Subcortical targets involved in the action of psilocybin in learned and innate escape behaviors

皮层下目标参与裸盖菇素在习得和先天逃避行为中的作用

• 批准号: 10678202
• 负责人: Pasha A Davoudian
• 金额: $ 3.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-16 至 2026-04-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678202
• 关键词: Acute; Address; Attention; Behavior; Behavioral; Behavioral Paradigm; Biological Assay; Brain; Brain region; Clinical; Clinical Treatment; Clinical Trials; Data; Disease; Dorsal; Dose; Exhibits; Genetic; Hallucinogens; Hippocampus; Immediate-Early Genes; Innovative Therapy; Knowledge; Learned Helplessness; Learning; Major Depressive Disorder; Maps; Measures; Mediating; Mental Depression; Mood Disorders; Mus; Neocortex; Neurobiology; Patients; Pattern; Physicians; Property; Psilocybin; Psychiatry; Research; Role; Saline; Scientist; Silicon; Stimulus; Structure; Testing; Thalamic structure; Time; Training; Viral; Work; antidepressant effect; clinical effect; density; designer receptors exclusively activated by designer drugs; disability; early phase clinical trial; experience; experimental study; in vivo; interest; mind control; neocortical; neural; neural circuit; novel; skills; tool

PROJECT TITLE Subcortical targets involved in the action of psilocybin in learned and innate escape behaviors PROJECT SUMMARY Mood disorders such as depression now represent a leading cause of disability throughout the world, with conventional first-line treatments failing to provide relief for most patients. In recent years, novel treatments with fast-acting properties have garnered significant interest as innovative therapies. The psychedelic psilocybin, in particular has recently gained attention for its ability to produce substantial and rapid antidepressant effects in early-phase clinical trials. This combination of increasing need and exciting preliminary clinical results has led to the recent ‘breakthrough therapy’ status designation for psilocybin to be studied as a treatment for major depressive disorder. Yet despite these exciting results in pilot clinical trials, the neurobiology underlying the effect of psilocybin remains less understood. Thus, a critical opportunity to further our understanding of the action of psilocybin will be addressed here. Among early studies examining the mechanisms of action of psilocybin, most have focused on the neocortex and hippocampus. However, previous cellular and circuit-level research has clearly implicated subcortical structures as key in the action of psilocybin. Our own preliminary work using whole-brain cFos mapping has identified several candidate subcortical regions that are modulated by psilocybin. Aim 1 will determine the activity of two of these key subcortical brain regions via in vivo recording with high-density silicon probes to determine how neural activity changes following systemic psilocybin administration. Aim 2 will use causal manipulation during psilocybin treatment to determine the relative role of subcortical regions during innate and learned escape behaviors in mice. Specifically, chemogenetics will be used to bidirectionally control brain region activity during a looming stimulus and learned escape behavioral paradigms. Cumulatively, this work will determine the relative roles of key subcortical brain regions in the action of psilocybin during escape behaviors and expand the framework for psilocybin’s use in clinical treatment.

项目名称 皮质下靶点参与裸盖菇素在习得和先天逃避行为中的作用 项目摘要 抑郁症等情绪障碍现在是全世界残疾的主要原因， 传统的一线治疗不能为大多数患者提供缓解。近年来，小说 具有快速作用特性的治疗作为创新疗法已经引起了极大的兴趣。的 特别是迷幻裸盖菇素，最近因其产生大量和快速的 早期临床试验中的抗抑郁作用。不断增长的需求和令人兴奋的 初步的临床结果使得裸盖菇素最近的“突破性治疗”状态被指定为 作为治疗重度抑郁症的药物然而，尽管在试点临床试验中取得了这些令人兴奋的结果， 裸盖菇素作用的神经生物学基础仍然不太清楚。因此，一个关键的机会， 我们对裸盖菇素的作用的理解将在这里阐述。 在研究裸盖菇素作用机制的早期研究中，大多数集中在 新皮层和海马体。然而，以前的细胞和电路水平的研究已经清楚地表明， 皮质下结构作为裸盖菇素作用的关键。我们使用全脑cFos的初步工作 映射已经识别了几个被裸盖菇素调制的候选皮层下区域。目标1将 通过高密度硅在体记录，确定这些关键皮层下大脑区域中的两个区域的活动 探针，以确定如何神经活动的变化后，全身裸盖菇素管理。目标2将使用 在裸盖菇素治疗过程中的因果操纵，以确定皮质下区域在 天生的和习得的逃避行为。具体来说，化学遗传学将用于双向控制 在一个隐约可见的刺激和学习逃避行为模式的大脑区域活动。累积起来，这 这项工作将确定关键的皮层下脑区在逃避过程中裸盖菇素作用的相对作用。 行为和扩展裸盖菇素在临床治疗中的应用框架。