Claustral Control of Cortical Networks by Serotonin

血清素对皮质网络的幽闭控制

• 批准号: 10740851
• 负责人: Maxwell Blair Madden
• 金额: $ 4.08万
• 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/10740851
• 关键词: Action Potentials; Acute; Agonist; Alzheimer' s Disease; Anxiety; Brain; Cell Nucleus; Cells; Claustral structure; Cognition; Cognitive; Cognitive Therapy; Data; Development; Dissociation; Electrophysiology (science); Event; Exposure to; Foundations; Functional Imaging; Glutamates; Hallucinogens; Human; Impaired cognition; Injections; Investigation; Knowledge; Life; Maps; Measures; Mediating; Mental Depression; Mus; Neurons; Parietal Lobe; Pharmaceutical Preparations; Pharmacology; Positioning Attribute; Post-Traumatic Stress Disorders; Prodrugs; Psilocybin; 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; frontal lobe; human imaging; improved; innovation; interest; network dysfunction; neural circuit; neuronal excitability; neuropsychiatric disorder; neuropsychiatry; neuroregulation; novel; optogenetics; patch clamp; pharmacologic; 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.

项目摘要 认知灵活性缺陷是无数疾病中减少生命和治疗结果的主要因素 神经精神疾病，包括阿尔茨海默氏症、抑郁症和精神分裂症。经典的迷幻， psilocybin，诱导认知灵活性的长期改善，但广泛使用是不可行的， 立法限制和不希望的非治疗效果。理想情况下， 迷幻药可以从迷幻之旅中分离出来，尽管这需要调查 迷幻认知效应的机制认知和认知灵活性是通过大脑皮层 网络：额叶皮质定向的共同激活的皮质区域，参与合作处理，以满足 认知需求。了解致幻剂如何影响皮层网络下的神经回路 调节对于开发再现促认知迷幻效应的疗法是必要的。 屏状核是一个皮质下核，通过“皮质- 在认知要求较高的任务中， 非要求性任务，并在任务积极的皮层网络出现时被激活，以响应 困难的认知任务。屏状核表达5-羟色胺受体，5-羟色胺受体被活性代谢物裸盖菇素靶向 裸盖菇素（5-HTR 2a，1d和1b）和屏状体失活在裸盖菇素管理相关 psilocybin介导的皮层网络功能障碍。因此，屏状体代表了一个主要目标， 迷幻药认知效应的研究我们在小鼠身上的初步数据导致我们的假设， 5-羟色胺信号通过抑制额叶皮质输入而急性抑制皮质-幽闭-皮质回路 增加屏状核投射神经元的局部抑制（Aim 2），降低屏状核投射神经元的局部抑制（Aim 1）。 屏状核投射神经元的兴奋性（目的3）。为了验证这个新的假设，我将确定 负责每一种5-羟色胺介导的神经调节作用，证实这种作用也是由 Psylocibin代谢物psilocin，并评估皮质-幽闭-皮质回路强度的相应变化 对于每种目的/神经调节作用。这将使用光遗传学，病毒道- 示踪和全细胞电生理学。全细胞电生理学和光遗传学代表了 技术培训在这个项目中。本研究的结果为该系统引入了一种新的电路机制。 致幻剂的促认知作用，并为促认知疗法的发展奠定了基础 适用于广泛的神经精神疾病。总的来说，这一创新建议将 提供大量的概念和技术培训机会，这是必要的PI最终获得 研究独立性。