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.

项目概要 成瘾对成瘾者具有破坏性，同时也会造成毁灭性的社会后果。 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 有证据表明，长期使用精神兴奋剂会改变海马功能，这可能会改变海马功能。 导致促进成瘾循环的情绪状态 海马体在功能上是分离的。 它的纵轴分为背侧和腹侧区域，其中腹侧区域优先调节压力和 焦虑，而背侧优先调节空间学习和记忆。 增加对可卡因调节海马功能机制的了解 肺门苔藓细胞是局部电路的一个未被充分研究的组成部分。 海马形成。谷氨酸能苔藓细胞支配兴奋性颗粒细胞和抑制性颗粒细胞。 因此，苔藓细胞的一个主要功能是整合大量的功能 沿海马间隔颞轴的神经元是糖原合酶激酶 3β (GSK3β)。 高度保守的丝氨酸/苏氨酸蛋白激酶参与海马调节行为。 再次暴露于可卡因配对后激活肺门苔藓细胞和苔藓细胞 GSK3β 通路活性 背侧和腹侧海马的环境特征（目标 1）接下来，多巴胺的作用。 可卡因相关的发育和表达中可卡因激活 D2 受体和 GSK3β 将调查条件性地点偏好行为（目标 2）。 证明可卡因暴露对局部海马回路和细胞通路的影响 这些研究将为更多研究奠定基础。 调查精神兴奋剂对海马回路影响的综合研究 提供了关于苔藓细胞对可卡因改变机制的贡献的重要见解 海马功能和可塑性与成瘾相关行为有关。 对海马体的诱导适应可能有助于治疗复杂的过程 瘾。