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 皮层下目标参与裸盖菇素在习得和先天逃避行为中的作用 项目概要 抑郁症等情绪障碍现已成为全世界残疾的主要原因， 近年来，传统的一线治疗未能为大多数患者提供缓解。 具有速效特性的治疗作为创新疗法引起了人们的极大兴趣。 致幻剂裸盖菇素最近因其能够产生大量且快速的能力而受到关注 早期临床试验中的抗抑郁作用不断增加的需求和令人兴奋的结合。 初步临床结果导致裸盖菇素最近获得“突破性疗法”地位 研究用于治疗重度抑郁症然而，尽管试点临床试验取得了这些令人兴奋的结果，但 裸盖菇素作用背后的神经生物学仍然知之甚少，因此，这是进一步研究的关键机会。 我们对裸盖菇素作用的理解将在此阐述。 在检查裸盖菇素作用机制的早期研究中，大多数都集中在 然而，之前的细胞和回路水平研究已经明确暗示了这一点。 我们自己使用全脑 cFos 进​​行的初步工作是皮层下结构是裸盖菇素作用的关键。 映射已识别出受裸盖菇素调节的几个候选皮层下区域。 通过高密度硅体内记录确定两个关键皮层下大脑区域的活动 目标 2 将使用探针来确定全身注射裸盖菇素后神经活动如何变化。 裸盖菇素治疗期间的因果操作以确定皮层下区域在治疗期间的相对作用 具体来说，化学遗传学将用于双向控制小鼠的先天和后天逃避行为。 迫在眉睫的刺激期间大脑区域的活动以及习得的逃避行为范例。 这项工作将确定逃亡过程中关键皮质下大脑区域在裸盖菇素作用中的相对作用 行为并扩展裸盖菇素在临床治疗中的使用框架。