Pathway specific ecstasy-induced plasticity of excitability in the subiculum

描述（由申请人提供）：海马体形成的下丘（SUB）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，SUB很容易受到精神兴奋剂引起的兴奋性可塑性变化的影响。这种形式的可塑性可以改变突触输入的亚整合，并相应地改变其输出，从而破坏信息从海马体到亚目标结构的路径，包括伏隔核和前额皮质。很明显，重复的MDMA暴露会破坏海马和与奖励相关的学习和记忆，但负责这些影响的神经生理机制迄今尚未被发现。我们已经证明，亚破裂神经元更容易受到d-安非他明诱导的反复可塑性的影响，这降低了它们的Na+通道功能，改变了它们破裂输出的时间，但不知道MDMA是否也能做到这一点。虽然SUB的两个主要目标结构已经很好地确定，但投射到SUB的两个主要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，因为我们已经将亚神经元的两个功能类别描述为破裂和非破裂，它们对MDMA诱导的功能改变的潜在易感性不同。我们计划使用一种创新的组合，逆行染料标记和贴片夹测量亚神经元的内在兴奋性，这些亚神经元特异性地投射到前额叶皮层或伏隔核，以功能表征与其目标相关的神经元。这项工作将：1)确定重复MDMA是否改变亚神经元的内在兴奋性和树突形态；2)确定基于投射目标（伏隔或前额皮质）或输出模式（爆裂或非爆裂）分类的亚神经元是否表现出mdma诱导的不同可塑性；3)为更大的研究计划提供基础，致力于了解途径特异性MDMA诱导可塑性的机制和意义。详细了解SUB向伏隔核或额叶皮层的目标发送的功能输出，以及这种输出如何因反复暴露于MDMA而改变，将大大提高我们对海马信息流和MDMA认知破坏性影响的解释。公共健康相关性：俱乐部毒品摇头丸能激活老鼠、猴子和人类大脑中控制情绪、记忆、动机和快乐的区域，但如果反复服用，仅仅几剂就能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，它在记忆系统和动机/情感系统之间起着重要的接口作用。这个提议的目的是用一个啮齿类动物模型来确定枕骨下传递什么样的信息，并检查短期和长期从摇头丸中退出后这种信息是如何改变的。

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.