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.

描绘认知控制和注意力基础的顶叶-前扣带回-屏状核回路 鉴于精神病患者认知功能障碍之间的联系，迫切需要治疗。 患者的功能障碍和结果，与尝试的公司进行了大量的临床试验 无论多么匆忙，所使用的临床前研究对认知领域的有效性有限。 因此，被测试的认知领域的电路参与很少得到验证。 迄今为止的临床试验已经失败，据报道与受影响的领域相关。 精神病学，但很少有机会验证这些行为背后的回路，更不用说调节药物了 这种电路和行为已经出现，本应用将利用针对电路的方法来确认。 使用 5 项选择的连续表现测试 (5C-CPT) 来衡量认知控制和注意力 具体目标 1 将针对参数优化触摸屏 5C-CPT。 5C-CPT 适用于小鼠、大鼠和人类，并且具有脑电图和功能磁共振成像版本。 然而，这是标准配置，主要是在 5 孔操作室中，但具有参数化功能的触摸屏版本 任务中的操作将提高人类测试的可翻译性，并实现基于任务绩效的 刺激的后向掩蔽以前曾用于认知控制任务，但直到最近才出现。 在这里，我们将证明这种掩蔽试验可以实现参数化。 对小鼠中 5C-CPT 性能的评估将确定药理学敏感性。 开发任务后，确认触摸屏5C-CPT是否灵敏非常重要。 操作，包括可用于人体药理学预测验证的操作。 莫达非尼改善了健康人类参与者在标准 5C-CPT 中的表现，同时 在这里，我们将确认莫达非尼和东莨菪碱也会产生类似的影响。 这个屏蔽触摸屏 5C-CPT，同时预测多巴胺 D4 受体激动剂将改善认知能力 我们将确认莫达非尼可以挽救东莨菪碱引起的缺陷，避免受体同义反复。 具体目标 3 将确认前扣带皮层 (ACC)→屏状核的作用和 屏状体顶叶皮层 (PC) 电路是该屏蔽触摸屏 5C-CPT 性能的基础。 与人类 CPT 一致，我们证实了 PC 对于小鼠 5 选择 (5C-)CPT 性能的必要性。 我们发现 ACC 到屏状核的投射在认知要求更高的试验中非常重要（从 参数操作），而屏状体到 PC 的投影发生对于选择是否 在试验过程中，我们将使用光纤光度测定和光遗传学技术来确认是否有反应。 该电路的激活和必要性，包括直接导致的活动变化 因此，认知控制的回路将被识别，也将被识别。 影响该回路的药物治疗很容易在健康人类参与者中进行测试。