Optimization of the 5-choice continuous performance test to reveal a parietal-anterior cingulate-claustrum circuit underlying cognitive control and attention

优化 5 项选择的连续表现测试，揭示认知控制和注意力背后的顶叶-前扣带回-屏状核回路

• 批准号: 10722710
• 负责人: Jared William Young
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722710
• 关键词: Address; Affect; Agonist; Animals; Anterior; Attention; Behavior; Behavioral; Brain region; Cholinergic Antagonists; Claustral structure; Clinical Trials; Cognition; Cognitive; DRD4 gene; Data; Drug Controls; Drug Modulation; Failure; Family; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Human; Ibotenic Acid; Impaired cognition; Impairment; Institution; Lesion; Link; Marketing; Masks; Measures; Mediating; Mental disorders; Modafinil; Modernization; Mus; Muscarinics; National Institute of Mental Health; Neurons; Neurosciences; Outcome; Parietal; Parietal Lobe; Participant; Patients; Performance; Pharmacological Treatment; Pharmacotherapy; Photometry; Process; Psychiatry; Quinolinic Acid; Rattus; Reporting; Research Domain Criteria; Rodent; Role; Scopolamine; Stimulus; Task Performances; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Validation; Work; attentional control; cingulate cortex; cognitive control; cognitive neuroscience; cost; dopamine transporter; efficacious treatment; functional magnetic resonance imaging/electroencephalography; improved; inhibitor; neural; neural circuit; neurophysiology; noradrenaline transporter; novel; off-label use; optogenetics; performance tests; pharmacologic; pre-clinical; preclinical study; receptor; response; sex; societal costs; success; suicide rate; touchscreen

Delineating a parietal-anterior cingulate-claustrum circuit underlying cognitive control and attention Treatments are urgently needed for cognitive dysfunction in psychiatric patients. Given the link between such dysfunction and outcome in patients, large numbers of clinical trials were conducted with companies attempting to be ‘first-to-market’. In the rush however, preclinical studies used had limited validity to the cognitive domains reportedly targeted. Thus, circuit-engagement of the cognitive domain tested was rarely if-at-all verified and all clinical trials to-date have failed. New paradigms have emerged with reported relevance to domains affected in psychiatry, but little opportunity to validate circuits underlying these behaviors, let-alone drugs that modulate such circuits and behavior, have arisen. This application will utilize a circuit-targeted approach to confirm the utility of the 5-choice continuous performance test (5C-CPT) to measure cognitive control and attention across multiple psychiatric disorders. Specific Aim 1 will optimize the touchscreen 5C-CPT for parametric manipulation. The 5C-CPT exists for mice, rats, and humans, with EEG & fMRI versions. The task has always been standard however, primarily in 5-hole operant chambers, but a touchscreen version with parametric manipulations within the task would improve translatability to human testing and enable task performance-based consistency. Backward masking of stimuli have been used in cognitive control tasks previously, but only recently used in human 5C-CPT studies. Here, we will demonstrate that such masked trials enable parametric assessment of 5C-CPT performance in mice. Specific Aim 2 will determine the pharmacological sensitivity of the touchscreen 5C-CPT. After developing the task, it is important to confirm that it is sensitive to manipulations, including those available for use in humans for pharmacological predictive validation. We demonstrated that modafinil improves healthy human participant performance of the standard 5C-CPT, while scopolamine impairs mouse performance. Here, we will confirm that modafinil and scopolamine similarly affect this masked touchscreen 5C-CPT, while predicting that a dopamine D4 receptor agonist would improve cognitive control. We will confirm that modafinil rescues scopolamine-induced deficits, avoiding receptor tautological complications. Specific Aim 3 will confirm the role of the anterior cingulate cortex (ACC)claustrum and claustrumparietal cortex (PC) circuit underlying this masked touchscreen 5C-CPT performance. Consistent with human CPTs, we confirmed the necessity of the PC for mouse 5-choice (5C-)CPT performance. We hypothesize that a ACC to claustrum projection is important during more cognitively demanding trials (from parametric manipulations), while a claustrum to PC projection occurs is important for selecting whether to respond or not during trials. Using fiber photometry and optogenetic techniques, we will confirm both the activation and necessity of this circuit respectively, including changes in activity as a direct result of pharmacological manipulation. Thus, circuitry underlying cognitive control will be identified, as will pharmacological treatments affecting this circuit that are readily testable in healthy human participants.

描绘出壁扣带回链路的基础电路和注意力的关注 精神病患者的认知功能障碍迫切需要治疗。给定这样的链接 患者的功能障碍和结果，尝试的公司试图进行大量临床试验 成为“第一到市场”。然而，在匆忙中，所使用的临床前研究对认知领域的有效性有限 据报道是针对的。那是认知域测试的电路参与，如果经过验证，很少是 迄今为止的临床试验失败了。已经出现了与受影响的域相关的新范式 精神病学，但很少有机会验证这些行为的基础电路，可调节的列出药物 这种电路和行为已经出现。该应用程序将利用符合电路的方法来确认 5-选择连续绩效测试（5C-CPT）的效用，以测量跨认知控制和注意力 多种精神疾病。特定的目标1将优化参数的触摸屏5C-CPT 操纵。 5C-CPT存在于小鼠，大鼠和人类，具有脑电图和FMRI版本。任务总是 但是是标准的，但是在5洞操作室中，主要是带有参数的触摸屏版本 任务中的操作将改善对人类测试的转换性，并启用基于任务的绩效 一致性。刺激的向后掩盖以前已经在认知控制任务中使用了，但直到最近 用于人类5C-CPT研究。在这里，我们将证明这种蒙版试验启用了参数 评估小鼠5C-CPT性能。特定的目标2将确定药物灵敏度 触摸屏5C-CPT制定任务后，重要的是要确认它对 操作，包括可用于人类用于药物预测验证的操作。我们 证明莫达非尼改善了标准5C-CPT的健康人参与表现，而 骨pol碱会损害鼠标性能。在这里，我们将确认Modafinil和Scopolamine类似地影响 这种蒙面的触摸屏5C-CPT，同时预测多巴胺D4受体激动剂将改善认知 控制。我们将确认Modafinil挽救了Scopolamine引起的缺陷，避免了受体重言式学 并发症。具体目标3将确认前扣带回皮层（ACC）的作用Claustrum和 Claustrum顶叶（PC）电路，该电路是该掩盖触摸屏5C-CPT性能。 与人类CPT一致，我们确认了PC的必要小鼠5选择性（5C）CPT性能。 我们假设在更加认知要求的试验期间，对恐怖分子投射的ACC非常重要（来自 参数操作），虽然发生claustrum到PC投影，对于选择是否是否 试验期间是否反应。使用纤维光度法和光遗传技术，我们将确认 该电路分别激活和必要 药理操作。那将确定认知控制的基础电路 在健康的人类参与者中易于测试的该电路的药理治疗方法。