Claustral Control of Cortical Networks by Serotonin

血清素对皮质网络的幽闭控制

• 批准号: 10607081
• 负责人: Maxwell Blair Madden
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2024-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607081
• 关键词: Action Potentials; Acute; Agonist; Alzheimer' s Disease; Anxiety; Brain; Cell Nucleus; Cells; Claustral structure; Cognition; Cognitive; Cognitive Therapy; Data; Development; Electrophysiology (science); Event; Exposure to; Foundations; Functional Imaging; Glutamates; Hallucinogens; Human; Impaired cognition; Injections; Investigation; Knowledge; Life; Measures; Mediating; Mental Depression; Mus; Neurons; Parietal; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Post-Traumatic Stress Disorders; Prodrugs; Ramp; Receptor Activation; Regulation; Research; Rodent; Schizophrenia; Serotonin; Serotonin Receptor 5-HT1B; Serotonin Receptor 5-HT2A; Signal Transduction; Synapses; Synaptic Transmission; Task Performances; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Training; Viral; addiction; antagonist; cognitive enhancement; cognitive performance; cognitive task; drug action; effective therapy; flexibility; human imaging; innovation; interest; network dysfunction; neural circuit; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel; optogenetics; patch clamp; postsynaptic; psilocin; receptor; recruit; response; serotonin receptor; support network; therapeutic development; therapy outcome; training opportunity; transmission process

Project Summary Cognitive flexibility deficits are a major contributor to diminished life and therapeutic outcomes across myriad neuropsychiatric disorders including Alzheimer’s, depression, and schizophrenia. The classical psychedelic, psilocybin, induces long-lasting improvement of cognitive flexibility, but widespread use is infeasible due to legislative restrictions and undesirable non-therapeutic effects. Ideally, the therapeutic pro-cognitive effects of psychedelics could be dissociated from the psychedelic trip, though this requires investigation as to the mechanisms of psychedelic cognitive effects. Cognition, and cognitive flexibility, is achieved through cortical networks: frontal cortically-directed coactivated cortical regions that engage in cooperative processing to meet cognitive demands. Understanding how psychedelics impact neural circuits underlying cortical network regulation is necessary for the development of therapeutics that reproduce the pro-cognitive psychedelic effect. The claustrum, a subcortical nucleus, connects frontal cortical and parietal cortical network nodes via “cortico- claustro-cortical circuits”, is required for optimal task performance in cognitively demanding tasks over nondemanding tasks, and is activated at the emergence of a task-positive cortical networks in response to a difficult cognitive task. The claustrum expresses serotonin receptors targeted by psilocin, the active metabolite of psilocybin (5-HTR2a,1d, and 1b) and claustrum deactivation during psilocybin administration is associated with psilocybin-mediated cortical network dysfunction. As such the claustrum represents a prime target for investigation of the cognitive effects of psychedelics. Our preliminary data in mice leads to our hypothesis that serotonin signaling acutely suppresses cortico-claustro-cortical circuits by: suppression of frontal cortical input to claustrum (Aim 1), increased local inhibition of claustrum projection neurons (Aim 2), and decreasing excitability of claustrum projection neurons (Aim 3). To test this novel hypothesis, I will determine the receptor responsible for each serotonin mediated neuromodulatory effect, confirm that the effect is also recruited by the psylocibin metabolite psilocin, and assess corresponding changes to the cortico-claustro-cortical circuit strength for each Aim/neuromodulatory effect. This will be performed using a combination of optogenetics, viral tract- tracing, and whole-cell electrophysiology. Whole-cell electrophysiology and optogenetics represent the primary technical training in this proposal. The results of this study stand to introduce a novel circuit mechanism for the pro-cognitive effects of psychedelics and set the foundation for the development of pro-cognitive therapies applicable across a wide range of neuropsychiatric disorders. Taken together, this innovative proposal will provide substantial conceptual and technical training opportunities that are necessary for the PI to ultimately gain research independence.

项目概要 认知灵活性缺陷是导致无数生命和治疗结果减少的主要原因 神经精神疾病，包括阿尔茨海默病、抑郁症和精神分裂症。 裸盖菇素可导致认知灵活性的持久改善，但广泛使用是不可行的，因为 立法限制和不良的非治疗作用 理想情况下，治疗的促认知作用。 迷幻剂可以与迷幻之旅分离，尽管这需要调查 迷幻认知效应的机制和认知灵活性是通过皮质实现的。 网络：额叶皮质定向的协同激活皮质区域，参与协作处理以满足 认知需求。了解迷幻药如何影响皮层网络的神经回路。 监管对于开发再现促认知迷幻效应的疗法是必要的。 屏状核是皮质下核，通过“皮质- 幽闭皮质回路”，是在认知要求较高的任务中实现最佳任务表现所必需的 要求不高的任务，并在任务积极的皮层网络出现时被激活，以响应 屏状核表达活性代谢物 psilocin 所靶向的血清素受体。 裸盖菇素（5-HTR2a、1d 和 1b）的浓度与裸盖菇素给药期间屏状核失活相关 因此，屏状核是裸盖菇素介导的皮质网络功能障碍的主要目标。 我们对小鼠的初步数据的认知影响的研究得出了这样的假设： 血清素信号传导通过以下方式强烈抑制皮质-幽闭-皮质回路： 抑制额叶皮质输入 屏状核（目标 1），增加屏状核投射神经元的局部抑制（目标 2），并减少 屏状核投射神经元的兴奋性（目标 3） 为了检验这个新假设，我将确定受体。 负责每种血清素介导的神经调节作用，确认该作用也是由 赛洛西宾代谢赛洛辛，并评估皮质-幽闭-皮质回路强度的相应变化 对于每个目标/神经调节作用，这将使用光遗传学、病毒道的组合来执行。 全细胞电生理学和光遗传学代表了主要技术。 这项研究的结果将为该提案引入一种新颖的电路机制。 致幻剂的促认知作用，并为促认知疗法的发展奠定了基础 总而言之，这一创新提案将适用于多种神经精神疾病。 为 PI 最终获得所需的大量概念和技术培训机会 独立研究。