Identifying and Targeting Physiological Assays of Circuit Engagement to Improve Impulsivity

项目摘要 行为抑制包括我们在追求过程中抑制强势、反身性或持之以恒行为的能力 更长远的目标。行为抑制方面的障碍与更高水平的冲动有关。 冲动可以分为三大类。使用专注于任务的方法来测量运动冲动性 在等待方面--冲动的受试者在做出反应之前不能等那么长时间。冲动也可以与 选择--例如，选择一个较小的直接奖励，而不是较大的延迟奖励。最后， 冲动的受试者倾向于坚持不懈(即不加思考地行动)，因此不能灵活地改变行为 当环境发生变化时需要。冲动是泛诊断的，发生在注意缺陷多动中 精神障碍(ADHD)，药物和酒精成瘾，情感障碍，甚至神经障碍，如 额颞部痴呆。 人们设计了各种行为任务来测量冲动的上述特征。这样的模式有 已经被用来测试药物对最小化冲动的效果。在这些任务中使用的药物可以调节 行为，但并不总是以可预测的方式，甚至在实验室、品系或物种之间复制。这有 排除了测试药理制剂如何改善冲动的简单尝试。这笔赠款如下 RFA规范的重点是评估冲动的电生理测量是否可以提供 一种更稳定的与冲动相关的电路活动的“中介”测量，可用于临床前研究 药理测试和开发。 这项资助的目标是首先确定神经生理学(基于LFP)亚域的标记 上面描述的冲动，特别关注识别翻译过来的生理标记 在人类中具有相关性和潜在的可测量的非侵入性。接下来，我们将评估这些生理上的 测量可用作治疗发展的测试，通过测试已识别的生理学 已知的影响冲动的特定亚域的不同剂量的药物对标记物的反应变化。 最后，利用针对5-羟色胺或多巴胺的光遗传学，我们将能够直接测试 这些神经递质系统在时间上的精细调节会影响生理和行为。

Project Summary Behavioral inhibition includes our ability to inhibit prepotent, reflexive or perseverative behaviors in the pursuit of longer-term goals. Impairments in behavioral inhibition are associated with greater levels of impulsivity. Impulsivity can be classified into at three major categories. Motor impulsivity is measured using tasks focused on waiting – impulsive subjects cannot wait as long prior to responding. Impulsivity can also be related to choice – for example, choosing a smaller immediate reward instead of a larger delayed reward. Finally, impulsive subjects tend to perseverate (i.e. act without thinking), and thus cannot flexibly shift behaviors as needed when the environment changes. Impulsivity is pan-diagnostic, occurring in attention deficit hyperactivity disorder (ADHD), drug & alcohol addiction, affective disorders and even neurologic disorders like frontotemporal dementia. Various behavioral tasks have been designed to measure the above features of impulsivity. Such models have been used to test the effects of drugs on minimizing impulsivity. Drugs used in these tasks can modulate behavior, but not always in a predictable or even replicable manner across labs, strains or species. This has precluded simple attempts at testing how pharmacologic agents can improve impulsivity. This grant, following RFA specifications, is focused on assessing whether electrophysiological measures of impulsivity can provide a more stable “intermediary” measure of circuit activity relevant to impulsivity that can be used for preclinical pharmacologic testing and development. The goals of this grant are first to identify neurophysiological (LFP-based) markers of subdomains of impulsivity described above, with a particular focus on identifying physiological markers that are translationally relevant and potentially measurable non-invasively in humans. Next, we will assess whether these physiologic measures can be used as an assay for therapeutic development by testing how the identified physiological marker changes in response to varying dosages of drugs known to affect specific subdomains of impulsivity. Finally, using optogenetics targeted at serotonin or dopamine, we will be able to directly test whether modulation of these neurotransmitter systems in a temporally refined way affects physiology and behavior.