Circuit Mechanisms of Psilocybin Following Chronic Stress

慢性应激后裸盖菇素的回路机制

• 批准号: 10412159
• 负责人: Omar Jamil Ahmed
• 金额: $ 39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-10 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412159
• 关键词: Address; Atrophic; Brain; Brain region; Chronic; Chronic stress; Claustral structure; Coupling; Dendritic Spines; Dose; Electrodes; Electrophysiology (science); Excitatory Synapse; Exhibits; Genes; Glutamates; Growth; Hallucinogens; Human; Impairment; Investigation; Ketamine; Knock-out; Knowledge; Modification; Morphology; Mus; Neuronal Plasticity; Neurons; Patients; Pharmacological Treatment; Physiology; Play; Population; Prefrontal Cortex; Property; Pyramidal Cells; Rodent; Role; Serotonin; Serotonin Receptor 5-HT2A; Sleep; Specificity; Stress; Structure; Synapses; Thalamic structure; Therapeutic; Therapeutic Effect; Vertebral column; antagonist; awake; cell type; cognitive reappraisal; density; design; efficacious treatment; emotion regulation; functional disability; hippocampal pyramidal neuron; in vivo; neural circuit; neuropsychiatric disorder; neuropsychiatry; neurotransmission; optogenetics; postsynaptic; presynaptic; repaired; stress related disorder; transcriptomics; transmission process; treatment response

ABSTRACT / PROJECT SUMMARY Chronic stress is thought to play a role in multiple neuropsychiatric disorders. Standard pharmacological treatments for stress-related disorders can take up to several months to elicit a therapeutic response and can produce long-term undesirable off-target effects. A single dose of the psychedelic drug psilocybin has been shown to rapidly promote long-lasting therapeutic effects in humans and in chronically stressed rodents. However, the neural circuit mechanisms underlying the lasting changes induced by psilocybin in healthy and chronically stressed brains remain unknown. The prefrontal cortex (PFC) is a key structure impacted by chronic stress. Decreased volume, hypoactivity, and impaired functional connectivity of the PFC has been observed in humans with stress-related disorders. Similarly, PFC pyramidal cells in chronically stressed rodents exhibit dendritic atrophy and excitatory synapse loss. Psilocybin enhances expression of neuroplasticity-related genes through a cascade involving the activation of the serotonin 5-HT2A receptor (5-HT2AR). While the 5-HT2AR is expressed postsynaptically in many cell-types, including PFC pyramidal cells, presynaptic 5-HT2ARs are also known to regulate synaptic input to PFC pyramidal neurons. Psilocybin induces dendritic growth and increases dendritic spine density in PFC pyramidal cells after a single dose. However, no studies to date have examined the rules governing which synapses (and which corresponding dendritic spines) are restored: does psilocybin non-specifically increase spine and synapse number, or does it preferentially enhance spines and synapses corresponding to specific inputs with higher 5-HT2AR expression? Answering this question is a critical step towards a mechanistic understanding of how psilocybin exerts therapeutic effects. To address this gap in knowledge, we will conduct a multiscale investigation of the effects of psilocybin on multiple brain regions. Our central hypothesis is that the synaptic inputs to PFC that are impaired following chronic stress are restored in an input-specific manner by psilocybin. In Aim 1, we will characterize the effects of psilocybin in vivo on input-specific changes in PFC connectivity and dynamics in chronically stressed rodents. In Aim 2, we will use both in vivo and ex vivo optogenetics to determine the effects of chronic stress and subsequent psilocybin treatment on input-specific synaptic physiology and dendritic morphology. The completion of these Aims will identify input-specific rules governing psilocybin-induced normalization of impaired prefrontal circuits, with important implications for the design of even more precise and efficacious neuropsychiatric therapies with minimal off-target effects.

摘要 /项目摘要 人们认为慢性压力在多种神经精神疾病中发挥作用。与压力相关疾病的标准药理治疗可能需要长达几个月的时间来引起治疗反应，并可能产生长期不良的脱靶效应。单一剂量的迷幻药物psilocybin已被证明可快速促进人类和慢性啮齿动物的持久治疗作用。然而，在健康和长期压力的大脑中，由psilocybin引起的持久变化的神经回路机制尚不清楚。 前额叶皮层（PFC）是受慢性应激影响的关键结构。在患有压力相关的疾病的人类中，已经观察到PFC的体积，低连通性和功能连通性的降低。同样，慢性应激啮齿动物中的PFC锥体细胞表现出树突状萎缩和兴奋性突触丧失。 psilocybin通过涉及血清素5-HT2A受体（5-HT2AR）激活的级联反应增强了与神经可塑性相关的基因的表达。尽管5-HT2AR在包括PFC锥体细胞在内的许多细胞类型中以突触后表达，但还已知突触前5-HT2AR会调节突触输入到PFC锥体神经元。 psilocybin诱导树突状生长，并在单剂量后增加PFC锥体细胞中的树突状脊柱密度。但是，迄今为止尚无研究尚未研究控制哪些突触（以及哪些相应的树突状刺）的规则：psilocybin非特定特异性地增加脊柱和突触数量，还是优先增强刺和突触，与更高5-HT2AR表达的特定输入相对应？回答这个问题是朝着对psilocybin如何发挥治疗作用的机械理解的关键一步。 为了解决知识的这一差距，我们将对psilocybin对多个大脑区域的影响进行多尺度研究。我们的中心假设是，通过psilocybin以特异性方式恢复了慢性应激后PFC的突触输入。在AIM 1中，我们将表征体内psilocybin对慢性啮齿动物中PFC连通性和动力学的输入特异性变化的影响。在AIM 2中，我们将同时使用体内和离体光遗传学来确定慢性应激和随后的psilocybin治疗对输入特异性突触生理学和树突状形态的影响。这些目标的完成将确定有关psilocybin诱导的前额叶电路归一化的投入特定规则，对设计更精确，更有效的神经精神疗法的设计具有重要意义，具有最小的离心剂效应。