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.

项目概要 我们的长期目标是了解额叶皮层树突的结构和功能如何 大量证据表明速效药物的作用。 氯胺酮等抗抑郁药依赖于额叶皮质的突触可塑性。 可塑性是树突棘中钙的流入，然而，迄今为止，经验数据详细说明了抗抑郁剂如何发挥作用。 在体内调节树突棘钙水平的可能在初步研究中，我们使用了亚细胞- 分辨率双光子显微镜可观察内侧树突棘中的局部钙瞬变 我们发现，给予速效抗抑郁药氯胺酮后，小鼠的额叶皮层会发生变化。 由于树突棘的抑制，导致顶端树突棘中钙信号的急剧升高 在初步结果和先前研究的基础上，我们追求增强抑制。 突触钙信号是氯胺酮抗抑郁作用的必要步骤。 确定压力和氯胺酮对突触钙信号的交互影响（目标 1）。 同一树突棘中的形态和钙信号，以询问钙升高是否先于结构升高 我们将确定从特定远程传入区域接收输入的脊柱是否是重塑（目标 2）。 选择性靶向（目标 3），结果预计将提供对生物学基础的见解。 由于钙是额叶皮层突触可塑性的重要检查点，因此氯胺酮的作用。 它在抗抑郁作用中的作用将加速候选化合物的评估和开发 更有针对性的治疗。