A Dendritic Substrate for Fast-Acting Antidepressant Action

具有快速抗抑郁作用的树突状基质

• 批准号: 10386910
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 34.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2022-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386910
• 关键词: Acute; Affect; Amygdaloid structure; Animals; Antidepressive Agents; Apical; Architecture; Behavioral; Biological; Biology; Brain; Brain region; Calcium; Calcium Signaling; Caliber; Chronic stress; Color; Data; Dendrites; Dendritic Spines; Development; Dorsal; Electric Stimulation; Evaluation; Exhibits; Frequencies; Goals; Head; Heterogeneity; Hour; Image; Ketamine; Lead; Measures; Mechanics; Medial; Mental Depression; Molecular; Morphology; Mus; Process; Research; Resolution; Role; Saline; Source; Specificity; Stress; Structure; Synapses; Synaptic plasticity; Testing; Thalamic structure; Vertebral column; Work; antidepressant effect; behavioral outcome; density; experimental study; frontal lobe; imaging approach; in vivo; in vivo optical imaging; insight; nerve supply; novel; postsynaptic; predictive marker; social defeat; two photon microscopy

PROJECT SUMMARY Our long-term goal is to understand how the structure and function of dendrites in the frontal cortex are affected by stress and antidepressants. Considerable evidence indicates that the action of fast-acting antidepressants such as ketamine relies on synaptic plasticity in the frontal cortex. An essential ingredient for plasticity is calcium influx in dendritic spines. However, to date, empirical data detailing how antidepressants may modulate calcium levels in dendritic spines in vivo are lacking. In preliminary studies, we used subcellular- resolution two-photon microscopy to visualize localized calcium transients in dendritic spines in the medial frontal cortex of the mouse in vivo. We found that the administration of the fast-acting antidepressant ketamine leads to an acute elevation of calcium signals in apical dendritic spines, due to a suppression of dendritic inhibition. On the basis of the preliminary results and prior research, we hypothesize that the enhanced synaptic calcium signal is a necessary step towards ketamine’s antidepressant action. In this project, we will determine the interactive effects of stress and ketamine on synaptic calcium signals (Aim 1). We will track morphology and calcium signals in the same dendritic spines to ask if the calcium elevations precede structural remodeling (Aim 2). We will determine if spines receiving inputs from specific long-range afferent regions are selectively targeted (Aim 3). Together, the results are expected to provide insights into the biological basis of ketamine’s action. As calcium is an essential checkpoint for synaptic plasticity in the frontal cortex, delineating its role in antidepressant action will accelerate the evaluation of candidate compounds and the development of more targeted treatments.

项目摘要 我们的长期目标是了解额叶皮层中树突的结构和功能如何 受压力和抗抑郁药的影响。大量证据表明快速行动的作用 抗抑郁药（例如氯胺酮）依赖于额叶皮质中的合成可塑性。一种基本要素 可塑性是树突状棘的钙影响。但是，迄今为止，详细介绍抗抑郁药的经验数据 可能缺乏体内树突状棘的钙水平。在初步研究中，我们使用了亚细胞 分辨率两光子显微镜可视化培养基中树突状刺中的局部钙瞬变 鼠标的额叶皮质在体内。我们发现快速作用抗抑郁剂氯胺酮的给药 由于树突状的抑制作用，导致顶端树突状棘中钙信号的急性升高 抑制。根据初步结果和先前的研究，我们假设增强了 突触钙信号是迈向氯胺酮抗抑郁作用的必要步骤。在这个项目中，我们将 确定应激和氯胺酮对突触钙信号的相互作用（AIM 1）。我们将跟踪 同一树突状棘中的形态和钙信号询问钙升高是否在结构之前 重塑（AIM 2）。我们将确定从特定远程传入区域接收输入的刺是 有选择的目标（AIM 3）。总之，结果有望提供有关生物学基础的见解 氯胺酮的动作。由于钙是额叶皮质中突触可塑性的必不可少的检查点，因此描绘 它在抗抑郁作用中的作用将加速候选化合物的评估和发展 更多针对性的治疗。