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

• 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
• 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

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调查妊娠乙醇（EtOH）的影响， 暴露于背侧纹状体回路，导致一些行为异常，如受损 在胎儿酒精谱系障碍中观察到的决策、冲动性增加和运动缺陷 （FASD）。使用小鼠模型，我们将通过蒸汽室将个体暴露于乙醇中， 胚胎期和出生后早期，以模仿人类发育的三个月 （妊娠期EtOH），并检查背侧纹状体回路的分布和相关行为， 成年迄今为止的初步研究结果表明，在暴露于妊娠期乙醇的成年小鼠中， 显示背侧纹状体（DLS）中GABA能传递减少，似乎涉及 增强内源性大麻素的调节作用。我们没有观察到妊娠期EtOH诱导的 电磁波传输。乙醇也会损害习惯学习，这是一种联想性的工具。 涉及DLS的调节。1将确定这些妊娠EtOH的机制 通过实现以下特定目标来实现效果：1）确定异常突触的突触特异性。 暴露于妊娠EtOH的小鼠DLS中的GABA能微电路。为了实现这一点，我提议病毒， 光遗传学和电生理学实验来检查三个主要的GABA能突触， 纹状体中棘神经元（MSNs），由小白蛋白中间神经元形成的那些，由其他神经元形成的那些， MSN，和那些形成低阈值尖峰生长抑素中间神经元。2)妊娠期EtOH抢救 暴露于联想学习和纹状体神经传递：可能的治疗途径。使用 具体目标1，1中获得的信息将使用药理学试剂降低内源性大麻素浓度， 拯救受损的习惯学习和GABA能神经传递。综合考虑， 该项目将为评估纹状体GABA能微电路的中断 是FASD中许多行为异常的基础，并提出了补偿FASD的方法。 这些影响。