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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要树突棘是神经元上非凡的、高度专业化的膜室，它容纳突触后，大脑中许多兴奋性谷氨酸突触的接收端。它们具有很强的可塑性并且随着学习、发育和疾病而改变。树突棘和突触的变化与对快速起效的抗抑郁药物的治疗反应，但我们对其后果的理解这些治疗在特定神经元类别中是有限的。该提案依赖于 2 光子多激光测定诱导和评估新突触的形成，以测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拥有一个新平台，用于针对与重度抑郁症有关的细胞类别进行基因靶向蛋白质组学障碍及其通过快速作用的抗抑郁药改善症状。这项工作将提供基础深入而广泛地了解抑郁状态引起的突触和细胞变化并迅速作用抗抑郁药物。新型光学显微镜方法、分子工具、蛋白质组学化学代表了研究可塑性的经典方法的重大进步神经回路。目标是建立一个概念框架来利用新突触的起源以及心理健康治疗的可塑性调节。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。