Pathway specific ecstasy-induced plasticity of excitability in the subiculum

描述(申请人提供)：海马体结构的下丘脑(亚)亚区作为大脑记忆系统和动机/奖励系统之间的接口。我们已经证明，潜伏期对心理刺激剂诱导的可塑性变化的兴奋性是脆弱的。这种形式的可塑性可以改变突触输入的亚整合，并相应地改变其输出，从而扰乱信息从海马体到亚目标结构的路由，包括伏隔核和前额叶皮质。很明显，反复接触MDMA会扰乱与海马区和奖赏相关的学习和记忆，但到目前为止，导致这些影响的神经生理机制还没有被发现。我们已经证明，亚爆发性神经元更容易受到重复d-苯丙胺诱导的可塑性的影响，这种可塑性降低了它们的Na+通道功能，改变了它们爆发性输出的时间，但MDMA是否可以做到这一点尚不清楚。虽然亚单位的两个主要靶结构已经确定，但投射到亚单位两个主要输出结构的神经元之间的功能差异尚不清楚。这一点特别相关，因为我们已经将两种功能类别的亚神经元描述为爆发性和非爆发性，它们对MDMA诱导的功能改变的敏感性可能不同。我们计划使用逆行染料标记和膜片钳测量的创新组合，测量特定投射到前额叶皮质或伏隔核的亚神经元的内在兴奋性，以确定与其目标相关的神经元的功能特征。这项工作将：1)确定重复MDMA是否改变了亚神经元的固有兴奋性和树突形态；2)确定根据其投射目标(伏隔或前额叶皮质)或其输出模式(爆裂或非爆裂)分类的亚神经元是否表现出不同的MDMA诱导可塑性；以及3)为致力于了解特定途径的MDMA诱导可塑性的机制和意义的更大研究计划提供基础。详细了解潜水器向伏隔或额叶皮质的目标发送的功能输出，以及反复接触MDMA可能会如何改变这一输出，将极大地改善我们对海马体外信息流的解释，以及MDMA的认知干扰效应。与公共健康相关：俱乐部药物摇头丸激活了大鼠、猴子和人类大脑中控制情绪、记忆、动机和快感的区域，但如果反复服用，只需少量剂量就可能对这些区域造成广泛损害。大脑中最容易受到损伤的区域被称为下丘脑，它在记忆系统和动机/情绪系统之间起着重要的接口作用。这项提议的目的是使用啮齿动物模型来确定下丘脑传递什么样的信息，并检查这种信息在短期和长期停止摇头丸后是如何改变的。

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.