Structural plasticity basis of fast-acting antidepressant action

速效抗抑郁作用的结构可塑性基础

• 批准号: 9291526
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 20.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291526
• 关键词: Affect; Anterior; Antidepressive Agents; Architecture; Axon; Behavior; Behavioral; Chimeric Proteins; Chronic; Chronic stress; Consensus; Contralateral; Data; Dendritic Spines; Dependovirus; Development; Distal; Dorsal; Dose; Employee Strikes; Hour; Image; Injectable; Injection of therapeutic agent; Ketamine; Label; Lead; Link; Location; Major Depressive Disorder; Medial; Mental disorders; Methods; Microscopy; Midline Thalamic Nuclei; Modeling; Mood Disorders; Mus; N-Methyl-D-Aspartate Receptors; Pathway interactions; Patients; Pharmaceutical Preparations; Process; Property; Protocols documentation; Research; Research Personnel; Rewards; Rodent Model; Saline; Site; Social Interaction; Specificity; Stress; Synapses; Testing; Thalamic structure; Time; Validation; Vertebral column; Viral; Virus; antidepressant effect; behavioral outcome; cohort; density; depressive symptoms; experimental study; frontal lobe; hippocampal pyramidal neuron; human imaging; imaging study; in vivo; in vivo imaging; in vivo optical imaging; innovation; mouse model; neuromechanism; novel; postsynaptic; preference; presynaptic; restoration; social; social stress; two-photon; vesicle-associated membrane protein

PROJECT SUMMARY A single subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, leads to fast- acting antidepressant effects. In rodent models, systemic ketamine administration is associated with higher dendritic spine density in the frontal cortex, reflecting structural remodeling that could underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo. The time course and specificity of ketamine's effect on structural plasticity remain unclear. In preliminary studies, we used longitudinal two- photon microscopy to repeatedly visualize the same set of dendritic branches in the mouse medial frontal cortex before and after a single injection of ketamine or saline. Our data suggest that the higher dendritic spine density associated with ketamine administration is driven by an elevated rate of spine formation, and that a fraction of these newly formed spines becomes persistent. But what is special about these added synapses? In this proposal, we will test whether spines form at random or at particular dendritic locations, e.g. preferentially postsynaptic to particular axonal inputs or at sites affected by chronic stress. In Aim 1, we will test whether ketamine preferentially restores thalamocortical synapses. We will adapt a novel viral strategy to label axonal boutons in vivo. We will quantify effects of ketamine on in vivo dendritic spine turnover in the medial frontal cortex, focusing on spines postsynaptic to fluorescently tagged thalamocortical or callosal inputs. In Aim 2, we will test whether ketamine preferentially reverses social stress-induced synaptic deficits. We will characterize the interactive effects of chronic social defeat and ketamine on structural plasticity in the frontal cortex. Completing these aims would link rapidly acting antidepressants to reversals of specific connectivity and stress-induced deficits. Restoration of pathway-specific synapses could be a novel mechanism for antidepressant action that operates at the circuit level.

项目概要 单次亚麻醉剂量的氯胺酮（一种 N-甲基-D-天冬氨酸受体拮抗剂）会导致快速 发挥抗抑郁作用。在啮齿动物模型中，全身性氯胺酮给药与较高的 额叶皮质中的树突棘密度，反映了可能是行为行为基础的结构重塑 变化。然而，树突棘的周转是体内的一个动态过程。时间进程和特殊性 氯胺酮对结构可塑性的影响仍不清楚。在初步研究中，我们使用纵向二 光子显微镜可重复观察小鼠额内侧的同一组树突分支 单次注射氯胺酮或盐水之前和之后的皮质。我们的数据表明，较高的树突棘 与氯胺酮给药相关的密度是由脊柱形成率升高驱动的，并且 这些新形成的刺的一部分变得持久。但这些增加的突触有什么特别之处呢？在 在这个提议中，我们将测试刺是随机形成的还是在特定的树突位置形成，例如优先地 突触后特定的轴突输入或受慢性应激影响的部位。在目标 1 中，我们将测试是否 氯胺酮优先恢复丘脑皮质突触。我们将采用一种新颖的病毒策略来标记轴突 体内的按钮。我们将量化氯胺酮对额叶内侧树突棘周转的影响 皮质，重点关注突触后棘至荧光标记的丘脑皮质或胼胝体输入。在目标 2 中，我们 将测试氯胺酮是否优先逆转社会压力引起的突触缺陷。我们将表征 慢性社交失败和氯胺酮对额叶皮层结构可塑性的交互影响。 完成这些目标将把快速起效的抗抑郁药与特定连通性的逆转联系起来 压力引起的缺陷。通路特异性突触的恢复可能是一种新机制 在电路层面发挥抗抑郁作用。