Pathway specific ecstasy-induced plasticity of excitability in the subiculum

途径特异性摇头丸诱导的下托兴奋性可塑性

• 批准号: 7636741
• 负责人: DONALD C COOPER
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636741
• 关键词: Animal Model; Apical; Area; Axon; Bathing; Body Temperature; Brain; Brain region; Caliber; Cells; Cognitive; Dendrites; Dendritic Spines; Detection; Dextroamphetamine; Distal; Dose; Dyes; Emotions; Exhibits; Exposure to; Fever; Fluorescent Dyes; Frequencies; Goals; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Injection of therapeutic agent; Label; Learning; Length; Link; Measurement; Measures; Memory; Memory impairment; Monkeys; Morphology; Motivation; Nerve; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Physiological; Plastics; Play; Predisposition; Prefrontal Cortex; Property; Rattus; Reporting; Research; Rewards; Rodent Model; Role; Route; Saline; Schedule; Serotonin; Short-Term Memory; Signal Transduction; Staining method; Stains; Structure; Synapses; System; Testing; Time; Treatment Protocols; Trees; Vertebral column; Width; Withdrawal; Work; base; club drug; cocaine exposure; density; ecstasy; frontal lobe; hippocampal pyramidal neuron; improved; innovation; mind control; nerve supply; neuronal cell body; neurophysiology; neurotoxic; nonhuman primate; patch clamp; pleasure; psychostimulant; public health relevance; reconstruction; research study; response; voltage

DESCRIPTION (provided by applicant): The subiculum (SUB) subregion of the hippocampal formation functions as an interface between the brain's memory systems, and motivation/reward systems. We have shown that the SUB is vulnerable to psychostimulant-induced plastic changes in its excitability. This form of plasticity can alter the SUB integration of synaptic input, and accordingly, its output, thus disrupting the routing of information out of the hippocampus to the SUB target structures, including the nucleus accumbens and prefrontal cortex. It is clear that repeated MDMA exposure disrupts hippocampal and reward related learning and memory, but the neurophysiological mechanisms responsible for these effects have thus far escaped detection. We have shown that SUB bursting neurons are more vulnerable to repeated d-amphetamine-induced plasticity, which decreases their Na+ channel function and alters the timing of their bursting output but it is not known whether MDMA can do the same. Although the two main target structures of the SUB are well established the functional differences between neurons that project to the two major output structures of the SUB are unknown. This is particularly relevant since we have characterized two functional classes of SUB neurons as bursting and non-bursting with potentially differing susceptibility to MDMA induced functional alterations. We plan to use an innovative combination of retrograde dye labeling and patch-clamping measurements of intrinsic excitability from SUB neurons that project specifically to either the prefrontal cortex or nucleus accumbens to functionally characterize neurons in association with their target. This work will: 1) Establish if repeated MDMA alters SUB neuronal intrinsic excitability and dendritic morphology; 2) Determine if SUB neurons classified based on their projection target (accumbens or prefrontal cortex) or their output mode (bursting or nonbursting) exhibit differential MDMA-induced plasticity; and 3) Provide the basis for a larger research plan dedicated to understanding the mechanism and significance of the pathway specific MDMA induced plasticity. A detailed understanding of the functional output that the SUB sends to its targets in the accumbens or frontal cortex and how this output may be altered by repeated exposure to MDMA will greatly improve our interpretation of information flow out of the hippocampus and the cognitive disruptive effects of MDMA. PUBLIC HEALTH RELEVANCE: The club drug ecstasy activates areas of the brain that control emotion, memory, motivation and pleasure in rats, monkeys and humans alike, but if it is taken repeatedly, just a few doses can cause widespread damage to these regions. The brain region most vulnerable to damage is called the subiculum and it plays an important role as an interface between memory systems and motivation/emotion systems. The goal of this proposal is to use a rodent model to determine what kind of information the subiculum transmits and examine how this is altered after short and long-term withdrawal from ecstasy.

描述（由申请人提供）：海马形成的亚面（子）子区域作为大脑记忆系统和动机/奖励系统之间的接口。我们已经表明，该潜艇容易受到精神刺激诱导的塑性变化的攻击。这种可塑性形式可以改变突触输入的子整合，因此，其输出，从而破坏了海马中信息从海马到子靶结构的路由，包括八核和前额叶皮层。显然，重复的MDMA暴露破坏了海马和奖励相关的学习和记忆，但是造成这些影响的神经生理机制迄今已逃脱了检测。我们已经表明，子爆发神经元更容易受到重复的D-苯丙胺诱导的可塑性的影响，从而降低了其Na+通道功能并改变其爆发输出的时机，但尚不知道MDMA是否可以做同样的事情。尽管该子的两个主要目标结构已经很好地确定了向子的两个主要输出结构投射到两个主要输出结构的神经元之间的功能差异。这尤其重要，因为我们将两个功能类别的子神经元的功能类别表征为爆发和非爆炸，并且对MDMA诱导的功能改变的敏感性有所不同。我们计划利用逆行染料标记和贴片夹夹的创新组合，这些结合是从子神经元中的固有兴奋性测量，这些兴奋性是专门针对前额叶皮层或伏隔核的，以使神经元与靶靶相关。这项工作将：1）确定是否重复使用MDMA会改变下神经元的内在兴奋性和树突形态； 2）确定基于其投影靶标（伏伏或额叶皮层）或其输出模式（爆发或非爆炸）分类的亚神经元表现出差异MDMA诱导的可塑性； 3）为更大的研究计划提供了基础，该计划致力于理解途径特定MDMA诱导可塑性的机制和意义。对子伏隔或额叶皮层中子发送到其目标的功能输出的详细理解，以及如何通过反复接触MDMA来改变该输出，这将大大改善我们对信息流从海马的解释以及MDMA的认知破坏性效应。公共卫生相关性：俱乐部毒品摇头丸激活大脑的区域，以控制大鼠，猴子和人类的情绪，记忆力，动机和愉悦感，但是如果反复服用，只有几剂剂量会对这些地区造成广泛的损害。最容易受到损害的大脑区域称为亚致，它在记忆系统与动机/情感系统之间的接口中起着重要作用。该提案的目的是使用啮齿动物模型来确定下部传输类型的信息，并检查在短期和长期退出摇头丸后如何改变这种情况的信息。