Brain-wide circuits for drug-induced changes to cognition

药物引起的认知变化的全脑回路

• 批准号: 10494006
• 负责人: Lisa Giocomo
• 金额: $ 30.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494006
• 关键词: Acute; Animals; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Code; Cognition; Cognitive; Complex; Dissociation; Drug Addiction; Drug usage; Electrophysiology (science); Environment; Genetic; HCN1 channel; HCN1 gene; Hippocampus; Impairment; Ketamine; Knock-out; Knockout Mice; Left; Link; Location; Long-Term Effects; Measures; Medial; Memory; Methamphetamine; Molecular; Molecular Target; Morphine; Movement; Mus; NR2A NMDA receptor; Nature; Neurons; Parietal; Persons; Pharmaceutical Preparations; Physiological; Positioning Attribute; Prevalence; Property; Relapse; Rewards; Running; Site; Space Perception; Speed; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Training; Update; Viral; Visual; Work; brain behavior; cognitive process; drug action; drug of abuse; drug seeking behavior; entorhinal cortex; experience; hypnotic; in vivo; insight; interest; neural; neural circuit; neural correlate; operation; psychologic; response; spatial memory; virtual reality environment; way finding

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. .

项目总结(项目2) 解离和非解离药物，如氯胺酮、五氯苯酚、甲基苯丙胺和吗啡，对 通过诱导大脑状态的深刻改变而产生强大的心理效应。这些药物的受欢迎程度，他们的 心理和生理上瘾的性质和一类解离药物的日益流行 由于潜在的治疗药物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，在我们对潜在的电路机制的理解中存在着很大的差距 药物改变的状态本身。为了弥补这一鸿沟，我们试图阐明分子、电路和网络 药物诱发认知状态的机制--利用一组高度易处理的反应特性 支持空间认知的多个大脑区域的神经元。我们对空间认知的关注是 受解离和非解离药物改变神经表征的共同能力的推动 太空。有充分的证据表明，解离药物会导致体外体验，并可能损害空间 记忆。非解离性滥用药物可以利用空间记忆系统来编码药物上下文 这种联系导致与毒品有关的环境成为吸毒复发的有力诱因。然而， 这些空间认知变化背后的全脑回路机制，以及这种变化如何影响 行为，仍然没有完全被理解。在这里，我们使用了最先进的大规模活体电生理学 结合行为技术检查药物诱导的空间认知效应和 空间编码和记忆编码的微电路。首先，我们进行大范围的电生理来测量 在导航到期间多个皮质和皮质下脑区空间估计的神经相关性 研究解离和非解离药物如何导致空间认知的变化。接下来，我们来磨练 在自由活动动物的特定大脑感兴趣区域上检查如何分离和非分离 药物会导致空间任务中行为的神经关联发生变化。最后，活体电生理学是 结合遗传和行为方法解析氯胺酮潜在的分子基础 治疗效果与对空间认知的负面影响。总之，这项工作将为以下方面提供新的见解 药物成瘾相关认知状态的脑广路机制及行为 这些药物诱导的认知状态对空间记忆和导航行为的影响。 。