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

项目名称 裸盖菇素在后天逃逸行为中作用的皮质下靶点 项目总结 情绪障碍，如抑郁症，现在是全世界导致残疾的主要原因， 传统的一线治疗无法为大多数患者提供缓解。近年来，小说 具有快速起效特性的疗法作为创新疗法引起了人们的极大兴趣。这个 尤其是迷幻裸盖菇素，最近因其产生大量和快速的能力而受到关注。 早期临床试验中的抗抑郁作用。这种不断增长的需求和令人兴奋的结合 初步的临床结果导致最近对裸盖菇素的“突破性治疗”状态被指定为 作为一种治疗严重抑郁障碍的研究。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知之甚少。因此，这是进一步 我们将在这里阐述我们对裸盖菇素作用的理解。 在研究裸盖菇素作用机制的早期研究中，大多数都集中在 大脑皮层和海马体。然而，以前的细胞和电路水平的研究已经清楚地表明 皮质下结构是裸盖菇素作用的关键。我们自己使用全脑CFO的初步工作 图谱已经确定了几个受裸盖菇素调制的候选皮质下区域。目标1将 通过高密度硅的活体记录来确定这些关键的皮质下大脑区域中的两个区域的活动 研究如何确定全身应用裸盖菇素后神经活动的变化。AIM 2将使用 裸盖菇素治疗期间确定皮质下区域相对作用的因果处理 小鼠的先天和后天逃逸行为。具体地说，化学遗传学将被用于双向控制 大脑区域活动在隐约可见的刺激和习得的逃避行为范式。总体而言，这 这项工作将确定大脑皮质下关键区域在裸盖菇素逃逸过程中的相对作用 并为裸盖菇素在临床治疗中的应用拓展了框架。

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.