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抑制优势，渗透行为的能力长期目标。冲动性可以分为三个主要类别。在等待 - 冲动之前的冲动也不能与冲动性相关。选择 - 例如，选择一个较小的IMEDIATE奖励，而不是较大的延迟奖励。冲动的主体倾向于坚持不懈（即无思考的行动），因此不能弹性的转变行为当环境发生变化时需要。疾病（ADHD），毒品和酒精，情感障碍甚至神经病学障碍额颞痴呆。各种行为任务已经衡量了这些模型的上述特征使用测试药物对这些任务中使用的药物的影响行为，但并非总是以实验室，菌株或物种的可预测或事件可复制的方式。批准了这项赠款的简单尝试 RFA规格的重点是评估脉冲的电生理粒细胞测量方法是否可以提供与冲动性相关的电路活动的更稳定的“中介”度量可以用于临床前药理学测试和开发。该赠款的目标首先是确定子域的神经生理学（基于LFP）的标记涉及的冲动性尤其着重于识别转化的生理标记在人类中，我们将评估这些物理学是否相关且潜在的可测量。可以通过测试鉴定的生理方式来使用ASASA测定法进行治疗开发标记因响应而变化，以改变已知会影响冲动性特定亚域的药物的剂量。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以时间精致的方式调节神经递质系统会影响和行为。