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

描述认知控制和注意的顶叶-前扣带-屏风环路 精神病患者的认知功能障碍亟需治疗。考虑到这种联系， 患者的功能障碍和结局，进行了大量临床试验，公司试图 成为“第一个进入市场的人”。然而，在匆忙中，使用的临床前研究对认知领域的有效性有限。 据报道，袭击目标是。因此，被测试的认知域的回路参与很少得到验证。 到目前为止，临床试验都失败了。出现了新的范例，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 这样的循环和行为已经出现。此应用程序将利用针对电路的方法来确认 5项连续操作测验(5C-CPT)在测量认知控制和注意力方面的效用 多发性精神障碍。特定目标1将针对参数优化触摸屏5C-CPT 操纵。5C-CPT存在于小鼠、大鼠和人类身上，有EEG和fMRI版本。这项任务一直以来 标准配置，主要用于5孔操作室，但带有参数的触摸屏版本 任务中的操作将提高人工测试的可翻译性，并实现基于任务性能的 一致性。对刺激的后向掩蔽以前曾用于认知控制任务，但直到最近才被使用 用于人体5C-CPT研究。在这里，我们将演示这样的掩蔽试验能够实现参数 5C-CPT在小鼠体内的性能评价。具体目标2将确定药理敏感性 触摸屏5C-CPT。开发任务后，务必确认它对以下各项敏感 操作，包括那些可用于人类进行药理学预测验证的操作。我们 证明莫达非尼改善了标准5C-CPT的健康受试者的表现，而 东莨菪碱会损害小鼠的行为能力。在这里，我们将确认莫达非尼和东莨菪碱类似地影响 这个蒙面触摸屏5C-CPT，同时预测多巴胺D4受体激动剂将改善认知 控制力。我们将证实莫达非尼可以挽救东莨菪碱诱导的缺陷，避免受体重复性。 并发症。具体目标3将确认前扣带回(Acc)屏状核和 屏蔽式顶叶皮质(PC)电路是这款屏蔽式触摸屏5C-CPT性能的基础。 与人类CPT一致，我们证实了PC对小鼠5选(5C-)CPT性能的必要性。 我们假设，在对认知要求更高的试验中，Acc到Caustrum的投射是重要的(来自 参数操作)，而发生频谱到PC的投影对于选择是否 在试验过程中是否做出反应。使用光纤光度学和光遗传技术，我们将证实 这个回路的激活和必要性，包括作为直接结果的活动的变化 药理操控。因此，认知控制的基础电路将被识别，也将被识别 影响这一回路的药物治疗，很容易在健康的人类参与者身上进行测试。

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.