The objective of the proposed research Is to make novel discoveries regarding the functional and structural central nervous system (CNS) pathology that results from early prenatal alcohol exposure (PAE). Extending our previous research illustrating exposure stage-dependent patterns of brain dysmorphology in fetal mice, we propose to examine 3 distinct, but interrelated forebrain circuits that are expected to play key roles in the behavioral or functional manifestations of alcohol neuroteratogenesis in the postnatal animal. The proposed studies will utilize a well-established FASD mouse model, with acute, as well as dietary maternal alcohol administration at times equivalent to 3-6 weeks of human gestation. Innovative technologies and approaches will be employed to address 3 Aims.
Aim 1 is designed to test the hypothesis that early PAE induces hippocampal pathology (esp. altered hippocampal volume and related fiber tract Integrity and circuitry) and deficiencies in the performance of hippocampus-mediated learning and memory tasks in adult mice. For this work, high-resolution ex vivo diffusion tensor imaging will be utilized to define structural deficiencies associated with PAE, while a behavioral test battery will be used to probe hippocampal-dependent learning and memory.
Aim 2 is designed to test the hypothesis that early PAE causes defects in medial hypothalamic and pituitary circuitry as well as altered HPA axis regulation in adulthood. For this, immunohlstochemistry and in situ hybridization will be employed to characterize hypothalamic and pituitary pathology in fetal mice. HPA axis function will be examined in adults by measurement of adrenocorticotropic hormone and corticosterone plasma levels both prior and subsequent to an acute alcohol challenge or an acute restraint stress.
Aim 3 is designed to test the hypothesis that early PAE results in deficient inhibitory GABAergic circuitry in corticostriatal circuits underlying reward perception and alcohol intake. For this, intracranial self-stimulation (ICSS), intermittent access drinking, and design-based stereology will be employed. Overall, the proposed work is in keeping with the binge alcohol pathology/neurocircuitry-directed central goal of the Alcohol Research Center (ARC) and will profit from ARC support and interaction. The results of the proposed studies promise to fill a significant FASD research void, inform human clinical research, and continue to highlight the first trimester as a critical period for alcohol-induced CNS defects.

Public Health Relevance

Structural and functional neurological defects are major components of Fetal Alcohol Spectrum Disorder (FASD) and remain a major public health problem. With exploration of forebrain pathology, learning and memory deficits, drug reward perception and HPA axis alterations, the proposed basic research promises to provide important new, clinically-relevant FASD data.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Comprehensive Center (P60)
Project #
Application #
Study Section
Special Emphasis Panel (ZAA1-GG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer et al. (2018) Functional role for cortical-striatal circuitry in modulating alcohol self-administration. Neuropharmacology 130:42-53
Vetreno, Ryan P; Lawrimore, Colleen J; Rowsey, Pamela J et al. (2018) Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin. Front Neurosci 12:200
Broadwater, Margaret A; Lee, Sung-Ho; Yu, Yang et al. (2018) Adolescent alcohol exposure decreases frontostriatal resting-state functional connectivity in adulthood. Addict Biol 23:810-823
Fiorenza, Amanda M; Shnitko, Tatiana A; Sullivan, Kaitlin M et al. (2018) Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue. Alcohol Clin Exp Res 42:1051-1061
Hwa, Lara S; Neira, Sofia; Pina, Melanie M et al. (2018) Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling. Neuropsychopharmacology :
Faccidomo, Sara; Swaim, Katarina S; Saunders, Briana L et al. (2018) Mining the nucleus accumbens proteome for novel targets of alcohol self-administration in male C57BL/6J mice. Psychopharmacology (Berl) 235:1681-1696
Bohnsack, John Peyton; Hughes, Benjamin A; O'Buckley, Todd K et al. (2018) Histone deacetylases mediate GABAA receptor expression, physiology, and behavioral maladaptations in rat models of alcohol dependence. Neuropsychopharmacology 43:1518-1529
Coleman Jr, Leon G; Zou, Jian; Qin, Liya et al. (2018) HMGB1/IL-1? complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun 72:61-77
Fish, E W; Wieczorek, L A; Rumple, A et al. (2018) The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice. Behav Brain Res 338:173-184
Beattie, Matthew C; Reguyal, Christopher S; Porcu, Patrizia et al. (2018) Neuroactive Steroid (3?,5?)3-hydroxypregnan-20-one (3?,5?-THP) and Pro-inflammatory Cytokine MCP-1 Levels in Hippocampus CA1 are Correlated with Voluntary Ethanol Consumption in Cynomolgus Monkey. Alcohol Clin Exp Res 42:12-20

Showing the most recent 10 out of 227 publications