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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011945-03
Application #
6168692
Study Section
Special Emphasis Panel (ZRG4-HPD (02))
Program Officer
Foudin, Laurie L
Project Start
1998-09-08
Project End
2003-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
3
Fiscal Year
2000
Total Cost
$232,263
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Lindquist, Derick H; Sokoloff, Greta; Milner, Eric et al. (2013) Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats. Alcohol 47:447-57
Young, Brandt W; Sengelaub, Dale R; Steinmetz, Joseph E (2010) MK-801 administration during neonatal ethanol withdrawal attenuates interpositus cell loss and juvenile eyeblink conditioning deficits. Alcohol 44:359-69
Lindquist, Derick H; Mahoney, Luke P; Steinmetz, Joseph E (2010) Conditioned fear in adult rats is facilitated by the prior acquisition of a classically conditioned motor response. Neurobiol Learn Mem 94:167-75
Brown, Kevin L; Burman, Michael A; Duong, Huan B et al. (2009) Neonatal binge alcohol exposure produces dose dependent deficits in interstimulus interval discrimination eyeblink conditioning in juvenile rats. Brain Res 1248:162-75
Watson, Deborah J; Stanton, Mark E (2009) Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats. Neurobiol Learn Mem 92:89-98
Lindquist, Derick H; Vogel, Richard W; Steinmetz, Joseph E (2009) Associative and non-associative blinking in classically conditioned adult rats. Physiol Behav 96:399-411
Watson, Deborah J; Herbert, Mariel R; Stanton, Mark E (2009) NMDA receptor involvement in spatial delayed alternation in developing rats. Behav Neurosci 123:44-53
Watson, Deborah J; Stanton, Mark E (2009) Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist. Learn Mem 16:564-72
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
Watson, Deborah J; Stanton, Mark E (2009) Medial prefrontal administration of MK-801 impairs T-maze discrimination reversal learning in weanling rats. Behav Brain Res 205:57-66

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