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7/26/10 Pan W

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  • 1. Introduction to Neurobiology of Disease
    • Overview of neurological disorders
    • Common mechanisms
    • Animal models
    • Integration of basic and clinical perspectives
  • 2. Approaches to neurological diseases
    • 1. Localization in the neuraxis
    • Focal vs multifocal vs diffuse
    • CNS – cerebrum, WM, BG, thalamus, hypothalamus, cerebellum, CNI-II, BS, SC
    • PNS – CNIII-XII, cauda equina, roots, plexuses, peripheral nerves, NMJ
    • Muscle
  • 3. Approaches to neurological diseases
    • 2. Categorization – nature of the lesion
      • Congenital or developmental
      • Vascular
      • Neoplastic
      • Traumatic
      • Systemic – toxic
      • Degenerative
      • Infectious
      • Inflammatory, autoimmune, or demyelinative
      • Epileptic
      • Psychiatric
  • 4. Approaches to neurological diseases
    • 3. Pattern recognition through history and exams
    • Paroxysmal vs acute vs chronic time course
    • Neurological symptoms and examination make the specialty specific
    • Tests of CSF, imaging, neuropathology, neurophysiology (EMG & EEG), and CNS functions (fMRI, SPECT, neuropsychological testing)
    • Many syndromes
  • 5. Neurobiological mechanisms
    • Development
    • Excitability
    • Programmed cell death
    • Repair
  • 6. Ramon y Cajal
    • Neuroembryology
    • Wilhelm His (1831 – 1904)
    • Santiago Ramon y Cajal (1852 – 1934)
    • Synapse
    • Growth cone
    • Tropisms
    • Contiguity vs continuity
    • Protoplasmic outgrowth vs cell chains
    • & other models in the origin of nerve
    • fibers
  • 7. Surface ectoderm (primary epidermis) Neural crest (peripheral nerves, pigment, facial cartilage) Neural tube (brain and spinal cord)
  • 8. Interestingly, the vascular endothelial cells forming the BBB are from the mesoderm…
  • 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. Development
    • Migration & Synaptogenesis
    • - cortical proliferation zones; cortical lamination; radial glia; gliogenesis and myelination; synaptic targeting
    • Activity-dependent plasticity in developing neural circuits
    • -abnormal cell migration, sprouting, or connectivity  neonatal seizures
    • Glial-neuronal interactions
  • 11. Animal models - dismyelination and demyelination
    • Trembler mouse: defective Schwann cells
    • Jimpy mouse: meylin deficiency in the CNS
    • EAE: autoimmune demyelination
  • 12. Animal models for epilepsy
    • Tottering, lethargic, ducky, stargazer, stargazer-3 Jackson, waggler
    • Defective voltage-dependent Ca channel
    • Models for absence seizures
  • 13. Excitability
    • Mechanisms of excitability: membrane receptors, intracellular events, depolarization-induced injury
    • Epilepsy: abnormal synchronization
    • Ion channel diseases – channelopathies affecting nerve, muscle, and the brain
  • 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. Ion channel disorders affecting muscles and peripheral nerves
    • Mutations in the pore-forming subunits of sodium and chloride channels  myotonia
    • Mutations in muscle sodium and calcium channels  periodic paralysis
    • Mutations in the sarcoplasmic calcium release channel  malignant hyperthermia
    • acetylcholine receptor mutations reduce the number of channels at the cell surface or affect rate of opening  myesthenia syndromes
  • 16. Ion channel disorders in the CNS
    • Neuronal Na channel: generalized epilepsy with febrile seizures plus
    • M-type K channel: benign neonatal familial convulsions
    • K channel (likely): episodic ataxia with myokymia
  • 17. Best comprehensive review: http://www.neuro.wustl.edu/neuromuscular/mother/chan.html
  • 18. Cell death in neurobiology
    • Programmed cell death
    • neurodegeneration
  • 19. Apoptosis
    • Two phases: latent & execution
    • Genetic analysis in C. elegans: ced-3, ced-4, and ced-9 cell death genes
    • Proteins regulating apoptosis: Bcl-2 family; p53
    • Executing proteins: caspases, scaffolding proteins, adapters, caspase activated DNase
    • Two pathways leading to cell death: the death receptor (Fas) & mitochondrial pathways
    • Apoptosis is a key factor in neurodegnerative disease
  • 20. Trinucleotide repeat diseases
    • Polyglutamine disease – CAG repeats
    • DRPLA (dentatorubral pallidoluysian atrophy), Huntington’s Disease, SBMA (spinal and bulbar muscular atrophy or Kennedy’s disease), SCA1,2,3,6,7
    • Non-polyglutamine disease
    • FRAXA, FRAXE (CGG), FRDA (GAA, in intron), DM (myotonic dystrophy, CTG), SCA8, SCA12
  • 21. Animal models for neurodegeneration
    • Alzheimer’s disease: APP transgenic
    • Amyotrophic lateral sclerosis: SOD1-G93A; NMD mutants (defect in Ig S-mu binding protein 2)
    • Ataxia: Harlequin mouse; cerebellar deficient folia (cdf) mouse
    • Huntington’s disease: R6/2 strain with expanded CAG repeat
    • Parkinson’s disease: alpha-synuclein transgenic
    • Spinal muscular atrophy: mutation in survival motor neuron (smn) gene
  • 22. Repair
    • Neurotrophins
    • Gene therapy
  • 23.  
  • 24. Pan W, CPD 11:10 &11 preface
  • 25.  
  • 26. Neurobiology of obesity: Nature Neurosci. April 2005
  • 27.  
  • 28.  
  • 29. Integration of basic neuroscience and clinical neurology
    • Treatment based on mechanisms
    • Multipotency of drugs
    • Animal models reflect certain aspects of human disorders
    • Think the organism as a whole
  • 30. Summary
    • Development, remodeling, and neuroplasticity
    • Excitability
    • Balance of trophic support and apoptosis
    • Neuroendocrine circuits and rewarding pathways
    • Environmental factors – the BBB, interactions between neurons and glia
  • 31. What is your role as a neurobiologist? The end