Cocaine Regulation of Hilar Mossy Cell Activity

可卡因对肺门苔藓细胞活性的调节

• 批准号: 9181015
• 负责人: Jeffrey Loren Barr
• 金额: $ 7.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181015
• 关键词: Abstinence; Adaptive Behaviors; Affective; Anxiety; Behavior; Brain; Brain region; Cells; Chronic; Clinical; Cocaine; Cocaine Dependence; Complex; Cues; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Emotional; Environment; Exposure to; Genetic; Glutamates; Glycogen Synthase Kinase 3; Goals; Hilar; Hippocampal Formation; Hippocampus (Brain); Homeostasis; Immunofluorescence Immunologic; Individual; Interneurons; Lead; Learning; Mediating; Memory; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Play; Population; Predisposition; Process; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Recording of previous events; Regulation; Relapse; Research; Rewards; Role; Signal Transduction; Stimulus; Stress; Structure; System; Testing; Western Blotting; addiction; base; behavior influence; cocaine exposure; conditioning; density; drug of abuse; drug reward; glycogen synthase kinase 3 beta; granule cell; inhibitor/antagonist; insight; memory process; nerve supply; neurobiological mechanism; neurochemistry; neurotransmission; preference; prevent; psychostimulant; response

Project Summary Addiction is destructive for addicted individuals and, simultaneously, has devastating societal consequences. An important goal of addiction research is to understand the neurobiological mechanisms underlying this disease state. Evidence suggests that chronic psychostimulant use alters hippocampal function which may lead to emotional states that promote the cycle of addiction. The hippocampus is functionally segregated along its longitudinal axis into dorsal and ventral regions where the ventral region preferentially regulates stress and anxiety, while the dorsal preferentially regulates spatial learning and memory. The proposed studies will increase understanding of the mechanisms through which cocaine modulates hippocampal function to influence behavior. Hilar mossy cells are an under-investigated component of the local circuitry of the hippocampal formation. The glutamatergic mossy cell innervates both excitatory granule cells and inhibitory interneurons, therefore, a proposed major function of mossy cells is to integrate the functions of large numbers of neurons along the septotemporal axis of the hippocampus. Glycogen synthase kinase-3β (GSK3β) is a highly conserved serine/threonine protein kinase involved in hippocampus-regulated behaviors. Accordingly, the activation of hilar mossy cells and mossy cell GSK3β pathway activity by re-exposure to a cocaine-paired environment will be characterized in the dorsal and ventral hippocampus (Aim 1). Next, the role of dopamine D2 receptors and GSK3β activation by cocaine in the development and expression of cocaine-associated conditioned place preference behavior will be investigated (Aim 2). The results of the proposed studies will demonstrate the impact of cocaine exposure on the local hippocampal circuitry and the cellular pathways involved in cocaine reward-context associations. These studies will lay the groundwork for more comprehensive studies investigating the influence of psychostimulants on the hippocampal circuitry and provide critical insight into the contribution of mossy cells to the mechanisms through which cocaine alters hippocampal function and plasticity implicated in addiction-related behaviors. Reversing or preventing drug- induced adaptations to the hippocampus may prove beneficial in the treatment of the complex process of addiction.

项目摘要 成瘾对成瘾者来说是毁灭性的，同时也会产生毁灭性的社会后果。 成瘾研究的一个重要目标是了解其背后的神经生物学机制 疾病状态。有证据表明，长期使用精神兴奋剂会改变海马体的功能， 导致情绪状态，促进成瘾的循环。海马体在功能上是沿着 它的纵轴分为背侧和腹侧区域，其中腹侧区域优先调节应力， 焦虑，而背侧优先调节空间学习和记忆。拟议的研究将 增加对可卡因调节海马功能的机制的理解， 影响行为。肺门苔藓细胞是肺门局部电路的一个研究不足的组成部分， 海马结构海马能苔藓细胞既支配兴奋性颗粒细胞，又支配抑制性颗粒细胞。 因此，苔藓细胞的一个主要功能是整合大量的功能， 神经元沿着海马体的隔颞轴。糖原合成酶激酶-3 β（GSK 3 β）是一种 参与海马调节行为的高度保守的丝/苏蛋白激酶。因此，委员会认为， 再暴露于可卡因对门苔藓细胞和苔藓细胞GSK 3 β通路活性的激活 环境将在背侧和腹侧海马中表征（目标1）。接下来，多巴胺的作用 可卡因诱导的D2受体和GSK 3 β在可卡因相关性胶质瘤的发生和表达中的作用 条件性位置偏好行为将被研究（目标2）。拟议研究的结果将 证明可卡因暴露对局部海马电路和细胞通路的影响 参与可卡因奖励相关的研究这些研究将为更多的 研究精神兴奋剂对海马电路影响的综合研究， 提供了关键的洞察苔藓细胞的贡献机制，通过可卡因改变 成瘾相关行为中的海马功能和可塑性。逆转或预防药物- 诱导适应海马可能证明有益于治疗复杂的过程， 成瘾