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 ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011945-08
Application #
6890384
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Ren, Zhaoxia
Project Start
1998-09-08
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
8
Fiscal Year
2005
Total Cost
$368,108
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
603007902
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
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
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

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