Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

青少年大脑中酒精作用的分子机制

• 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
• 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

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，饮酒的青少年出现记忆和认知缺陷的风险更大。青少年酗酒引起的这种认知和记忆障碍会严重影响社会心理功能，并可能持续到成年期。导致记忆缺陷持续存在的分子机制尚不清楚，但可能涉及乙醇诱导的记忆形成突触变化。我们的研究结果表明，在青少年早期长期接触乙醇的动物中，CA1 海马突触的突触反应的长期增强 (LTP) 得到了新的增强。老年动物中类似的乙醇暴露不会对海马 LTP 产生相同的影响。海马 LTP 是突触可塑性的一种形式，可导致兴奋性突触传递持续增强，被认为是记忆的基础。重要的是，LTP 由细胞内 Ca2+ 的流入触发，并启动信号级联和基因表达的下游作用。在控制条件下，CA1 突触处的 LTP 是由 Ca2+ 经由突触后 NMDA- 谷氨酸受体亚型流入而启动的；而我们的研究结果表明，在青春期早期暴露于乙醇的大鼠切片中，NMDA 受体并不参与增强的 LTP 反应。该提案将重点确定 Ca2+ 信号级联，这些级联有助于青少年乙醇暴露产生的独特 LTP 反应。实验将结合细胞（细胞外电生理学和细胞内电流钳记录）和生化工具（蛋白质印迹蛋白质分析）到暴露于慢性间歇性乙醇和年龄匹配的未接触乙醇的青少年大鼠的海马CA1切片中。我们将检验以下假设：青少年接触乙醇 (1) 上调海马 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； (2) 促进突触后L型电压门控钙通道的激活； (3) 激活关键信号蛋白，包括与 L 型 Ca2+ 通道激活相关的 MAPK/ERK1/2、CREB、BDNF 和 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。