Cerebellum And Alcohol

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Cerebellum And Alcohol

  1. 1. How Alcohol Affects the Cerebellum<br />Andrew Bonett<br />
  2. 2. Cerebellum Review<br />Balance<br />Coordination<br />Postural adjustment<br />Limb movements<br />Fine motor control and timing<br />Eye movement<br />Motor learning<br />Cognitive functions – attention, language/music processing<br />
  3. 3. Gross Anatomy<br />Anterior View<br />Superior View<br />
  4. 4. Functional Zones<br />SPINOCEREBELLUM<br />Body and limb movement<br />CEREBROCEREBELLUM<br />Planned movement<br />Motor learning<br />Cognitive functions<br />Balance and eye movement<br />VESTIBULOCEREBELLUM<br />
  5. 5. Cerebellar Peduncles<br />
  6. 6. Afferent/Efferent Tracts<br />ICP – mainly afferents from spinal cord and brainstem<br />Olivocerebellar fibers<br />Spinocerebellar fibers<br />Trigeminocerebellar fibers<br />Vestibulocerebellar fibers (some efferents as well)<br />MCP – massive input from contralateral pontine nuclei<br />Fibers originate in motor/sensory areas of cerebral cortex<br />SCP – mainly efferents to red nucleus and VA/VL<br />Some afferents from anterior spinocerebellar tract<br />
  7. 7. Cerebellar Cortex<br />Molecular layer<br />Purkinje layer<br />Granular layer<br />
  8. 8. Circuitry<br />Go<br />Cerebral Cortex<br />Vestibular Nuclei<br />Spinal Cord<br />Reticular Formation<br />Deep Nuclei (feedback)<br />Inferior Olivary Nucleus<br />
  9. 9. Deep Nuclei<br />Dentate Nucleus<br />Interposed Nucleus<br />Globose<br />Emboliform<br />Fastigial Nucleus<br />
  10. 10. Problems Associated with Damage<br />Postural instability<br />Limb ataxia<br />Hypotonia<br />Hyporeflexia<br />Dysmetria<br />Intention tremor<br />Dysdiadochokinesia<br />Scanning speech<br />CCAS<br />
  11. 11. Alcohol<br />BAC<br />Euphoria<br />Relaxed, social<br />Lethargy<br />Sleepy, stumbling<br />Slow reactions<br />Confusion<br />Mood swings, N/V<br />Impaired vision, speech<br />Poor coordination<br />Stupor <br />Severely impaired movement<br />Loss of body functions (bladder)<br />Coma<br />Death<br />0.03 - 0.12%<br />&gt;0.50%<br />
  12. 12. Alcohol is a Depressant<br />Enhances inhibitory pathways<br />GABAergic<br />GABAA & GABAC receptors<br />Ionotropic (ligand-gated ion channels)<br />GABAB receptors<br />Metabotropic (G protein-coupled)<br />Suppresses excitatory pathways<br />Glutamatergic<br />NMDA receptors<br />Ionotropic <br />Ethanol<br />g-aminobutyric acid<br />Glutamic acid<br />N-methyl-D-aspartic acid<br />
  13. 13. Developmental Effects<br />FAS<br />Hypoplasia of anterior vermis<br />Cerebellar dysgenesis<br />Purkinje/granule degeneration<br />Studies used rat, sheep models<br />Certain Purkinje population<br />Damage parallels peak BAC<br />Stage of development not an important factor<br />Cerebellar Hypoplasia<br />
  14. 14. Developmental Effects<br />CELL GROWTH<br />University of Colorado – ethanol promotes apoptosis of granule cells<br />NMDA has anti-apoptotic effect<br />suppresses caspase activity<br />Induces BDNF expression<br />BDNF (brain-derived neurotrophic factor)<br />Similar to IGF-1<br />Neurotrophin <br />BDNF<br />EtOH<br />GC<br />NMDA<br />NMDAR<br />mossy fibers<br />Caspases<br />APOPTOSIS<br />
  15. 15. Acute Effects – Granule Cells<br />EtOH increases Golgi cell excitability and enhances GABAergic transmission to granule cells.<br />Increases sIPSC frequency<br />Increases tonic current magnitude<br />Increases spontaneous firing of Golgi cells (reversible!)<br />Does not affect eIPSCs from Golgi<br />Glutamatergic transmission from mossy fibers unaffected <br />
  16. 16. Acute Effects – Climbing Fibers<br />2006<br />EtOH modulates climbing fiber  Purkinje synapses<br />Alters metabotropic NMDA activity<br />Inhibits EPSCs and LTD<br /><ul><li>2008
  17. 17. EtOH modulates parallel fiber  Purkinje synapses in same manner
  18. 18. Notable effects at 10mM (legal BAC = 17mM)</li></ul>EtOH reduces EPSCs in PN evoked by CFs<br />EtOH prevents LTD<br />
  19. 19. Role of Ca2+ - new studies<br />Ethanol<br />Increases in intracellular Ca2+, GABA release, and mIPSCs<br />Ethanol + Ca2+-free medium + VGCC inhibitor<br />Still increase in mIPSCs<br />Ethanol + thapsigargin<br />Reduced effects<br />CONCLUSION: Effect of ethanol is dependent on the release of calcium from intracellular stores.<br />
  20. 20. Chronic Alcohol Consumption<br />Cerebellum is particularly sensitive to thiamin (vitamin B1) deficiency<br />Alcoholism  thiamin deficiency  Wernicke-Korsakoff<br />Korsakoff’s Psychosis<br />Wernicke’s Encephalopathy (a.k.a. alcoholic encephalopathy)<br />Confusion <br />Ataxia<br />Ophthalmoplegia<br />Anisocoria <br />Nystagmus<br />
  21. 21. Summary<br />Exposure to alcohol during development and/or chronic consumption leads to hypoplasia/dysgenesis of cerebellum.<br />Acute effects involve disruptions of cortical circuitry at seemingly every synapse.<br />Overall effect is to enhance inhibitory action and suppress excitatory action, but many different mechanisms.<br />Chronic exposure to alcohol can indirectly cause damage to the cerebellum/brain due to nutritional deficiencies.<br />

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