Identifying and Targeting Physiological Assays of Circuit Engagement to Improve Impulsivity

识别和针对回路参与的生理分析以改善冲动

基本信息

批准号：
10615875
负责人：
Jyoti Mishra
金额：
$ 35.88万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615875
关键词：
Affect Alcohol dependence Animals Attention deficit hyperactivity disorder Behavior Behavioral Behavioral inhibition Biological Assay Bipolar Disorder Brain Brain region Categories Citalopram Classification Corpus striatum structure Cues Data Development Diagnostic Dimensions Disease Dopamine Dose Drug Addiction Drug usage Electroencephalography Electrophysiology (science)Environment Evaluation Frequencies Frontotemporal Dementia Goals Grant High Frequency Oscillation Human Impairment Impulsivity Learning Link Measurable Measures Medial Mental Depression Mental disorders Modeling Mood Disorders Motor Motor Cortex Neurotransmitters Obsessive compulsive behavior Performance Pharmaceutical Preparations Pharmacology Pharmacology Study Phase Physiologic Monitoring Physiological Physiological Processes Physiology Prefrontal Cortex Probability Process Research Reversal Learning Rewards Ritalin Serotonin Specific qualifier value Substance abuse problem System Testing Thinking Traumatic Brain Injury Ventral Striatum Visual activity marker autism spectrum disorder behavior change behavioral construct behavioral pharmacology biomarker identification cell type design discounting dopaminergic neuron dosage drug testing flexibility improved nervous system disorder neurophysiology optogenetics pharmacologic pre-clinical response substance use suicidal act targeted agent therapeutic development tool translation to humans

项目摘要

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.

项目摘要行为抑制包括我们在追求中抑制优先，反思性或持久行为的能力长期目标。行为抑制作用的损害与更大的冲动性有关。冲动性可以分为三个主要类别。使用专注于任务来衡量电动冲动性等待 - 冲动的受试者在响应之前就等不及了。冲动性也可能与选择 - 例如，选择较小的立即奖励，而不是较大的延迟奖励。最后，冲动的主体倾向于坚持不懈（即无思考的行为），因此不能灵活地将行为转移为当环境变化时需要。冲动性是泛诊断，发生在注意力不足多动症中疾病（多动症），毒品和酒精成瘾，情感障碍甚至神经系统疾病额颞痴呆。已经设计了各种行为任务，以衡量冲动的上述特征。这样的模型有用于测试药物对最小化冲动性的影响。这些任务中使用的药物可以调节行为，但并非总是以实验室，菌株或物种的可预测甚至可复制的方式。这就是排除了测试药理剂如何改善冲动性的简单尝试。这笔赠款，遵循 RFA规格的重点是评估冲动性的电生理测量方法与冲动性相关的电路活动的更稳定的“中介”度量，可用于临床前药理测试和开发。该赠款的目标首先是确定子域的神经生理学（基于LFP）的标记上面描述的冲动性，特别着重于识别翻译的物理标记在人类中相关且潜在的非侵入性。接下来，我们将评估这些生理学是否措施可以通过测试鉴定的生理方式来用作治疗性开发的测定标志物因各种剂量的响应而变化，这些药物已知会影响脉冲的特定亚域。最后，使用针对5-羟色胺或多巴胺的光遗传学，我们将能够直接测试是否是否这些神经递质系统以一种暂时完善的方式调节会影响生理和行为。