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: 10755878
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 16.98万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755878
• 关键词: Dendritic; Substrate; Fast; Acting; Antidepressant

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树突的结构和功能 受到压力和抗抑郁药的影响大量证据表明，速效 诸如克他命的抗抑郁药依赖于额叶皮层中的突触可塑性。一种基本成分， 可塑性是树突棘中的钙内流。然而，迄今为止，经验数据详细说明了抗抑郁药 可以调节体内树突棘中的钙水平。在初步研究中，我们使用了亚细胞- 分辨率双光子显微镜观察中膜树突棘局部钙瞬变 小鼠体内额叶皮质。我们发现服用速效抗抑郁药氯胺酮 导致顶端树突棘中钙信号的急性升高，这是由于树突状细胞的抑制。 抑制作用在初步结果和先前研究的基础上，我们假设， 突触钙信号是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（目的1）。我们将跟踪 形态学和钙信号在同一树突棘，以询问是否钙升高之前的结构 重塑（目标2）。我们将确定从特定的长距离传入区域接受输入的脊椎是否 选择性地定向（目标3）。总的来说，这些结果有望为了解 氯胺酮的作用由于钙是额叶皮层突触可塑性的重要检查点， 它在抗抑郁作用中的作用将加速候选化合物的评价和药物的开发。 更多针对性治疗