ul><ul><ul><li>Psychiatric </li></ul></ul>
  4. 4. Approaches to neurological diseases <ul><li>3. Pattern recognition through history and exams </li></ul><ul><li>Paroxysmal vs acute vs chronic time course </li></ul><ul><li>Neurological symptoms and examination make the specialty specific </li></ul><ul><li>Tests of CSF, imaging, neuropathology, neurophysiology (EMG & EEG), and CNS functions (fMRI, SPECT, neuropsychological testing) </li></ul><ul><li>Many syndromes </li></ul>
  5. 5. Neurobiological mechanisms <ul><li>Development </li></ul><ul><li>Excitability </li></ul><ul><li>Programmed cell death </li></ul><ul><li>Repair </li></ul>
  6. 6. Ramon y Cajal <ul><li>Neuroembryology </li></ul><ul><li>Wilhelm His (1831 – 1904) </li></ul><ul><li>Santiago Ramon y Cajal (1852 – 1934) </li></ul><ul><li>Synapse </li></ul><ul><li>Growth cone </li></ul><ul><li>Tropisms </li></ul><ul><li>Contiguity vs continuity </li></ul><ul><li>Protoplasmic outgrowth vs cell chains </li></ul><ul><li>& other models in the origin of nerve </li></ul><ul><li>fibers </li></ul>
  7. 7. Surface ectoderm (primary epidermis) Neural crest (peripheral nerves, pigment, facial cartilage) Neural tube (brain and spinal cord)
  8. 8. Interestingly, the vascular endothelial cells forming the BBB are from the mesoderm…
  9. 9. TEM picture of a growth cone “ neural crest cells on a leash” -The locomotor organelle of the neuron -Senses environmental cues tubulin actin in filopodia (phalloidin staining)
  10. 10. Development <ul><li>Migration & Synaptogenesis </li></ul><ul><li>- cortical proliferation zones; cortical lamination; radial glia; gliogenesis and myelination; synaptic targeting </li></ul><ul><li>Activity-dependent plasticity in developing neural circuits </li></ul><ul><li>-abnormal cell migration, sprouting, or connectivity  neonatal seizures </li></ul><ul><li>Glial-neuronal interactions </li></ul>
  11. 11. Animal models - dismyelination and demyelination <ul><li>Trembler mouse: defective Schwann cells </li></ul><ul><li>Jimpy mouse: meylin deficiency in the CNS </li></ul><ul><li>EAE: autoimmune demyelination </li></ul>
  12. 12. Animal models for epilepsy <ul><li>Tottering, lethargic, ducky, stargazer, stargazer-3 Jackson, waggler </li></ul><ul><li>Defective voltage-dependent Ca channel </li></ul><ul><li>Models for absence seizures </li></ul>
  13. 13. Excitability <ul><li>Mechanisms of excitability: membrane receptors, intracellular events, depolarization-induced injury </li></ul><ul><li>Epilepsy: abnormal synchronization </li></ul><ul><li>Ion channel diseases – channelopathies affecting nerve, muscle, and the brain </li></ul>
  14. 14. Copyright ©1999 by the National Academy of Sciences Cooper, Edward C. and Jan, Lily Yeh (1999) Proc. Natl. Acad. Sci. USA 96, 4759-4766 Channelopathy
  15. 15. Ion channel disorders affecting muscles and peripheral nerves <ul><li>Mutations in the pore-forming subunits of sodium and chloride channels  myotonia </li></ul><ul><li>Mutations in muscle sodium and calcium channels  periodic paralysis </li></ul><ul><li>Mutations in the sarcoplasmic calcium release channel  malignant hyperthermia </li></ul><ul><li>acetylcholine receptor mutations reduce the number of channels at the cell surface or affect rate of opening  myesthenia syndromes </li></ul>
  16. 16. Ion channel disorders in the CNS <ul><li>Neuronal Na channel: generalized epilepsy with febrile seizures plus </li></ul><ul><li>M-type K channel: benign neonatal familial convulsions </li></ul><ul><li>K channel (likely): episodic ataxia with myokymia </li></ul>
  17. 17. Best comprehensive review: http://www.neuro.wustl.edu/neuromuscular/mother/chan.html
  18. 18. Cell death in neurobiology <ul><li>Programmed cell death </li></ul><ul><li>neurodegeneration </li></ul>
  19. 19. Apoptosis <ul><li>Two phases: latent & execution </li></ul><ul><li>Genetic analysis in C. elegans: ced-3, ced-4, and ced-9 cell death genes </li></ul><ul><li>Proteins regulating apoptosis: Bcl-2 family; p53 </li></ul><ul><li>Executing proteins: caspases, scaffolding proteins, adapters, caspase activated DNase </li></ul><ul><li>Two pathways leading to cell death: the death receptor (Fas) & mitochondrial pathways </li></ul><ul><li>Apoptosis is a key factor in neurodegnerative disease </li></ul>
  20. 20. Trinucleotide repeat diseases <ul><li>Polyglutamine disease – CAG repeats </li></ul><ul><li>DRPLA (dentatorubral pallidoluysian atrophy), Huntington’s Disease, SBMA (spinal and bulbar muscular atrophy or Kennedy’s disease), SCA1,2,3,6,7 </li></ul><ul><li>Non-polyglutamine disease </li></ul><ul><li>FRAXA, FRAXE (CGG), FRDA (GAA, in intron), DM (myotonic dystrophy, CTG), SCA8, SCA12 </li></ul>
  21. 21. Animal models for neurodegeneration <ul><li>Alzheimer’s disease: APP transgenic </li></ul><ul><li>Amyotrophic lateral sclerosis: SOD1-G93A; NMD mutants (defect in Ig S-mu binding protein 2) </li></ul><ul><li>Ataxia: Harlequin mouse; cerebellar deficient folia (cdf) mouse </li></ul><ul><li>Huntington’s disease: R6/2 strain with expanded CAG repeat </li></ul><ul><li>Parkinson’s disease: alpha-synuclein transgenic </li></ul><ul><li>Spinal muscular atrophy: mutation in survival motor neuron (smn) gene </li></ul>
  22. 22. Repair <ul><li>Neurotrophins </li></ul><ul><li>Gene therapy </li></ul>
  23. 24. Pan W, CPD 11:10 &11 preface
  24. 26. Neurobiology of obesity: Nature Neurosci. April 2005
  25. 29. Integration of basic neuroscience and clinical neurology <ul><li>Treatment based on mechanisms </li></ul><ul><li>Multipotency of drugs </li></ul><ul><li>Animal models reflect certain aspects of human disorders </li></ul><ul><li>Think the organism as a whole </li></ul>
  26. 30. Summary <ul><li>Development, remodeling, and neuroplasticity </li></ul><ul><li>Excitability </li></ul><ul><li>Balance of trophic support and apoptosis </li></ul><ul><li>Neuroendocrine circuits and rewarding pathways </li></ul><ul><li>Environmental factors – the BBB, interactions between neurons and glia </li></ul>
  27. 31. What is your role as a neurobiologist? The end

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