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
16. Acute Effects Climbing Fibers
2006
EtOH modulates climbing fiber Purkinje synapses
Alters metabotropic NMDA activity
Inhibits EPSCs and LTD

2008

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
Korsakoffs Psychosis
Wernickes 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.