Investigating the role of locus coeruleus in conditioned cocaine-stimulus control of attention

研究蓝斑在条件性可卡因刺激注意力控制中的作用

• 批准号: 10669917
• 负责人: Mark Anton Presker
• 金额: $ 4.48万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669917
• 关键词: Adaptive Behaviors; Attention; Attenuated; Auditory; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain Stem; Calcium; Cocaine; Cocaine Dependence; Cocaine use disorder; Collaborations; Communities; Conditioned Stimulus; Disease; Electrophysiology (science); Environment; Esthesia; Faculty; Fellowship; Foundations; Future; Image; Imaging Techniques; Individual; Mediating; Mentorship; National Research Service Awards; Neurobiology; Occupational; Pharmaceutical Preparations; Physiology; Process; Rattus; Recovery; Relapse; Research; Research Personnel; Resolution; Role; Scientist; Sensory; Stimulus; Structure; Students; System; Training; Water; addiction; attentional control; career; effective therapy; experimental study; improved; locus ceruleus structure; member; neural correlate; neuromechanism; novel therapeutic intervention; prevent; programs; public health relevance; reinforced behavior; relating to nervous system; sensory system; social; societal costs; 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.

项目摘要/摘要 显著的环境刺激可以吸引注意力并驱动行为；这一过程对指导至关重要 适应性行为，被称为刺激控制。刺激控制在疾病状态下可能会变得不适应，例如 可卡因成瘾，与可卡因相关的刺激可以施加不适当的影响，扰乱正在进行的首选 行为(即职业或社会活动)和努力保持无毒。而改变的刺激控制是 众所周知，可卡因成瘾是导致可卡因上瘾的原因，但这一过程背后的神经机制并不充分 明白了。蓝斑是一种神经结构，调节注意力、感觉和行为。 控制，并受到可卡因的强烈影响。因此，LC可能是非适应性刺激控制的中心。 可卡因成瘾。已知LC和下游感觉系统中的刺激编码对刺激- 引导行为，尽管尚不清楚可卡因相关刺激是否编码在这些系统中。这个 NRSA中提出的研究计划将阐明LC在编码听觉可卡因-茎和 检查LC在通过这种刺激调节行为控制中是否有因果作用。我们将聘用 一种评估听觉刺激对水强化行为控制的大鼠行为范式 可卡因-刺激物。目标1将使用细胞分辨率、钙成像和电生理学来检查神经 LC和听性脑干刺激控制的相关性。目标2将使用一种化学遗传学 在获得或表达条件刺激控制期间选择性抑制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。加在一起，这些实验已经 为针对LC的治疗提供信息以减轻不良适应刺激驱动的行为的可能性 可卡因成瘾。 此外，拟议的奖学金将为我的职业生涯提供坚实的基础 独立调查人员专注于成瘾的神经生物学和行为基础。培训 本提案中描述的环境将包括师生指导和合作，旨在 为我提供这个项目核心领域的科学培训，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。作为一个整体， 这项研究具有巨大的潜力，可以产生与成瘾治疗相关的科学发现和 也是一位有能力成为成瘾研究界杰出成员的科学家。