Prenatal Alcohol Exposure: Neuropathology and cognition Integrating Behavioral & Neural
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Transcript of Prenatal Alcohol Exposure: Neuropathology and cognition Integrating Behavioral & Neural
Prenatal Alcohol Exposure: Neuropathology and cognition
Integrating Behavioral & NeuralApproaches in Rats and Humans
Rob SutherlandCanadian Centre for Behavioural NeuroscienceThe University of Lethbridge
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Project DirectorsRobert Sutherland
Dan SavageDerek Hamilton
Subject RecruitmentCarol ClericuzioLuther Robinson
Julia PowersJorge Ganem
Hannah OlivetsMRI, MRS & fMRI
Roland Lee Allison LindsayWilliam Brooks
Helen Petropoulos
Neuropsychological Assessment
P.W. KodituwakkuBarbara WilsonPaula Wilbourne
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MEGClaudia Tesche
Kim PaulsonSandra Moses
Rat ModelRob McDonald
Linda Beyer-Smith
Rafael Galindo
Janice Hoesing
Michael Thomas
Ying Wu
Patti Sorensen
Moderate Ethanol Exposure Paradigm
• 5% EtOH diet throughout gestation.
• Pair-Fed 0% EtOH and Ad Lib controls
• 16 Hour feeding / 8 hour water schedule.
• No significant effects of the ethanol diet on:- Litter size or Neonatal mortality.- Offspring birthweight or growth curves.- Brain weight or gross anatomy after
sacrifice.
4030201000
20
40
60
80
100Ad lib
Pair-fed
5% ethanol
Fixed, hidden platform task
Trial
Tim
e t
o fi
nd
pla
tform
(s)
Simple, constant learning tasks are unaffected
Ad lib Pair-fed 5% alcohol0
10
20 Trial 1Trial 2
Group
Late
ncy t
o fi
nd
pla
tform
(s)
One-trial learning tasks that tax hippocampus are affected
Time ( minutes )0 20 40 60 80 100
fEP
SP
( F
ract
iona
l Cha
nge
)
0.0
0.1
0.2
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0.5
0.6
0.7
0.8
0.0
0.1
0.2
0.3
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0.7
0.8Ad LibPair-Fed5% EtOH
Synaptic plasticity is impaired
Liquid Diet Ethanol Concentration
Mat
erna
l Blo
od E
than
ol
Con
cent
rati
on (
mg/
dL)
0
20
40
60
80
100
2% 3% 5%
Pot
enti
atio
n of
D-A
SP
Rel
ease
(S
2 / S
1)
1.0
1.2
1.4
B.Fraction Intervals (minutes)
0 6 12 18 24 84 90 96 102 108
Fra
ctio
nal R
elea
seof
D-A
SP
(%
)
1.5
2.0
2.5
S1 S2TET
A.
AdLib
2%EtOH
PF-2 PF-3 3%EtOH
PF-5 5%EtOH
Pair-fed to 3% EtOH3% EtOH Diet
Threshold for adult synaptic effect
is .03 BAL
TRIAL 1
TRIAL 2
A.PAIR-FED CONTROL 3% EtOH DIET
Impr
ovem
ent i
nE
scap
e L
aten
cy (
Sec
)
0
2
4
6
8
10
12
14
B.
AdLib
2%EtOH
PF-2 PF-3 3%EtOH
PF-5 5%EtOH
3% maternal alcohol affects adult learning
Green = neuronRed = new cellGold = new neuron
Adult hippocampus has thousands of new cells each day.
Alcohol exposed rats have many fewer new neurons in adult hippocampus
Visual acuity
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0.11
87
0.14
84
0.17
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0.20
78
0.23
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0.26
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0.29
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0.35
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0.53
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0.56
4
0.59
37
0.62
33
Spatial frequency
Corr
ect
Ad lib
Pair-fed
5%EtOH
Visual accuity not affected.
Fetal Alcohol - Induced Deficits
Hippocampus-sensitive memory tasks
Hippocampal synaptic plasticity
Neurochemical mechanisms associated with synaptic plasticity
Threshold is around .03 BAL for adult synaptic and learning deficits
Adult neurogenesis is decreased
Phase I: Place learning(Twenty trials)
Phase II: Probe trial
Phase III: Cued-navigation(Eight trials)
A virtual Morris water task
VMWT and Neuroimaging
Day 1 Neuropsychological test batteryTrain subjects on the VMWTMEG/EEG recording while performing
VMWT
Day 2 sMRI Proton MRS (right HPC & right DLPFC) fMRI recording while performing VMWT.
Virtual navigation with beacons. On different trial blocks participants must learn which cue is correct
or which location is correct
MEG Results
Right hippocampal activation during place learning was observed in 2/7 children with FAS
Right hippocampal activation during place learning was observed in 6/7 controls
MEG Results and Behavior
0
10
20
30
40
50
60
70
80
+ -
Right Hippocampal ECD
Init
ial
Hea
din
g E
rro
r (d
eg)
Structural MRI
An automated procedure separates white and grey matter from sMRIs and calculates volume of
hippocampal grey matter.
Magnetic Resonance Spectroscopy
MRS permits quantification of several neurochemicals from regions of prefrontal cortex
and hippocampus.
Magnetic Resonance Spectroscopy1H-Magnetic Resonance SpectroscopyN
AA
/ C
reati
ne
0.0
0.5
1.0
1.5
2.0
2.5
3.0
CONTROLFAS
HippocampalFormation
DL PrefrontalCortex
No significant differences in neurochemistry**
Human SummaryPlace learning in the VMWT
Participants with FAS were impaired at hippocampal- dependent place learning in the VMWT
Morphometrics/Volumetrics (sMRI)No evidence for alcohol-related differences in hippocampal volume/structure
Neurometabolites (1H-MRS)No evidence for alcohol-related differences in hippocampal neurometabolite profiles
Functional Neuroimaging (MEG)Participants with FAS were less-likely to display task-related activity in right hippocampus.Task-related activity in HPC was highly correlated with behavior in the VMWT
Conclusions
• Alcohol-related differences in brain function can be detected using technology that is currently available
• Alcohol-related differences in brain function may not correspond with neuroanatomical differences detected using structural MRI or MRS
• Functional techniques may be particularly useful and sensitive for identifying the neural bases of cognitive dysfunction in FASD
• Functional neuroimaging may help provide unique diagnostic information and may be helpful in assessing treatment
• It will be important to relate functional brain activation with behaviorally-relevant paradigms – Linking basic human and animal research on FASD with clinical research