Progress Report U01 014829 (Goodlett)
Aims 1 & 2: To test L-NAP and other compounds for
therapeutic potential in preventing alcohol-induced damage
to the cerebellum in a neonatal rodent model of 3rd-trimester
alcohol exposure during binge drinking
Accomplishments:
• Vitamin E fails to protect against neontal alcohol-induced
activation of caspase-3 in neonatal cerebellum; permanent
loss of cerebellar cells; eyeblink conditioning deficits
{published in ACER}
• L-NAP fails to protect against activation of caspase-3 or loss
of cerebellar Purkinje cells {finishing data collection on cell
counts}
• Binge Alcohol on PD 4-9 induces dose-dependent deficits
on trace eyeblink conditioning that are similar to (but
somewhat more severe than) learning deficits seen with
delay conditioning
Progress Report:
Binge Neonatal Alcohol Exposure Impairs Trace
Eyeblink Conditioning
Progress Report:
Binge Neonatal Alcohol Exposure Impairs
Trace and Long Delay Eyeblink Conditioning
P4-9 Trace vs. LD
350
Adapative CR Max Amp
300
250
UD-D880
UD-T500
200
SI-D880
SI-T500
150
5gkg-D880
5gkg-T500
100
50
0
s1
s2
s3
s4
Sessions
s5
s6
Progress Report
Aim 3: To develop a neonatal mouse model of 3rdtrimester binge exposure and evaluate behavioral
correlates of alcohol-induced damage to hippocampal
formation and limbic cortex
Accomplishments:
• C57BL/6 mice given heavy binge exposure to alcohol
on P7 (2.5 g/kg in each of two injections, 2 hours apart)
• Activation of caspase-3 in caudate, cingulate cortex,
retrosplenial cortex, and hippocampal formation (Zhou)
• Unexpected enhancement of responding during
reversal of conditional discrimination in eyeblink
conditioning task (next slide)
Eyeblink Conditioning in Mice:
Unexpected Effects on Conditional Discrimination
Reversal following P7 Binge Exposure
CR Max Amplitude
400
Saline CS+
Saline CSEtOH CS+
EtOH CS-
Acquisition
400
CR Max Amplitude
• No effects on acquisition
• Modest resistance to
extinction on reversal
• Enhanced responding to
new CS+
• ? Altered processes of
inhibitory learning?
Reversal
Saline CS+
Saline CSEtOH CS+
EtOH CS-
300
200
100
300
200
0
R1
R2
R3
R4
R5
Session
100
0
A1
A2
A3
Session
A4
R6
R7
R8
Plans for Year and Renewal
•
L-NAP protection against Prenatal Exposure
in Rat and Mouse Models (liquid diet)
– Behavioral Studies
•
•
•
Spatial Learning & Memory (water maze working
memory; spatial delayed alternation; radial maze)
Eyeblink Conditioning: Trace vs. Delay
Behavioral Screening Battery for mice (Stanton/JHU
Center for Neurogenetics)
– Anatomical Studies
•
Volumetric and cell count studies of hippocampal
formation (adults tested above)
Plans for Year and Renewal
•
Antioxidant protection against hippocampal
/ limbic cortex damage in late neonatal rat
and mouse binge models (P7-P9)
– Behavioral Studies
•
•
•
Spatial Learning & Memory (water maze working
memory; spatial delayed alternation; radial maze)
Eyeblink Conditioning: Trace Conditioning
Eyeblink Conditioning: Conditioned Inhibition
– Anatomical Studies
•
•
Volumetric and cell count studies of hippocampal
formation (adults tested above)
Protection against caspase-3 activation (forebrain)
Plans for Year and Renewal
•
Pursue post-treatment interventions that
may help ameliorate the neonatal alcoholinduced damage (esp. targeting cerebellar
and hippocampal function)
– Potential interventions
•
•
•
Exercise
Choline Supplementation
Pharmacological Stimulation
– Eyeblink (trace vs. delay) is well-suited to assess
differential effects on hippocampal and
cerebellar function
– Other behavioral assessments can be
considered (spatial learning; motor coordination)