Prenatal ethanol exposure (PE) causes fetal alcohol spectrum disorders (FASD), which is characterized by severe cognitive, motor deficits and mood disorders including, major anxiety disorder. FASD affects up to 5% of children and exerts a devastating burden on families, individuals and costs to the society making it one of the most significant health problems in the USA and worldwide. Currently, effective treatments of FASD are limited, which underscores the need for a better understanding of the neuronal mechanisms underpinning the behavioral deficits associated with FASD. Research conducted over the last decades has established that PE impairs the development and function of serotonin (5-HT) system. Although it is widely recognized that dysfunctions of the serotonin (5-HT) system play a major role in depression and major anxiety disorders associated with FASD, the mechanisms by which PE alters the function of dorsal raphe (DRn) 5-HT neurons and the precise 5-HT networks affected remain unknown. To address these important knowledge gaps, we have examined the impact of PE on the function of dorsal raphe (DRn) 5-HT neurons. The results of these studies have established that PE, which induces anxiety phenotype, profoundly, increases the activity of DRn 5-HT neurons, via a persistent potentiation of glutamatergic transmission in the DRn. Importantly, a novel finding of our preliminary mechanistic studies is that these effects are mediated by enhanced nitric oxide (NO) signaling. In this application, we will build on this progress and test the novel hypothesis that enhanced nitrergic function in PE rats mediates the potentiation of glutamatergic transmission onto DRn 5-HT neurons, identify the subset(s) of 5-HT projecting neurons affected, and dissect the neuronal networks mediating anxiety phenotype of PE rats.
In Aim 1, we will test the hypothesis that enhanced NO signaling mediates the potentiation of glutamate synapses in the DRn, and identify the subset(s) of DRn 5-HT projecting neurons affected.
In Aim 2, we will dissect the glutamatergic input(s) to DRn 5-HT neurons altered in PE rats.
In Aim 3, we will test whether reducing specific glutamatergic inputs to DRn 5-HT neurons alleviates anxiety in PE rats. This multidisciplinary approach will identify the cellular mechanisms mediating the dysfunction of 5-HT system and define the neuronal circuitries underlying anxiety phenotype of PE rats. The outcome of these experiments will also lay the foundation for future studies aiming at developing effective therapy of mood disorders associated with FASD.

Public Health Relevance

Dysfunction of the brain serotonin system plays is one of the major cause of psychiatric disorders associated with fetal alcohol spectrum disorder (FASD), yet how prenatal ethanol exposure alters the function of serotonin system, has remained a long-standing question in the field of FASD research. Using a translational animal model of FASD, the proposed studies seek to address this issue and elucidate the mechanisms and precise neuronal circuitries mediating the dysfunction of serotonin system in FASD. The outcome of this study will greatly enhance our understanding of the role of serotonin system in FASD and help the development of novel therapeutic strategies for FASD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA026601-01A1
Application #
9659030
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Powell, Elizabeth
Project Start
2018-09-20
Project End
2023-08-31
Budget Start
2018-09-20
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Organized Research Units
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228