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Prenatal Ethanol Exposure and Nitric Oxide Signaling in Serotonin Neurons

产前乙醇暴露和血清素神经元中的一氧化氮信号传导

基本信息

批准号：
10470171
负责人：
SAMIR HAJ-DAHMANE
金额：
$ 35.89万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470171
关键词：
Address Affect Animal Model Animals Anxiety Anxiety Disorders Behavioral Chemosensitization Child Cognitive Cognitive deficits Development Disease Dorsal Electrophysiology (science)Exhibits Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Foundations Functional disorder Future Glutamates Goals Health Homeostasis Impairment In Vitro Individual Knowledge Label Mediating Mental Depression Mental disorders Modeling Mood Disorders Neurons Neurotransmitters Nitric Oxide Outcome Outcome Study Patients Pharmaceutical Preparations Pharmacology Phenotype Play Rattus Research Role Serotonergic System Serotonin Signal Transduction Societies Stress Synapses Synaptic Transmission System Teratogenic effects Testing alcohol effect anxiety-like behavior brain dysfunction cost dorsal raphe nucleus effective therapy experimental study family burden interdisciplinary approach motor deficit neural circuit neurodevelopment neuronal circuitry neuropsychiatric disorder neurotransmission novel novel therapeutic intervention optogenetics transmission process wireless

项目摘要

Project Summary 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.

项目总结