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 thematically focuses on dose-related effects on cerebellar (Project 1) and hippocampal (Project 2) circuits known to 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 and correlated 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 1, proposed new studies will manipulate the interstimulus interval (ISI) to measure CR timing, a more sensitive indicator of cerebellar dysfunction, to expand our ability to detect cerebellar damage induced by lower doses.
Specific Aim I tests the hypothesis that neonatal alcohol exposure will produce dose-related deficits in the timing of eyeblink CRs with the ISI manipulations in adult rats, and will produce dose-related changes in learning-related neural activity recorded in critical regions of the cerebellum.
Specific Aim 2 tests the hypothesis that dose-related deficits in CR timing will be correlated with loss of neurons in these same critical cerebellar regions.
Specific Aim 3 tests the hypothesis that dose-related deficits in CR timing, correlated with cell loss, can be detected in juvenile rats. It also assesses potential age-related differences in dose-effect curves. In all studies, the ISI manipulations are expected to reveal dose-effect functions that are more sensitive than dose-effect curves for CR acquisition. Cerebellar unit activity and cell loss in specific regions of cerebellar cortex and in the interpositus nucleus will provide functional and structural correlates of the predicted effects on CR timing.
Specific Aim 4 tests the hypothesis that antioxidant supplements during the neonatal binge exposure can protect against alcohol-induced cerebellar neurotoxicity and deficits in eyeblink conditioning. These animal model outcomes can guide and 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 in both species ? ?
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