Inhaled Anesthestic Modulation of Hippocampal Circuits

海马回路的吸入麻醉调节

• 批准号: 8473886
• 负责人: ROBERT A PEARCE
• 金额: $ 27.55万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8473886
• 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.

与许多静脉注射药物不同，吸入麻醉剂调节多个目标以实现其作用 影响。我们之前的研究表明，异氟烷的记忆删除浓度会显着改变 突触功能由兴奋性 A/-甲基-D-天冬氨酸受体 (NMDA-R) 和 抑制性 v-氨基丁酸 A 型受体 (GABAA-RS)，但单独的作用是不够的 解释了异氟烷的记忆消除作用。我们建议研究针对这些问题的限制行动 两个系统，检查支持突触的几个集成细胞和网络过程 海马体的可塑性和记忆编码。这些研究解决了中心假设 吸入麻醉剂对 exUatop/ 和抑制性 siqnslina 的联合作用可抑制 学习和 ivdmoiv hv inloifeiiiia 与树突整合约会初始编码过程 导致突触萎缩。因此，我们将测试 (1) 麻醉剂是否会抑制和调节 选择性药物（单独或联合）的兴奋是拮抗的、相加的或协同的 电路、网络和行为！反应，以及这些行动的结合是否可以解释 用于异氟烷的记忆删除作用； (2) 异氟烷的循环和网络水平效应是否 在携带基因改变的小鼠中减弱，使特定受体对吸入不敏感 麻醉剂； (3) 网络振荡状态下兴奋性是否有节律性波动 影响麻醉剂抑制树突整合和海马可塑性的能力。