Interrogating and sculpting synapses and circuits for rapidly acting antidepressant effects

项目总结 树突棘是神经元上显著的、高度专门化的膜室，它容纳着 突触后，大脑中许多兴奋性谷氨酸能突触的接收端。它们是高度可塑性的， 随着学习、发展和疾病而改变。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 这些针对特定神经元类别的治疗是有限的。这项提议依赖于双光子多激光分析来 诱导和评估新的突触的形成，以衡量严重抑郁和快速 作用疗法调节特定神经元组的可塑性规则。我们将补充这些重点分析 有了一个新的平台，可以在与重度抑郁症有关的细胞类别中进行基因靶向蛋白质组学 障碍及其通过快速起作用的抗抑郁药物的症状改善。这项工作将为以后的研究提供依据 对抑郁状态引起的突触和细胞变化有深入而广泛的了解 代理抗抑郁药物。新的光学显微镜方法、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。我们的目标是建立一个概念性的框架，以利用新突触的产生 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谜团，并将为神经科学开发有用的工具 社区。

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.