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.

描述认知控制和注意的顶叶-前扣带-屏状核回路 精神病患者的认知功能障碍迫切需要治疗。考虑到这种联系， 为了研究患者的功能障碍和结果，与试图 成为“第一个进入市场”。然而，在匆忙中，临床前研究对认知领域的有效性有限 据报道，针对。因此，测试的认知领域的电路参与很少被验证， 迄今为止的临床试验都失败了。新的范例已经出现，据报道与受影响的领域相关， 精神病学，但几乎没有机会验证这些行为背后的电路，更不用说调节的药物了。 这样的电路和行为已经出现。此应用程序将利用电路目标方法来确认 5-选择连续性能测试（5C-CPT）的实用性，以测量认知控制和注意力 多种精神疾病具体目标1将优化触摸屏5C-CPT的参数 操纵5C-CPT适用于小鼠，大鼠和人类，具有EEG和fMRI版本。任务总是 然而，主要在5孔操作室中是标准的，但是具有参数的触摸屏版本 任务中的操作将提高对人类测试的可翻译性，并使基于任务性能的 一致性向后掩蔽的刺激已被用于认知控制任务以前，但只是最近 用于人体5C-CPT研究。在这里，我们将证明这种设盲试验能够实现参数 小鼠中5C-CPT性能的评估。具体目标2将确定药理学敏感性 触摸屏5C-CPT。在开发任务之后，确认它对 操作，包括可用于人体的药理学预测验证。我们 证明莫达非尼改善了标准5C-CPT的健康人类参与者的表现， 东莨菪碱损害小鼠的表现。在这里，我们将确认莫达非尼和东莨菪碱同样影响 这掩盖了触摸屏5C-CPT，同时预测多巴胺D4受体激动剂将改善认知能力 控制我们将证实莫达非尼挽救东莨菪碱诱导的缺陷，避免受体同义反复 并发症具体目标3将证实前扣带皮层（ACC）的作用， 屏状核顶叶皮层（PC）电路的基础上，这个掩蔽的触摸屏5C-CPT性能。 与人类CPT一致，我们证实了PC对小鼠5-选择（5C-）CPT性能的必要性。 我们假设ACC到屏状核的投射在认知要求更高的试验中是重要的（从 参数操作），而屏状核到PC投影的发生对于选择是否 在审判中回答或不回答。使用纤维光度学和光遗传学技术，我们将证实这两个 这一电路的激活和必要性，包括活动的变化，作为直接结果 药理学操作因此，认知控制的基础电路将被识别， 影响该回路的药理学治疗在健康人类参与者中是容易测试的。