Gestational ethanol effects on dorsal striatal function and associated behaviors

拟议的研究计划的目标是调查妊娠乙醇(Etoh)的影响。 暴露在导致某些行为异常的背侧纹状体回路上，如受损 胎儿酒精谱障碍患者的决策、冲动增加和运动障碍 (FASD)。使用小鼠模型，我们将通过蒸汽室使个体在整个 胚胎和出生后早期，以模拟人类发育的三个三个月 (妊娠期Etoh)，并检查纹状体背侧回路和相关行为在 成人期。到目前为止的初步发现表明，在暴露于妊娠乙醇的成年小鼠中 在背侧纹状体(DLS)显示GABA能传递减少，似乎涉及 内源性大麻素的调节作用增强。我们没有观察到乙醇诱导的妊娠效应 谷氨酸能传递。妊娠期乙醇还会损害习惯学习；一种联想工具 涉及DLS的条件反射。1将确定这些妊娠期酒精中毒的机制 通过实现以下特定目的而产生的效果：1)确定异常的突触特异性 孕期乙醇染毒小鼠DLS中的GABA能微回路。为了实现这一点，我提出了一个病毒般的建议， 光遗传学和电生理实验检测三种主要的GABA能突触 纹状体中棘神经元(MSN)，由小白蛋白中间神经元形成的，由其他神经元形成的 MSN，以及由低阈值刺激的生长抑素中间神经元形成的神经元。2)妊娠期无水乙醇的抢救 接触联想学习和纹状体神经传递：可能的治疗途径。使用 在特定目标1中获得的信息1将使用药物来降低内源性大麻素的紧张程度 挽救受损的习惯学习和GABA能神经传递。加在一起，完成这个 该项目将为评估纹状体GABA能微电路的破坏奠定基础 是FASD中许多行为异常的基础，并提出了补偿方法 这些影响。

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.