Alcohol consumption during pregnancy can produce central nervous system (CNS) dysfunction in offspring, including disorders of learning and memory. There is wide variability in the frequency and severity of CNS fetal alcohol effects, even among offspring of women known to have drunk heavily during pregnancy. Three factors strongly influence the likelihood or severity of human fetal alcohol effects: heavy consumption, drinking that lasts into the third trimester, and binge drinking. These risk factors have been further explored in rat models of alcohol exposure, particularly in a neonatal rat model of binge alcohol exposure during the third trimester equivalent. Precise experimental manipulations of dose and timing of exposure during the first 10 postnatal days indicate that restricted temporal windows of vulnerability exist for specific structural and behavioral alterations. this new application proposes to use this established neonatal rat model of exposure during the third trimester equivalent, to begin to establish correlations between specific structural damage in the hippocampus and functional deficits in learning and memory. Using neonatal artificial rearing to manipulate the developmental timing and the dose of alcohol exposure, the studies will attempt to dissociate two structural alterations known to occur in the hippocampus following neonatal alcohol exposure -- aberrant mossy fibers and loss of CA1 pyramidal cells. Preliminary evidence indicates that these two effects have different temporal windows of vulnerability and have different blood alcohol thresholds necessary to elicit them. Aberrant (hyperdeveloped) mossy fiber projections are induced in the distal infrapyramidal zone of CA3 in the mid-temporal hippocampus following alcohol exposure during postnatal day [PD] 1 to PD10 (BACs averaging 160 mg/dl), but not following exposure during PD4 to PD9 (BACs above 250 mg/dl). In contrast, the same alcohol exposure on PD4 to PD9 produces significant pyramidal cell loss in CA1 without depleting other hippocampal fields. Importantly, other experimental models have shown that aberrant mossy fibers are correlated with deficient shuttle avoidance acquisition but enhanced spatial working memory, whereas CA1 damage impairs spatial working memory but has no effect on shuttle avoidance. Six experiments will test these established links between hippocampal structural changes and specific learning impairments in the context of neonatal alcohol exposure. Exps. #1 and #2 will use Timm stain and stereological cell counts to confirm that aberrant mossy fibers and CA1 cell loss are produced by alcohol exposure from PD1 to PD9. Behavioral studies on the same subjects will confirm that active avoidance and spatial working memory impairments also are produced. Exps. #3 and #4 will determine the extent to which the structural effects can be dissociated on the basis of temporal windows of vulnerability, and the extent to which the structural changes are correlated with the specific behavioral effects. The final experiments will evaluate the structure/function correlates by manipulating the dose of alcohol. These studies will help bridge the wide gaps in knowledge of links between fetal alcohol effects on brain structure and functional outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AA009596-01
Application #
3452962
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1993-04-01
Project End
1998-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Arts and Sciences
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Goodlett, C R; Pearlman, A D; Lundahl, K R (1998) Binge neonatal alcohol intubations induce dose-dependent loss of Purkinje cells. Neurotoxicol Teratol 20:285-92
Stanton, M E; Goodlett, C R (1998) Neonatal ethanol exposure impairs eyeblink conditioning in weanling rats. Alcohol Clin Exp Res 22:270-5
Thomas, J D; Goodlett, C R; West, J R (1998) Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance. Brain Res Dev Brain Res 105:159-66
Goodlett, C R; Johnson, T B (1997) Neonatal binge ethanol exposure using intubation: timing and dose effects on place learning. Neurotoxicol Teratol 19:435-46
Goodlett, C R; Peterson, S D; Lundahl, K R et al. (1997) Binge-like alcohol exposure of neonatal rats via intragastric intubation induces both Purkinje cell loss and cortical astrogliosis. Alcohol Clin Exp Res 21:1010-7
Thomas, J D; Wasserman, E A; West, J R et al. (1996) Behavioral deficits induced by bingelike exposure to alcohol in neonatal rats: importance of developmental timing and number of episodes. Dev Psychobiol 29:433-52
Goodlett, C R; Lundahl, K R (1996) Temporal determinants of neonatal alcohol-induced cerebellar damage and motor performance deficits. Pharmacol Biochem Behav 55:531-40
Goodlett, C R; Peterson, S D (1995) Sex differences in vulnerability to developmental spatial learning deficits induced by limited binge alcohol exposure in neonatal rats. Neurobiol Learn Mem 64:265-75