Interactions Among Hippocampal Interneuron Circuits

海马中间神经元回路之间的相互作用

• 批准号: 7595718
• 负责人: BRADLEY E ALGER
• 金额: $ 27.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595718
• 关键词: Affect; Behavior; Behavioral; Brain; Brain Diseases; CNR1 gene; Cannabinoids; Cholecystokinin; Complex; Drug Delivery Systems; Drug abuse; Endocannabinoids; Epilepsy; Hippocampus (Brain); In Vitro; Interneurons; Link; Mediating; Molecular; Neurons; Neuropeptides; Opioid; Opioid Receptor; Optics; Output; Parvalbumins; Predisposition; Property; Pyramidal Cells; Role; Schizophrenia; Slice; Structure; System; Techniques; Testing; Tetragastrin; Ursidae Family; Work; drug of abuse; endogenous cannabinoid system; endogenous opioids; mu opioid receptors; neurophysiology; receptor; response

DESCRIPTION (provided by applicant): The endogenous opioid and cannabinoid systems are powerful neurophysiological modulators of excitability in the brain, and have been linked to numerous behaviors. They are also substrates for drugs of abuse. Yet despite their unique molecular and pharmacological identities, the systems often appear to be intertwined, and drugs targeted to one system can modify responses mediated by the other system. The cellular interface between opioids and cannabinoids is not generally understood: it probably varies depending on the brain structures and behaviors involved. The mammalian hippocampus has intricate endogenous opioid and cannabinoid systems which have been studied individually. However, there is virtually no information about the ways in which they overlap or how they might interact. A potentially crucial link may be provided by the neuropeptide, cholecystokinin (CCK), which potently controls actions mediated by a major opioid receptor, the f-receptor (MOR), at both cellular and behavioral levels. The endogenous cannabinoid system in hippocampus is targeted mainly to the particular set of GABAergic interneurons that also contain CCK. In hippocampus, the brain cannabinoid receptor, CB1, is almost exclusively expressed by CCK-containing interneurons. The f-opioid receptor is localized on the neurochemically-distinct, parvalbumin-containing interneurons, that express neither CCK nor CB1. The precise and complex convergence of these three systems onto interneurons that target pyramidal cells, which are the major hippocampal output neurons, cannot be a chance occurrence. The objective of this proposal is to test the Working Hypothesis that the endogenous opioid, cannabinoid and CCK systems mutually interact via hippocampal interneurons, and thereby jointly regulate the excitability and susceptibility to short- and long-term plasticity of the pyramidal cells. The prominent roles of these systems in drug abuse and major brain disorders such as epilepsy and schizophrenia underscore the significance of the inherent unresolved questions. We will use a variety of experimental approaches in in vitro brain slices, including electrophysiological, immunocytochemical, and optical techniques, to test the major hypothesis of this project. The Specific Aims are to test the following hypotheses: 1. The interneurons that are sensitive to opioids and cannabinoids can be functionally classified by their pharmacological properties. 2. CCK affects both f-opioid and endocannabinoid-sensitive interneurons. 3. Short-term inhibitory response plasticities mediated via MORs and CB1 interact with each other and with CCK. 4. Long-term inhibitory response plasticities mediated via MORs and CB1 interact with each other and with CCK.

描述(申请人提供)：内源性阿片和大麻素系统是大脑兴奋性的强大神经生理调节剂，并与许多行为有关。它们也是滥用药物的底物。然而，尽管它们具有独特的分子和药理学特性，但这些系统往往看起来是相互交织的，而针对一个系统的药物可以改变另一个系统介导的反应。阿片类药物和大麻素之间的细胞界面并不普遍被理解：它可能会根据所涉及的大脑结构和行为而变化。哺乳动物的海马体具有复杂的内源性阿片和大麻素系统，这些系统已经被单独研究过。然而，几乎没有关于它们重叠的方式或它们可能如何相互作用的信息。一个潜在的关键联系可能是神经肽CCK(CCK)，它在细胞和行为水平上有效地控制主要阿片受体f-受体(MOR)介导的活动。海马区的内源性大麻素系统主要针对特定的GABA能中间神经元，这些神经元也含有CCK。在海马区，大脑大麻素受体CB1几乎完全由含有CCK的中间神经元表达。F-阿片受体定位于神经化学不同的、含有小白蛋白的中间神经元，既不表达CCK，也不表达CB1。这三个系统精确而复杂地会聚到以锥体细胞为目标的中间神经元上，锥体细胞是海马体的主要输出神经元，这不可能是偶然的。这个建议的目的是验证内源性阿片、大麻和CCK系统通过海马神经元相互作用的工作假说，从而共同调节锥体细胞的兴奋性和对短期和长期可塑性的敏感性。这些系统在药物滥用以及癫痫和精神分裂症等重大大脑疾病中的突出作用，突显了内在悬而未决的问题的重要性。我们将在体外脑片上使用各种实验方法，包括电生理学、免疫细胞化学和光学技术，来检验这个项目的主要假设。具体目的是验证以下假设：1.对阿片类药物和大麻类药物敏感的中间神经元可以根据其药理学特性进行功能分类。2.CCK既影响f-阿片敏感中间神经元，也影响内源性大麻敏感中间神经元。3.由MORS和CB1介导的短期抑制反应可塑性相互作用，并与CCK相互作用。4.通过MORS和CB1介导的长期抑制反应可塑性相互作用，并与CCK相互作用。