Gestational ethanol effects on dorsal striatal function and associated behaviors

妊娠期乙醇对背侧纹状体功能和相关行为的影响

基本信息

批准号：
9042902
负责人：
Verginia Carmella Cuzon Carlson
金额：
$ 24.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042902
关键词：
2-arachidonylglycerol Adult Age-Months Alcohol consumption Alcohols Basal Ganglia Behavior Behavioral Biological CNR1 gene Cells Centers for Disease Control and Prevention (U.S.)Congenital Abnormality Control Animal Corpus striatum structure Data Decision Making Defect Dorsal Electrophysiology (science)Embryo Endocannabinoids Enzyme Inhibition Enzymes Ethanol Exposure to Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Glutamates Human Human Development Hyperactive behavior Impairment Impulsivity Individual Infant Interneurons Lateral Lead Learning Manuscripts Memory impairment Mentors Molecular Movement Mus Neurons Operant Conditioning Output Parvalbumins Phase Play Pregnancy Production Psyche structure Reporting Research Role Somatostatin Specificity Symptoms Synapses System Technology Testing Viral Western Blotting Woman alcohol effect anandamide binge drinking cannabinoidergic transmission classical conditioning disability drinking endocannabinoid signaling habit learning inhibitor/antagonist learning strategy lipoprotein lipase motor deficit motor disorder mouse model neural circuit neurotransmission optogenetics partial recovery patch clamp postnatal receptor research study transmission process vapor

项目摘要

The objective of the proposed research plan is to investigate the effects of gestational ethanol (EtOH) exposure on dorsal striatal circuitry that contribute to some of the behavioral abnormalities, such as impaired decision making, increased impulsivity, and motor deficits that observed in Fetal Alcohol Spectrum Disorder (FASD). Using a mouse model, we will expose individuals via a vapor chamber to ethanol throughout the embryonic and early postnatal period in order to mimic the three trimesters of human development (gestational EtOH) and examine the disposition of dorsal striatal circuitry and associated behaviors during adulthood. Preliminary findings to date indicate that in adult mice that were exposed to gestational EtOH display decreased GABAergic transmission in the dorsal lateral striatum (DLS) that appears to involve increased modulation by endocannabinoids. We observed no gestational EtOH-induced effect of glutamatergic transmission. Gestational EtOH also impairs habit learning; a type of associative instrumental conditioning that involves the DLS. 1 will determine the mechanisms underlying these gestational EtOH effects by accomplishing the following specific aims: 1) Determine the synaptic specificity of aberrant GABAergic microcircuits in the DLS of mice exposed to gestational EtOH. To accomplish this 1 propose viral, optogenetic, and electrophysiological experiments to examine the three major GABAergic synapses onto striatal medium spiny neurons (MSNs), those formed by parvalbumin interneurons, those formed by other MSNs, and those formed by low-threshold spiking somatostatin interneurons. 2) Rescue of gestational EtOH exposure on associative learning and striatal neurotransmission: possible avenues for treatment. Using the information gained in specific aim 1,1 will use pharmacological agents to decrease endocannabinoid tone to rescue the impaired habit learning and GABAergic neurotransmission.Taken together, the completion of this project will lay the groundwork for assessing how disruptions of the GABAergic microcircuitry of the striatum underlie many of the behavioral abnormalities seen in FASD and suggest approaches to compensate for these effects.

拟议的研究计划的目的是研究妊娠乙醇（ETOH）的影响在背侧纹状体电路上暴露有助于某些行为异常，例如受损在胎儿酒精谱系中观察到的决策，冲动性增加和运动不足（FASD）。使用鼠标模型，我们将通过蒸气室暴露于整个乙醇为了模仿人类发展的三个三物（妊娠ETOH）并检查背纹状体电路的处置和相关行为成年。迄今为止的初步发现表明，在暴露于妊娠ETOH的成年小鼠中显示出似乎涉及的背侧纹状体（DLS）中的GABA能传播降低内源性大麻素的调节增加。我们观察到没有妊娠ETOH诱导的作用谷氨酸能传输。妊娠ETOH也会损害习惯学习；一种协会工具涉及DLS的条件。 1将确定这些妊娠ETOH的基础机制通过完成以下特定目的来效果：1）确定异常的突触特异性暴露于妊娠ETOH的小鼠DLS中的GABA能微电路。为了完成这一提出病毒，光遗传学和电生理实验，以检查三个主要的GABA能突触纹状体培养基神经元（MSN），由白细胞蛋白中间神经元形成的纹状体培养基神经元（MSN） MSN以及由低阈值尖峰的生长抑素中间神经元组成的。 2）营救妊娠ETOH 相关学习和纹状体神经传递的暴露：可能的治疗途径。使用在特定AIM 1,1中获得的信息将使用药理学剂将内源性大麻素的张力降低至营救受损的习惯学习和GABA能神经传递。一起完成项目将为评估纹状体的GABA能微电路的干扰奠定基础 FASD中看到的许多行为异常的基础，并提出了补偿的方法这些影响。