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: 10188646
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 53.87万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10188646
• 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.

项目总结