Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

青少年大脑中酒精作用的分子机制

基本信息

批准号：
7467320
负责人：
JILLA SABETI
金额：
$ 9万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-10 至 2009-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7467320
关键词：
Adolescence Adolescent Adult Age Alcohol abuse Alcohol consumption Alcohol dependence Alcoholism Alcohols Allopregnanolone Animals Antibodies Award Behavioral Binding Biochemical Brain Brain region Brain-Derived Neurotrophic Factor CREB1 gene Calcium Channel Chromosome Pairing Chronic Cognitive Cognitive deficits Condition Development Electrophysiology (science)Ethanol Gene Expression Glutamate Receptor Glutamates Grant Hippocampus (Brain)Impaired cognition Laboratories Learning Link Long-Term Potentiation Maintenance Mediating Memory Memory impairment Mentors Molecular N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist National Institute on Alcohol Abuse and Alcoholism National Research Service Awards Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Pathway interactions Pharmacology Phosphorylation Plasma Predisposition Probability Protein Analysis Proteins Publications Rattus Research Personnel Risk Role Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Slice Steroids Synapses Synaptic Transmission Synaptic plasticity Testing Time Western Blotting age group age related alcohol effect alcohol exposure extracellular insight neurotensin mimic 2 novel postsynaptic pregnenolone sulfate presynaptic programs psychosocial receptor coupling research study response sigma receptors sigma-1 receptor tool voltage

项目摘要

DESCRIPTION (provided by applicant): Adolescents who use alcohol have a greater risk for developing memory and cognitive deficits compared to adults. Such cognitive and memory disturbances elicited by adolescent alcohol abuse significantly impact psychosocial functioning and can persist long into adulthood. The molecular mechanisms responsible for the persistence of memory deficits are unknown, but likely involve ethanol-induced changes at synapses involved in memory formation. Our findings show a novel enhancement of long-term potentiation (LTP) of synaptic responses in CA1 hippocampal synapses in animals that have been chronically exposed to ethanol as early adolescents. Similar ethanol exposure in older animals does not produce the same effects on hippocampal LTP. Hippocampal LTP is a form of synaptic plasticity that results in the persistent enhancement of excitatory synaptic transmission and is considered a substrate for memory. Importantly, LTP is triggered by an influx of intracellular Ca2+ and initiates downstream actions on signaling cascades and gene expression. Under control conditions LTP at CA1 synapses is initiated by Ca2+ influx via postsynaptic NMDA- subtype of glutamate receptors; whereas our findings show that NMDA-receptors are not involved in the enhanced LTP response in slices from rats exposed to ethanol as early-adolescents. The proposal will focus on identifying the Ca2+ signaling cascades that contribute to the unique LTP response produced by adolescent ethanol exposure. The experiments will incorporate cellular (extracellular electrophysiology and intracellular current-clamp recordings) and biochemical tools (Western blot protein analysis) in hippocampal CA1 slices from adolescent rats exposed to chronic intermittent ethanol and age-matched ethanol-na¿ve controls. We will test the hypotheses that ethanol exposure in adolescents (1) upregulates the expression and/or function of sigma-1-receptors in hippocampus, which are endogenous targets of neuroactive steroids and regulators of intracellular Ca2+ dynamics; (2) facilitates the activation of postsynaptic L-type voltagegated calcium channels; (3) activates critical signaling proteins, including the MAPK/ERK1/2, CREB, BDNF and TrKB-receptors that are linked to L-type Ca2+ channel activation. These experiments will provide critical insights into the molecular mechanisms responsible for the age-dependent switch in the LTP-activated pathways elicited by ethanol exposure during the adolescent period of development.

描述（由申请人提供）：与成年人相比，酗酒的青少年出现记忆和认知缺陷的风险更大。记忆缺陷持续存在的原因尚不清楚，但可能涉及乙醇诱导的参与记忆形成的突触变化。我们的研究结果表明，CA1 区突触反应的长期增强 (LTP) 出现了新的增强。青少年早期长期接触乙醇的动物的海马突触不会对年长动物的海马 LTP 产生相同的影响。 LTP 是一种突触可塑性，会导致兴奋性突触传递和增强。重要的是，LTP 由细胞内 Ca2+ 的流入触发，并在控制条件下启动信号级联和基因表达的下游作用。 CA1 突触的 LTP 是由 Ca2+ 通过谷氨酸受体的突触后 NMDA 亚型流入启动的；而我们的研究结果表明，在青少年早期暴露于乙醇的大鼠切片中，NMDA 受体不参与增强的 LTP 反应。确定 Ca2+ 信号级联有助于青少年乙醇暴露产生的独特 LTP 反应。这些实验将结合细胞（细胞外电生理学和细胞外电生理学）。暴露于慢性间歇性乙醇和年龄匹配乙醇-na的青少年大鼠海马CA1切片中的细胞内电流钳记录）和生化工具（蛋白质印迹蛋白质分析）我们将测试以下假设：青少年接触乙醇 (1) 上调海马中 sigma-1 受体的表达和/或功能，这些受体是神经活性类固醇的内源性靶标和细胞内 Ca2+ 动力学的调节剂；突触后 L 型电压门控钙通道的激活；(3) 激活关键信号蛋白，包括 MAPK/ERK1/2、CREB、BDNF 和与 L 型 Ca2+ 通道激活相关的 TrKB 受体这些实验将为青春期发育期间乙醇暴露引起的 LTP 激活途径中年龄依赖性开关的分子机制提供重要的见解。