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优势、反射或坚持行为的能力 长期目标。行为抑制的损伤与更高水平的冲动有关。 冲动可以分为三大类。运动冲动性是用专注于 关于等待-冲动的受试者不能在反应之前等待那么长时间。冲动也可能与 选择-例如，选择较小的即时奖励而不是较大的延迟奖励。最后， 冲动的受试者倾向于固执（即不假思索地行动），因此不能灵活地改变行为， 当环境发生变化时。冲动是泛诊断，发生在注意缺陷多动 注意力缺陷多动障碍（ADHD），药物和酒精成瘾，情感障碍，甚至神经系统疾病， 额颞叶痴呆 人们设计了各种行为任务来测量冲动性的上述特征。这些模型具有 被用来测试药物对减少冲动的影响。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甚至可复制的方式跨实验室，菌株或物种。这 排除了简单地测试药物如何改善冲动的尝试。这笔赠款，继 RFA规范的重点是评估冲动的电生理测量是否可以提供 与冲动性相关的回路活动的更稳定的"中间"测量， 药理学测试和开发。 这项资助的目标是首先确定神经生理学（基于LFP）的亚结构域标记物， 以上描述的冲动，特别关注于识别生理标记， 相关的和潜在的可测量的非侵入性的人类。接下来，我们将评估这些生理 测量可以用作治疗开发的测定， 标记物的变化对不同剂量的药物的反应，这些药物已知会影响冲动的特定子域。 最后，使用针对血清素或多巴胺的光遗传学，我们将能够直接测试是否 这些神经递质系统以时间上精确的方式的调节影响生理和行为。

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.