The studies of this proposal comprise Project 2 of an Interactive Research Project Grant (IRPG). The long-term goals of this IRPG are to use well-studied variants of Pavlovian eyeblink conditioning to understand the developmental consequences of early exposure to alcohol on the structure, function, and development of defined neural systems underlying classical conditioning. The IRPG focuses on dose-related effects on cerebellar (Project 1) and hippocampal (Project 2) circuits that mediate specific forms of conditioning. Developmental analyses of the dose-effect functions and tests of antioxidant protection against damage to these circuits are proposed in both projects. Project 1 has confirmed that heavy binge alcohol exposure in neonatal rats, a model of 3rd trimester human exposure, produces severe impairments in eyeblink conditioning that are correlated with deficits in cerebellar neuron numbers and learning-related unit activity. However, deficits in acquisition of conditioned responses [CRs] were observed only with the highest dose used. In Project 2, we propose new studies that will use trace eyeblink conditioning to characterize potential disruption of behavioral functions involving neural interactions between cerebellum and hippocampus induced by lower doses of alcohol.
Specific Aim 1 tests the hypothesis that neonatal alcohol exposure will produce dose-related deficits in trace eyeblink conditioning in juvenile and adult rats, and that these deficits will correlate with dose-related changes in neuronal cell counts in CA1 of the hippocampus.
Aim 1 will also compare effects of alcohol on trace conditioning with those on other hippocampal-dependent tasks---eyeblink discrimination and reversal, spatial delayed alternation, and contextual-fear conditioning--to develop converging evidence toward the specificity of alcohol-related effects on hippocampal-cerebellar function.
Specific Aim 2 will examine a developmental period of alcohol exposure that may target the hippocampus preferentially over the cerebellum, in order to determine the relative role of damage to both structures (Aim 1), vs. the hippocampus alone (Aim 2), in alcohol-induced trace conditioning deficits. ? Specific Aim 3 tests the hypothesis that neonatal alcohol exposure will produce dose-related deficits in trace conditioning in adult rats. Hippocampal unit activity and quantitative assessment of hippocampal cell loss will provide functional and structural correlates of alcohol effects on trace conditioning.
Specific Aim 4 tests the hypothesis that antioxidant supplements during the neonatal binge exposure can protect against alcohol- induced hippocampal cell loss and deficits in trace eyeblink conditioning. These animal studies can inform future studies of effects of prenatal alcohol exposure in infants and children, because the behavioral procedures and neural circuits underlying eyeblink conditioning are similar across species ? ?

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Matochik, John A
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University of Delaware
Schools of Arts and Sciences
United States
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Hamilton, G F; Jablonski, S A; Schiffino, F L et al. (2014) Exercise and environment as an intervention for neonatal alcohol effects on hippocampal adult neurogenesis and learning. Neuroscience 265:274-90
Murawski, Nathen J; Jablonski, Sarah A; Brown, Kevin L et al. (2013) Effects of neonatal alcohol dose and exposure window on long delay and trace eyeblink conditioning in juvenile rats. Behav Brain Res 236:307-18
Murawski, N J; Klintsova, A Y; Stanton, M E (2012) Neonatal alcohol exposure and the hippocampus in developing male rats: effects on behaviorally induced CA1 c-Fos expression, CA1 pyramidal cell number, and contextual fear conditioning. Neuroscience 206:89-99
Jablonski, Sarah A; Schiffino, Felipe L; Stanton, Mark E (2012) Role of age, post-training consolidation, and conjunctive associations in the ontogeny of the context preexposure facilitation effect. Dev Psychobiol 54:714-22
Schiffino, Felipe L; Murawski, Nathen J; Rosen, Jeffrey B et al. (2011) Ontogeny and neural substrates of the context preexposure facilitation effect. Neurobiol Learn Mem 95:190-8
Murawski, Nathen J; Stanton, Mark E (2011) Effects of dose and period of neonatal alcohol exposure on the context preexposure facilitation effect. Alcohol Clin Exp Res 35:1160-70
Jablonski, Sarah A; Watson, Deborah J; Stanton, Mark E (2010) Role of medial prefrontal NMDA receptors in spatial delayed alternation in 19-, 26-, and 33-day-old rats. Dev Psychobiol 52:583-91
Murawski, Nathen J; Stanton, Mark E (2010) Variants of contextual fear conditioning are differentially impaired in the juvenile rat by binge ethanol exposure on postnatal days 4-9. Behav Brain Res 212:133-42
Burman, M A; Murawski, N J; Schiffino, F L et al. (2009) Factors governing single-trial contextual fear conditioning in the weanling rat. Behav Neurosci 123:1148-52
Brown, Kevin L; Stanton, Mark E (2008) Cross-modal transfer of the conditioned eyeblink response during interstimulus interval discrimination training in young rats. Dev Psychobiol 50:647-64

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