Claustral Control of Cortical Networks by Serotonin

项目摘要 认知灵活性缺陷是导致生活质量下降和治疗效果下降的主要原因 神经精神障碍，包括阿尔茨海默氏症、抑郁症和精神分裂症。经典的迷幻剂， 裸盖菇素，可导致认知灵活性的长期改善，但由于 立法限制和不良的非治疗效果。理想情况下，药物的治疗促进认知作用 迷幻剂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实现的 网络：额叶皮质导向的共同激活的皮质区域，参与合作处理以满足 认知需求。了解迷幻药如何影响皮层网络潜在的神经回路 对于复制前认知迷幻效应的治疗方法的发展来说，监管是必要的。 屏核是一个皮质下核团，通过“皮质-顶叶”连接额叶皮质和顶叶皮质网络结点。 在认知要求高的任务中，最佳任务表现所必需的是屏蔽皮层回路。 要求不高的任务，在出现任务阳性的皮层网络时被激活，以响应 困难的认知任务。屏蔽体表达5-羟色胺受体，其靶向是活性代谢物裸鼠毒素。 裸盖菇素(5-HTR2a、1d和1b)和在裸盖菇素给药期间的屏蔽门失活有关 裸盖菇素介导的皮质网络功能障碍。因此，屏蔽门是 迷幻剂认知效应的研究。我们在老鼠身上的初步数据导致了我们的假设 5-羟色胺信号通过抑制额叶皮质输入而显著抑制皮质-屏蔽区-皮质环路 对于屏蔽区(目标1)，屏蔽区投射神经元的局部抑制增加(目标2)，并降低 屏核投射神经元的兴奋性(目标3)。为了验证这一新的假设，我将确定受体 负责每一种5-羟色胺介导的神经调节效应，确认该效应也由 ，并评估皮质-屏气-皮质环路强度的相应变化 对于每个目标/神经调节效应。这将使用光遗传学、病毒载体- 示踪和全细胞电生理学。全细胞电生理学和光遗传学是主要的 这项建议的技术培训。这项研究的结果将为该系统提供一种新的电路机制。 迷幻剂的认知前效应，为认知前治疗的发展奠定了基础 适用于广泛的神经精神障碍。综上所述，这项创新的建议将 提供重要的概念和技术培训机会，这是PI最终获得的必要机会 研究独立性。

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.