Although fetal alcohol syndrome was discovered over forty years ago and is entirely preventable, the incidence of fetal alcohol spectrum disorder (FASD) has not diminished. The type and severity of alcohol-induced alterations following prenatal alcohol exposure is strongly impacted by genetics. Dr. Kristin Hamre has demonstrated in BXD recombinant inbred mouse strains with differential vulnerability to FASD that genetics is a principal factor defining susceptibility to alcohol-induced neuron death in the fetal hippocampus, one of the regions central to FASD cognitive deficits. However, the mechanisms behind the genetic contribution has not been identified. Research by Dr. Cynthia Kane has shown that alcohol exposure in the developing brain of C57BL/6J (B6) mice (a parental strain of the BXD lines) produces neuroinflammatory responses that lead to neuron death, including production of pro-inflammatory molecules and glial activation in the hippocampus. Her lab has also found that administration of the peroxisome proliferator-activated receptor-y agonist, pioglitazone, reduces alcohol-induced neuroinflammatory responses in the developing central nervous system. However, the role of genetics in neuroinflammatory responses to developmental alcohol exposure has not been determined. We hypothesize that differential fetal vulnerability to FASD is mediated, at least in part, by genetic differences leading to variation in the neuroinflammatory response to alcohol in the developing hippocampus. Experiments outlined in this proposal will: 1) determine whether alcohol-induced neuroinflammatory responses contribute to the differential genetic vulnerability to alcohol-induced cell loss in the developing hippocampus in Specific Aim 1 and 2) investigate whether administration of the anti-inflammatory drug, pioglitazone, protects highly sensitive BXD strains from hippocampal cell loss by suppressing alcohol-induced neuroinflammatory responses in neonatal mice in Specific Aim 2. The effects will be determined by examining expression of mRNA, expression of protein, percentage of cell loss, and activation of microglia and astrocytes in the hippocampus of neonatal mice exposed to developmental alcohol. This research will result in a further understanding of 1) the genetic contributions to the severity of FASD, 2) the genetic influence of alcohol-induced neuroinflammatory responses, and 3) whether pioglitazone is equally effective at inhibiting alcohol-induced cell loss across animals of differing genetic backgrounds.

Public Health Relevance

Although entirely preventable, fetal alcohol spectrum disorder (FASD) is still a leading developmental disorder with higher incidence rate in the United States than Autism or Down syndrome combined. Alcohol-induced cell death in the developing central nervous system is influenced by genetic factors as well as neuroinflammatory responses. This proposal will investigate the hypothesis that genetic susceptibility to cell loss in the developing hippocampus after alcohol exposure is mediated, at least in part, by variations in the neuroimmune responses and determine whether administration of the anti-inflammatory drug, pioglitazone, protects neurons from neuroinflammatory cell loss across animals of differing genetic backgrounds.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AA026498-03
Application #
9828524
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Akbar, Mohammed
Project Start
2017-12-01
Project End
2020-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38103