Fetal alcohol spectrum disorders (FASD) produces neurologic sequelae that persist throughout life and there is no treatment. The goal of our research is to understand the mechanisms that lead to the neurologic deficits of FASD and identify pharmaceutical interventions to prevent or treat these deficits. Damage to the cerebellum is common in FASD and contributes to deficits in motor function. Studies by us and others in rodent models of FASD reveal that fetal alcohol exposure produces loss of neurons in the cerebellum and deficits in motor function. Importantly, our studies in FASD models also reveal that alcohol induces neuroinflammation in the cerebellum. Furthermore, our studies indicate that treatment with anti-inflammatory PPAR-? agonists protect against alcohol-induced neuroinflammation and neuron loss. We hypothesize that ethanol activates specific immune signaling pathways resulting in neuroinflammation in the developing cerebellum which contributes to neuron loss and long-term behavioral deficits associated with FASD. As a corollary, ethanol-induced neuroinflammation, neuron loss, and behavioral deficits in the developing cerebellum can be blocked by anti- inflammatory agents including PPAR-? agonists. We will test this hypothesis using our well-established neonatal mouse model of FASD.
Aim 1 : Determine the molecular mechanisms of ethanol-induced neuroinflammation and PPAR-? agonist protection in the developing cerebellum. The role of TLR4 and CX3CL1-CX3CR1 signaling in ethanol-induced neuroinflammation and neuron loss will be probed using mice in which critical molecules in these signaling pathways are genetically knocked out. Furthermore, the mechanisms of PPAR-? agonist protection against ethanol will be explored by investigating agonist impact on neuroinflammation, neuron loss, TLR4 and downstream signaling, and CX3CL1-CX3CR1 signaling.
Aim 2 : Determine whether treatment with PPAR-? agonists will prevent ethanol-induced long-term motor function deficits in FASD and whether ethanol-induced neuroinflammation contributes to these deficits. The ability of PPAR-? agonists to protect against long-term ethanol-induced motor coordination, balance, and gait dysfunction will be assessed with CatWalk, beam walk, and rotarod behavioral analyses. Furthermore, we will determine if TLR-4 or CX3CL1-CX3CR1 signaling pathways play a critical role in ethanol-induced motor deficits using mice in which critical molecules in these signaling pathways are knocked out. Impact: This study will provide proof-of-principle that anti-neuroinflammatory agents including PPAR-? agonists can exert protective effects against neuroinflammation, neurodegeneration, and long-term behavioral deficits in FASD. This study will also define molecular mechanisms by which ethanol induces and PPAR-? agonists suppress neuroinflammation, neurodegeneration, and long-term behavioral deficits. These findings will foster development of new anti-inflammatory strategies for intervention in FASD.

Public Health Relevance

Fetal alcohol spectrum disorders (FASD) occurs in 1-5 of 100 births in the U.S. Damage to the brain produces neurologic sequelae that persist throughout life and there is no treatment. The goal of our research is to understand the cellular and molecular mechanisms that lead to the motor deficits of FASD and identify pharmaceutical interventions to prevent or treat these deficits. The proposed study will use FASD mouse models to provide proof-of-principle that anti-inflammatory pharmaceuticals such as PPAR-? agonists will protect against long-term motor deficits associated with the cerebellum region of the brain in FASD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA024695-01A1
Application #
9126759
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Regunathan, Soundar
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205