Prenatal exposure to alcohol can damage the central nervous system (CNS) and produce life-long learning disabilities, but there is unexplained variability in the observed effects. Different patterns, durations, and timing of drinking episodes during pregnanc may have major influences on the extent of damage, but systematic analysis still is needed in animal models. There has never been integrated, systematic analysis of alcohol-induced effects on the structural integrity and functional plasticity within a defined neural system that has a known, essential role in mediating associative learning. Such an effort requires a well-defined animal model with control over the alcohol exposure, in which the damage involves a key CNS structure and models human outcomes. The behavioral responses and neuronal correlates of learning must be operationally defined and precisely measured, and the neural circuits mediating the associative learning must be known. The studies proposed in this application fulfill each of these requirements. Binge alcohol exposure of neonatal rats has been extensively characterized as a model of third trimester exposure. Dose-related loss of cerebellar neurons during an early neonatal period of enhanced vulnerability i now well established, and the structural damage is similar to effects seen in MRI studies of prenatally exposed children. Recent studies have found that neonatal binge exposure induces profound impairments in classical conditioning of eyeblink responses. Cerebellar mediation of eyeblink conditioning is one of the best-understood models of mammalian associative learning in neuroscience. The components of the cerebellar-brainstem circuit essential for learned eyeblink responses, i.e., the deep cerebellar nuclei, cerebellar cortex, inferior olive, and pontine nuclei, appear to be targets of alcohol neurotoxicity in development.
Five specific aims are proposed to test this by evaluating alcohol-induced deficits in structure, functional plasticity, and behavior.
Aim 1 will evaluate the deficits in eyeblink conditioning in juveniles and adults, including an assessment of threshold, dose-response, and will extend the analysis to complex motor learning for adults.
Aim 2 will determine the extent of cell loss in the four populations, using the same rats tested in Aim 1.
Aim 3 will systematically assess learning-related neuronal activity and plasticity in the four areas.
Aim 4 will evaluate neonatal temporal windows of vulnerability to structural and behavioral effects.
Aim 5 will test whether the cerebellar effects are observed with gestational exposur or whether exposure that extends into the hypothesized critical period of vulnerability is required for cerebellar damage.
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