Inhaled Anesthestic Modulation of Hippocampal Circuits

与许多静脉注射剂不同，吸入麻醉剂调节多个靶点以实现其作用。 方面的影响.我们以前的研究表明，异氟烷的遗忘浓度实质上改变了 由兴奋性N-甲基-D-天冬氨酸受体（NMDA-Rs）和 但单独的作用都是不够的 以解释异氟烷的遗忘作用。我们建议研究这些措施的配套措施， 两个系统，检查几个整合的细胞和网络过程，支持突触 海马体的可塑性和记忆编码。这些研究解决了中心假设 吸入麻醉剂对前体和抑制性信号的联合作用抑制了 学习和ivdmoiv hv inloifeiiiiiiiia与树突状整合，确定初始编码过程的日期 导致突触性兴奋。因此，我们将测试（1）麻醉剂是否具有抑制作用， 与选择性药物（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，以及这些行动的组合是否可以解释 异氟醚的遗忘作用;（2）异氟醚的回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 麻醉剂;（3）振荡网络状态下兴奋性的节律性波动 影响麻醉剂抑制树突整合和海马可塑性的能力。

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.