Pathway specific ecstasy-induced plasticity of excitability in the subiculum

描述（由申请人提供）：海马结构的下托（subiculum）亚区作为大脑记忆系统和动机/奖励系统之间的界面发挥作用。我们已经证明，大脑皮层的兴奋性易受精神兴奋剂诱导的可塑性变化的影响。这种形式的可塑性可以改变突触输入的整合，因此，它的输出，从而破坏了信息从海马体到海马体目标结构的路由，包括丘脑核和前额叶皮层。很明显，反复接触MDMA会破坏海马和奖赏相关的学习和记忆，但迄今为止，导致这些影响的神经生理学机制尚未被发现。我们已经证明，MDMA爆裂神经元更容易受到重复的d-苯丙胺诱导的可塑性，这会降低它们的Na+通道功能，并改变它们爆裂输出的时间，但目前尚不清楚MDMA是否也能做到这一点。虽然两个主要的目标结构的神经元投射到两个主要的输出结构的神经元之间的功能差异是未知的。这是特别相关的，因为我们的特点是两个功能类的神经元爆裂和非爆裂潜在不同的易感性MDMA诱导的功能改变。我们计划使用逆行染料标记和膜片钳测量的内在兴奋性的一个创新的组合，从特定的项目，无论是前额叶皮层或核神经元的功能特征与他们的目标。这项工作将：1）确定重复的MDMA是否改变了神经元的内在兴奋性和树突形态; 2）确定神经元是否基于其投射靶点分类（大脑皮层或前额叶皮层）或其输出模式（爆裂或非爆裂）表现出不同的MDMA诱导的可塑性;和3）为致力于了解通路特异性MDMA诱导可塑性的机制和意义的更大研究计划提供基础。详细了解海马体向其位于海马体或额叶皮层的目标发送的功能输出，以及这种输出如何被重复暴露于MDMA所改变，将大大改善我们对海马体信息流和MDMA认知破坏效应的解释。公共卫生相关性：俱乐部毒品摇头丸激活了大脑中控制情绪，记忆，动机和快乐的区域，在老鼠，猴子和人类身上都是如此，但如果反复服用，只需几次剂量就可以对这些区域造成广泛的损害。最容易受到损伤的大脑区域被称为下托，它作为记忆系统和动机/情感系统之间的接口发挥着重要作用。这项提议的目的是使用啮齿动物模型来确定下托传递什么样的信息，并研究在短期和长期戒断摇头丸后，下托是如何改变的。

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.