Inhaled Anesthestic Modulation of Hippocampal Circuits

海马回路的吸入麻醉调节

• 批准号: 8672658
• 负责人: ROBERT A PEARCE
• 金额: $ 22.94万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672658
• 关键词: Accounting; Acids; Address; Affect; Aminobutyric Acids; Amnesia; Anesthetics; Animals; Attenuated; Behavioral; Breathing; Chemosensitization; Collaborations; Complement; D Aspartate; Dose; Electrodes; Etomidate; Excitatory Synapse; Frequencies; Funding; Genetic; Hippocampus (Brain); In Vitro; Individual; Inhibitory Synapse; Intravenous; Isoflurane; Knowledge; Learning; Limes; Measures; Mediating; Memory; Modeling; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurons; Pattern; Pharmaceutical Preparations; Phase; Phosphonic Acids; Process; Relative (related person); Signal Transduction; Site; Slice; Stimulus; Synapses; Synaptic plasticity; System; Testing; Time; aspartate receptor; attenuation; awake; gamma-Aminobutyric Acid; in vivo; memory encoding; mutant; prevent; receptor; response; synaptic function

Unlike many intravenous agents, inhaled anesthetics modulate multiple targets to achieve their effects. Our previous studies showed that amnestic concentrations of isoflurane substantially alter synaptic function mediated by both excitatory A/-methyl-D-aspartate receptors (NMDA-Rs) and inhil)itory v-aminobutyrlc acid type A receptors (GABAA-RS), but that neither action alone is sufficient lo account for the amnestic effect of isoflurane. We propose to study the corribined actions on these two systems, examining several integrative cellular and network processes that support synaptic plasticity and memory encoding by the hippocampus. These studies address the central hypothesis that the combinod action of inhaled anesthetics on excUatop/ and inhibitory siqnslina suppresses learning and ivdmoiv hv inloifeiiiia with dendritic integration dating the initial encoding process leading to synaptic olaslicitv. Thus, Wewill test {1) whether anesthetic tnodulation of inhibition and excitation with selective drugs (alone or in cprnbination) is antagonistic, additive, or synergistic on circuit, network, and behavioral! responses, and whether these actions in combination can account for the amnestic effect of isoflurane; (2) whether circuil-and network-level effects of isoflurane are attenuated in mice carrying genelicalterations that render specific receptors insensitive to inhaled anesthetics; and (3) whether rhythmic fluctuations in excitability dunng oscillatory network states affect the capacity of anesthetics to suppress dendritic integration arid hippocampal plasticity.

与许多静脉注射麻醉剂不同，吸入麻醉剂调节多个靶点以实现其 效果。我们之前的研究表明，异氟醚的遗忘浓度基本上改变了 兴奋性A/-甲基-D-天冬氨酸受体(NMDA-Rs)介导的突触功能 抑制v-氨基丁酸A型受体(GABAA-RS)，但这两种作用本身都是不够的 LO解释了异氟醚的遗忘作用。我们建议研究在这些方面的协同作用 两个系统，检查支持突触的几个集成的细胞和网络过程 由海马体编码的可塑性和记忆。这些研究解决了中心假说 吸入麻醉药联合作用抑制兴奋性和抑制性Sqnslina 学习和IVDMOIV hv与树突整合的融合测定了最初的编码过程 导致了突触突触的分裂。因此，我们将测试{1)麻醉剂是否具有抑制和 选择性药物的兴奋(单独或联合)是拮抗的、相加的或协同的。 电路、网络和行为！响应，以及这些操作结合在一起是否可以解释 对于异氟醚的遗忘作用；(2)异氟烷的环路和网络水平效应是否 在携带使特定受体对吸入不敏感的基因改变的小鼠中减弱 麻醉药；以及(3)兴奋性节律性波动是否抑制振荡网络状态 影响麻醉药抑制树突整合和海马可塑性的能力。