Synaptic Transmission: Modulation, Plasticity And Effect

突触传递：调节、可塑性和效应

• 批准号: 6674347
• 负责人: David M Lovinger
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6674347
• 关键词: AMPA receptors; Rodentias; alcoholism /alcohol abuse; biological signal transduction; cannabinoid receptor; drug abuse; electrophysiology; hippocampus; intracellular; neural plasticity; neurochemistry; neurophysiology; nicotinic receptors; receptor expression; synapses

The focus of research in the Laboratory of Integrative Neuroscience (LIN) is the determination of mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neural functions. The LIN was established in 2001 and the Laboratory Chief and coworkers established a functional laboratory in the Section on Synaptic Physiology (SSP) in February 2002. Studies already underway in the laboratory are examining alcohol effects on NMDA and non-NMDA glutamate receptor function and synaptic transmission mediated by these receptors. Recent findings indicate that alcohol inhibits AMPA receptor function by promoting receptor desensitization. This alteration in receptor function may underlie ethanol inihibition of AMPAR-mediated synaptic transmission which is particularly prominent in the hippocampus of young rodents. Experiments in the laboratory are also conducted on the role of cannabinoid CB1 and nicotinic acetylcholine (ACh) receptors in synaptic plasticity in dorsal striaum. Both receptors play a role in the induction of striatal long-term synaptic depression (LTD). Nicotinic receptors stimulate dopamine release that is crucial for LTD induction, while CB1 receptors activated by an endocannabinoid "retrograde signal" are crucial in linking postsynaptic neuronal activation to presynaptic inhibition during the initial phases of LTD. Because these receptors are targets for drugs of abuse, it has been hypothesized that the role of these receptors in long-lasting plastic changes in striatal synaptic transmission such as LTD could play important roles in transition from drug-taking to addiction. Current studies are aimed at understanding the intracellular signals that link receptor activation to induction of plasticity, and determining the mechanisms involved in long-lasting depression of transmission. Future plans for LIN expansion include the formation of Sections on Behavioral Science and Genetics (SBSG) and Structural Biology (SB) that will take work in this laboratory group from single molecules up to the intact animal. Design of the SBSG is already underway, and plans are to combine new techniques for molecular genetic analysis and manipulation of rodents with sophisticated behavioral measurements. Topics to be examined are likely to include examinination of the genetic basis of alcohol sensitivity and withdrawal, and the molecular basis of learning and memory.

整合神经科学实验室（LIN）研究的重点是确定神经调节和可塑性的机制以及酒精和其他滥用药物对这些神经功能的影响。 LIN成立于2001年，实验室负责人和同事于2002年2月在突触生理学（SSP）部分建立了一个功能实验室。最近的发现表明，酒精通过促进受体脱敏抑制AMPA受体功能。受体功能的这种改变可能是AMPAR介导的突触传播的乙醇构成基础，这在年轻啮齿动物的海马中尤为突出。还针对大麻素CB1和烟碱乙酰胆碱（ACH）受体在背侧肌张力中的突触可塑性中的作用也进行了实验室的实验。两种受体在诱导纹状体长期突触抑郁症（LTD）中起作用。烟碱受体刺激对LTD诱导至关重要的多巴胺释放，而由内源性大麻素的“逆行信号”激活的CB1受体对于将突触后神经元激活与LTD初始阶段的突触前抑制作用联系起来至关重要。由于这些受体是滥用药物的靶标，因此已经假设这些受体在诸如LTD等纹状体突触传播中持久的塑性变化中的作用在从吸毒到成瘾的过渡中起着重要作用。当前的研究旨在了解将受体激活与塑性诱导联系起来的细胞内信号，并确定与持久传播抑郁有关的机制。 LIN扩展的未来计划包括对行为科学和遗传学（SBSG）和结构生物学（SB）的部分形成，这些部分将从单个分子到完整的动物，从而在该实验室中进行工作。 SBSG的设计已经在进行中，并且计划将新技术结合到分子遗传分析和对啮齿动物的操纵，并通过复杂的行为测量进行操纵。要检查的主题可能包括检查酒精敏感性和退缩的遗传基础，以及学习和记忆的分子基础。