Interrogating and sculpting synapses and circuits for rapidly acting antidepressant effects

询问和塑造突触和电路以实现快速发挥抗抑郁作用

• 批准号: 9542412
• 负责人: YEVGENIA KOZOROVITSKIY
• 金额: $ 45.02万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9542412
• 关键词: Antidepressive Agents; Area; Award; Behavior; Big Data; Biological Assay; Brain; Brain region; Cells; Chemicals; Chemistry; Communities; Complement; Data; Data Set; Dendritic Spines; Development; Disease; Disease model; Drug Design; Elements; Female; Future; Gene Expression; Glutamates; Goals; Human; Incidence; Knowledge; Lasers; Learned Helplessness; Learning; Life; Link; Major Depressive Disorder; Measures; Membrane; Mental Depression; Mental Health; Methodology; Microscopy; Mission; Modeling; Molecular; Mood Disorders; National Institute of Mental Health; Neocortex; Neuronal Plasticity; Neurons; Neurosciences; Optics; Other Genetics; Patients; Pharmaceutical Preparations; Physiological; Plasticizers; Protein Biosynthesis; Proteins; Proteome; Proteomics; Public Health; Publishing; RNA Interference; Regimen; Regulation; Research; Research Domain Criteria; Research Project Grants; Resistance; Scientist; Societies; Synapses; Techniques; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Validation; Work; antidepressant effect; biobehavior; brain cell; career; cell type; cost; depressive symptoms; excitatory neuron; experimental study; genetic manipulation; improved; infancy; inhibitory neuron; innovation; male; neural circuit; neuroproteomics; new therapeutic target; novel; postsynaptic; programs; proteomic signature; reduce symptoms; response; spatiotemporal; suicidal patient; synaptogenesis; tool; treatment response; two-photon

PROJECT SUMMARY Dendritic spines are the remarkable, highly specialized membrane compartments on neurons that house the postsynaptic, receiving end of many excitatory, glutamatergic synapses in the brain. They are highly plastic and change with learning, in development, and in disease. Dendritic spine and synapse changes have been linked to therapeutic responses to rapidly acting antidepressant drugs, but our understanding of the consequences of these treatments in specific neuronal classes are limited. This proposal relies on 2-photon multilaser assays to induce and evaluate the formation of new synapses, in order to measure how major depression and rapidly acting therapies regulate plasticity rules in specific neuronal groups. We will complement these focused assays with a new platform for genetically targeted proteomics in the cell classes implicated in major depressive disorder and its symptomatic amelioration by rapidly acting antidepressants. This work will provide the basis for a deep and broad understanding of synaptic and cellular changes induced by depressive state and rapidly acting antidepressant drugs. The unique synthesis of novel optical microscopy approaches, molecular tools, and proteomics chemistry represents a significant advance over canonical approaches to studying plasticity of neural circuits. The goal is to build a conceptual framework to enable harnessing the genesis of new synapses and the regulation of plasticity for mental health therapeutics. In addition, this work will help resolve fundamental mysteries surrounding the genesis of synapses and will develop useful tools for the neuroscience community.

项目摘要 树突棘是神经元上显著的、高度特化的膜隔室， 突触后，大脑中许多兴奋性突触的接收端。它们具有高度可塑性， 随着学习、发育和疾病而改变。树突棘和突触的变化与 快速作用的抗抑郁药物的治疗反应，但我们对后果的理解， 这些治疗在特定的神经元类别中是有限的。该提议依赖于双光子多激光测定， 诱导和评估新突触的形成，以衡量严重抑郁症和快速 作用疗法调节特定神经元群的可塑性规则。我们将补充这些重点分析， 在与抑郁症相关的细胞类别中进行基因靶向蛋白质组学的新平台 通过快速作用的抗抑郁药改善其症状。这项工作将提供基础 对抑郁状态引起的突触和细胞变化的深入和广泛的理解， 抗抑郁药独特的合成新的光学显微镜方法，分子工具， 和蛋白质组学化学代表了一个显着的进步，超过规范的方法来研究可塑性， 神经回路我们的目标是建立一个概念框架，使利用新的突触的起源 以及调节心理健康疗法的可塑性。此外，这项工作将有助于解决 围绕突触起源的基本奥秘，并将为神经科学开发有用的工具 社区