Stimulus control of attention in cocaine addiction: role of locus coeruleus

可卡因成瘾中注意力的刺激控制：蓝斑的作用

• 批准号: 9980176
• 负责人: Mark Anton Presker
• 金额: $ 4.54万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980176
• 关键词: Acute; Adaptive Behaviors; Arousal; Attention; Attenuated; Auditory; Auditory Brainstem Responses; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain Stem; Calcium; Cell Nucleus; Cocaine; Cocaine Dependence; Collaborations; Communities; Conditioned Stimulus; Cues; Disease; Electrophysiology (science); Environment; Esthesia; Exhibits; Faculty; Fellowship; Foundations; Future; Head; Human; Image; Imaging Techniques; Individual; Individual Differences; Mediating; Memory; Mentorship; Microscope; National Research Service Awards; Neocortex; Neurobiology; Neurons; Norepinephrine; Occupational; Outcome Study; Pharmaceutical Preparations; Phase; Physiology; Process; Property; Psychological reinforcement; Rattus; Recovery; Relapse; Research; Research Personnel; Resolution; Rewards; Rodent Model; Role; Scientist; Self Administration; Sensory; Sensory Process; Stimulus; Structure; Students; System; Techniques; Testing; Therapeutic; Training; Tyrosine 3-Monooxygenase; Virus; Water; addiction; attentional bias; attentional control; career; cocaine exposure; cocaine use; conditioning; craving; effective therapy; experience; experimental study; improved; in vivo calcium imaging; locus ceruleus structure; member; motivated behavior; neural correlate; neuromechanism; novel; novel therapeutics; preconditioning; prevent; programs; public health relevance; reinforced behavior; relating to nervous system; response; reuptake; selective expression; sensory system; social; societal costs; success; undue influence

Project Summary/Abstract Salient environmental stimuli can capture attention and drive behavior; this process, vital for guiding adaptive behavior, is called stimulus control. Stimulus control can become maladaptive in disease states, such as cocaine addiction, where cocaine-associated stimuli can wield undue influence and disrupt ongoing preferred behavior (i.e. occupational or social activities) and efforts to remain drug-free. While altered stimulus control is well-understood to contribute to cocaine addiction, the neural mechanisms underlying this process are poorly understood. The locus coeruleus (LC) is a neural structure, which modulates attention, sensation, and behavioral control and is strongly effected by cocaine. Thus, the LC may be at the center of maladaptive stimulus control in cocaine addiction. Stimulus encoding in LC and downstream sensory systems is known to be critical for stimulus- guided behavior although it is not known if cocaine-associated stimuli are encoded in these systems. The research plan proposed in this NRSA will elucidate the role of LC in encoding an auditory cocaine-stumulus and examine whether there is a causal role for LC in mediating control of behavior by this stimulus. We will employ a behavioral paradigm in rats which assesses stimulus control of water-reinforced behavior by an auditory cocaine-stimulus. Aim 1 will use cellular resolution calcium imaging and electrophysiology to examine neural correlates of stimulus control in the LC and auditory brainstem respectively. Aim 2 will use a chemogenetic approach to selectively inhibit LC activity during acquisition or expression of conditioned stimulus control by a cocaine-stimulus in order establish a causal role for LC in these processes. Combined, these experiments have the potential to inform therapies aimed at targeting LC to attenuate maladaptive stimulus-driven behavior in cocaine addiction. Furthermore, the proposed fellowship will provide me with a strong foundation for a career as an independent investigator focused on the neurobiological and behavioral underpinnings of addiction. The training environment described in this proposal will incorporate faculty-student mentorships and collaborations aimed at providing me with scientific training across the domains central to this project including LC physiology, calcium imaging techniques, and sensory processing. Additionally, the training plan will provide me with professional training which will prepared me for my future as I establish my own independent research program. As a whole, this Fellowship has significant potential to produce both scientific findings relevant to treatment of addiction and also a scientist well-equipped to become an outstanding member of the addiction research community.

项目总结/摘要 显著的环境刺激可以捕获注意力并驱动行为;这一过程对于引导 适应性行为，被称为刺激控制。在疾病状态下，刺激控制可能变得不适应， 可卡因成瘾，其中可卡因相关的刺激可以施加不适当的影响，并破坏正在进行的首选 行为（即职业或社会活动）和努力保持无毒品。虽然改变刺激控制是 众所周知，可卡因成瘾的原因是，这一过程背后的神经机制很差， 明白蓝斑（LC）是调节注意、感觉和行为的神经结构 控制，并强烈影响可卡因。因此，LC可能处于适应不良刺激控制的中心， 可卡因成瘾已知LC和下游感觉系统中的刺激编码对刺激至关重要- 引导的行为，尽管不知道可卡因相关的刺激是否在这些系统中被编码。的 NRSA提出的研究计划将阐明LC在编码听觉可卡因-stumulus中的作用， 检查是否有一个因果关系的作用，LC在介导控制的行为，这种刺激。我们会委聘 大鼠的行为范式，其通过听觉评估水强化行为的刺激控制 可卡因刺激目的1将利用细胞分辨率钙成像和电生理学检查神经元 LC和听觉脑干的刺激控制的相关性。Aim 2将使用化学遗传学 一种在条件刺激控制的获取或表达期间选择性抑制LC活性的方法， 可卡因刺激，以确定LC在这些过程中的因果作用。综合起来，这些实验 有可能告知旨在靶向LC的治疗，以减轻适应不良刺激驱动的行为， 可卡因成瘾 此外，拟议的奖学金将为我的职业生涯提供一个坚实的基础， 一位独立的研究者专注于成瘾的神经生物学和行为基础。培训 本提案中所描述的环境将包括师生指导和合作，旨在 为我提供了跨领域的科学培训，包括LC生理学，钙， 成像技术和感官处理。此外，培训计划将为我提供专业的 培训，这将为我的未来做好准备，因为我建立了自己的独立研究计划。总的来说， 该奖学金具有产生与成瘾治疗相关的科学发现的巨大潜力， 也是一位科学家，有能力成为成瘾研究界的杰出成员。