Brain-wide circuits for drug-induced changes to cognition

项目概要（项目2） 解离性和非解离性药物，如氯胺酮、PCP、甲基苯丙胺和吗啡， 通过诱导大脑状态的深刻改变而产生强大的心理效应。这些药物的流行， 心理和生理上的成瘾性以及一种分裂性药物的流行率不断上升 由于潜在的治疗剂表明迫切需要了解这些药物的急性和长期影响， 药物对大脑状态的影响然而，在我们对电路机制的理解中存在很大的差距， 毒品改变了自己。为了弥合这一差距，我们试图阐明分子，电路和网络 利用一组高度易处理的反应特性研究药物诱导认知状态的机制 神经元在支持空间认知的多个大脑区域中的分布。我们对空间认知的关注是 动机是解离性和非解离性药物的共同能力，以改变神经表征， 空间有充分的证据表明，解离性药物可诱导灵魂出窍，并可损害空间记忆。 记忆非分离性药物滥用可以利用空间记忆系统对药物背景进行编码 这些关联导致与毒品有关的情况成为吸毒复吸的一个有力触发因素。然而，在这方面， 这些空间认知改变背后的全脑电路机制，以及这如何影响 行为，仍然不完全理解。在这里，我们使用尖端的大规模体内电生理学 联合收割机与行为技术相结合，以检查药物诱导的空间认知效应与 空间和记忆编码的微电路首先，我们进行大范围的电生理学测量， 导航期间多个皮层和皮层下脑区域中空间估计的神经相关性， 研究解离性和非解离性药物如何诱导空间认知的变化。接下来， 在自由运动的动物中，研究分离和非分离的 药物驱动空间任务中行为的神经相关物的变化。最后，体内电生理学是 结合遗传学和行为学的方法来分析氯胺酮潜在的分子基础， 对空间认知的治疗和负面影响。总之，这项工作将提供新的见解， 药物成瘾认知状态的脑宽回路机制和药物成瘾行为的脑宽回路机制 这些药物诱导的认知状态对空间记忆和导航行为的影响。 .

PROJECT SUMMARY (Project 2) Dissociative and non-dissociative drugs, such as ketamine, PCP, methamphetamine and morphine, exert powerful psychological effects by inducing profoundly altered brain states. The popularity of these drugs, their psychologically and physiologically addictive nature and the rising prevalence of a subclass of dissociative drugs as potential therapeutic agents indicate an urgent need to understand the acute and long-term effects of these drugs on brain-states. A large gap exists however, in our understanding of the circuit mechanisms underlying drug-altered states themselves. To bridge this gap, we seek to elucidate the molecular, circuit and network mechanisms of drug induced cognitive states by taking advantage of a set of highly tractable response properties of neurons across the multiple brain regions that support spatial cognition. Our focus on spatial cognition is motivated by the shared capability of dissociative and non-dissociative drugs to alter neural representations of space. Dissociative drugs are well documented to induce out-of-body experiences and can impair spatial memory. Non-dissociative drugs of abuse can leverage the spatial memory system to encode drug-context associations, leading to drug-associated contexts serving as a potent trigger for relapse to drug use. However, the brain-wide circuit mechanisms underlying these alterations in spatial cognition, as well as how this impacts behavior, remain incompletely understood. Here, we use cutting-edge large scale in vivo electrophysiology combine with behavioral techniques to examine the link between drug-induced spatial cognitive effects and the microcircuits of spatial and memory coding. First, we perform wide-scale electrophysiology to measure the neural correlates of spatial estimates in multiple cortical and sub-cortical brain regions during navigation to investigate how dissociative and non-dissociative drugs induce changes in spatial cognition. Next, we hone in on particular brain regions of interest in freely moving animals to examine how dissociative and non-dissociative drugs drive changes in the neural correlates of behavior in spatial tasks. Finally, in vivo electrophysiology is combined with genetic and behavioral approaches to parse out the molecular basis of ketamine’s potentially therapeutic versus negative effects on spatial cognition. Together, this work will provide new insight regarding the brain wide-circuit mechanisms for cognitive states associated with drugs of addiction and the behavioral impacts of these drug-induced cognitive states on spatial memory and navigational behavior. .