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7/26/10 Pan W

7/26/10 Pan W






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    7/26/10 Pan W 7/26/10 Pan W Presentation Transcript

    • Introduction to Neurobiology of Disease
      • Overview of neurological disorders
      • Common mechanisms
      • Animal models
      • Integration of basic and clinical perspectives
    • 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
    • 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
    • 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
    • Neurobiological mechanisms
      • Development
      • Excitability
      • Programmed cell death
      • Repair
    • 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
    • Surface ectoderm (primary epidermis) Neural crest (peripheral nerves, pigment, facial cartilage) Neural tube (brain and spinal cord)
    • Interestingly, the vascular endothelial cells forming the BBB are from the mesoderm…
    • 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)
    • 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
    • Animal models - dismyelination and demyelination
      • Trembler mouse: defective Schwann cells
      • Jimpy mouse: meylin deficiency in the CNS
      • EAE: autoimmune demyelination
    • Animal models for epilepsy
      • Tottering, lethargic, ducky, stargazer, stargazer-3 Jackson, waggler
      • Defective voltage-dependent Ca channel
      • Models for absence seizures
    • Excitability
      • Mechanisms of excitability: membrane receptors, intracellular events, depolarization-induced injury
      • Epilepsy: abnormal synchronization
      • Ion channel diseases – channelopathies affecting nerve, muscle, and the brain
    • 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
    • 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
    • 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
    • Best comprehensive review: http://www.neuro.wustl.edu/neuromuscular/mother/chan.html
    • Cell death in neurobiology
      • Programmed cell death
      • neurodegeneration
    • 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
    • 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
    • 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
    • Repair
      • Neurotrophins
      • Gene therapy
    • Pan W, CPD 11:10 &11 preface
    • Neurobiology of obesity: Nature Neurosci. April 2005
    • 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
    • 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
    • What is your role as a neurobiologist? The end