1. How Alcohol Affects the Cerebellum Andrew Bonett

2. Cerebellum Review Balance Coordination Postural adjustment Limb movements Fine motor control and timing Eye movement Motor learning Cognitive functions – attention, language/music processing

3. Gross Anatomy Anterior View Superior View

4. Functional Zones SPINOCEREBELLUM Body and limb movement CEREBROCEREBELLUM Planned movement Motor learning Cognitive functions Balance and eye movement VESTIBULOCEREBELLUM

5. Cerebellar Peduncles

6. Afferent/Efferent Tracts ICP – mainly afferents from spinal cord and brainstem Olivocerebellar fibers Spinocerebellar fibers Trigeminocerebellar fibers Vestibulocerebellar fibers (some efferents as well) MCP – massive input from contralateral pontine nuclei Fibers originate in motor/sensory areas of cerebral cortex SCP – mainly efferents to red nucleus and VA/VL Some afferents from anterior spinocerebellar tract

7. Cerebellar Cortex Molecular layer Purkinje layer Granular layer

8. Circuitry Go Cerebral Cortex Vestibular Nuclei Spinal Cord Reticular Formation Deep Nuclei (feedback) Inferior Olivary Nucleus

9. Deep Nuclei Dentate Nucleus Interposed Nucleus Globose Emboliform Fastigial Nucleus

10. Problems Associated with Damage Postural instability Limb ataxia Hypotonia Hyporeflexia Dysmetria Intention tremor Dysdiadochokinesia Scanning speech CCAS

11. Alcohol BAC Euphoria Relaxed, social Lethargy Sleepy, stumbling Slow reactions Confusion Mood swings, N/V Impaired vision, speech Poor coordination Stupor Severely impaired movement Loss of body functions (bladder) Coma Death 0.03 - 0.12% >0.50%

12. Alcohol is a Depressant Enhances inhibitory pathways GABAergic GABAA & GABAC receptors Ionotropic (ligand-gated ion channels) GABAB receptors Metabotropic (G protein-coupled) Suppresses excitatory pathways Glutamatergic NMDA receptors Ionotropic Ethanol g-aminobutyric acid Glutamic acid N-methyl-D-aspartic acid

13. Developmental Effects FAS Hypoplasia of anterior vermis Cerebellar dysgenesis Purkinje/granule degeneration Studies used rat, sheep models Certain Purkinje population Damage parallels peak BAC Stage of development not an important factor Cerebellar Hypoplasia

14. Developmental Effects CELL GROWTH University of Colorado – ethanol promotes apoptosis of granule cells NMDA has anti-apoptotic effect suppresses caspase activity Induces BDNF expression BDNF (brain-derived neurotrophic factor) Similar to IGF-1 Neurotrophin BDNF EtOH GC NMDA NMDAR mossy fibers Caspases APOPTOSIS

15. Acute Effects – Granule Cells EtOH increases Golgi cell excitability and enhances GABAergic transmission to granule cells. Increases sIPSC frequency Increases tonic current magnitude Increases spontaneous firing of Golgi cells (reversible!) Does not affect eIPSCs from Golgi Glutamatergic transmission from mossy fibers unaffected

17. EtOH modulates parallel fiber  Purkinje synapses in same manner

18. Notable effects at 10mM (legal BAC = 17mM)EtOH reduces EPSCs in PN evoked by CFs EtOH prevents LTD

19. Role of Ca2+ - new studies Ethanol Increases in intracellular Ca2+, GABA release, and mIPSCs Ethanol + Ca2+-free medium + VGCC inhibitor Still increase in mIPSCs Ethanol + thapsigargin Reduced effects CONCLUSION: Effect of ethanol is dependent on the release of calcium from intracellular stores.

20. Chronic Alcohol Consumption Cerebellum is particularly sensitive to thiamin (vitamin B1) deficiency Alcoholism  thiamin deficiency  Wernicke-Korsakoff Korsakoff’s Psychosis Wernicke’s Encephalopathy (a.k.a. alcoholic encephalopathy) Confusion Ataxia Ophthalmoplegia Anisocoria Nystagmus

21. Summary Exposure to alcohol during development and/or chronic consumption leads to hypoplasia/dysgenesis of cerebellum. Acute effects involve disruptions of cortical circuitry at seemingly every synapse. Overall effect is to enhance inhibitory action and suppress excitatory action, but many different mechanisms. Chronic exposure to alcohol can indirectly cause damage to the cerebellum/brain due to nutritional deficiencies.