Determining how neurotensin mediates valence processing and compulsive cocaine seeking

确定神经降压素如何介导效价加工和强迫性可卡因寻求

基本信息

批准号：
10352031
负责人：
Hao Li
金额：
$ 17.26万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352031
关键词：
Adaptive Behaviors Affect Amino Acids Amygdaloid structure Award Behavior Behavioral CRISPR/Cas technology Cell Nucleus Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Cocaine Dependence Code Computer Vision Systems Conflict (Psychology)Control Groups Cues Data Decision Making Discrimination Disease Drug Addiction Drug usage E-learning Electrophysiology (science)Faculty Functional disorder Genes Glean Glutamates Human Impairment Intake Learning Machine Learning Mediating Mus Negative Valence Neural Pathways Neurons Neurotensin Nucleus Accumbens Pathologic Pattern Peptides Pharmaceutical Preparations Phase Play Population Positioning Attribute Positive Valence Property Punishment Research Research Project Grants Resistance Rewards Rodent Rodent Model Role Route Scientific Advances and Accomplishments Secure Self Administration Shock Signal Transduction Site Source Structure of paraventricular nucleus of thalamus Substance Use Disorder Sucrose Testing Thalamic structure Training Universities Viral adverse outcome approach behavior base behavioral response classification algorithm experimental study flexibility genetic manipulation in vivo knock-down motivated behavior neural correlate neuromechanism neuroregulation neurotensin type 1 receptor novel optogenetics receptor expression recreational drug use relating to nervous system response tenure track tool transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT A hallmark of substance use disorders is continued drug use despite profound adverse consequences. While studies in rodents have suggested that leveraging both positive and negative valence processing can affect this compulsive pattern of reward-seeking behavior in conflict with punishment, the underlying mechanisms that regulate valence processing and guide ultimate behavioral selections remain unknown. Studies have shown that the basolateral amygdala (BLA) projections to the nucleus accumbens (BLA-NAc) preferentially encode positive valence, including sucrose and cocaine predictive cues and drive approach behaviors, while projections to the central nucleus of the amygdala (BLA-CeM) encode negative valence and drive avoidance. This evidence strongly suggests that BLA-NAc and BLA-CeM neurons could encode valence processing during compulsive cocaine seeking and collectively mediate decision-making during ongoing behavior. This proposed project aims to identify basic neural substrates that guide the valence assignment among BLA-NAc and BLA-CeM neurons (K99 Phase), and examine whether the same mechanism contributes to the encoding of compulsive cocaine-seeking (R00 Phase). Preliminary data suggest that neurotensin (NT), a 13 amino acid peptide, plays a critical role in mediating valence processing in the BLA. Specifically, activation of terminals of the paraventricular nucleus of thalamus (PVT) NT neurons in the BLA enhanced reward learning and impaired punishment learning, while disruption of the PVT-BLA NTergic signaling produced the opposite behavioral effects. During the K99 phase of the award, the applicant will receive training on using CRISPR-Cas9 mediated gene manipulation to interrogate NTergic contributions without affecting glutamate and applying machine learning-based computer vision tools and classification algorithms to extract distinct behavioral motifs and decode neural correlates. This training will allow the applicant to investigate the specific roles of NT in valence assignment and coding properties of BLA neurons during valence processing. To test this, the applicant will examine the impact of the CRISPR-mediated knockdown of the Nt gene in BLA-projecting PVT neurons on reward and punishment learning (Aim 1) and the effects of the knockdown on valence encoding properties of BLA-NAc and BLA-CeM neurons during a reward and punishment discrimination task (Aim 2). After securing an independent research position, the applicant will begin the R00 phase of the award by combining these approaches gleaned from the K99 phase with applicant’s expertise in studying cocaine addiction with self- administration and punished reward-seeking paradigms, to investigate how PVT NTergic inputs modulate the encoding of compulsive cocaine-seeking (Aim 3). Together, the training and scientific advances that will be achieved through the completion of this project will allow the applicant to secure a tenure track faculty position in a top research university and provide critical pilot data necessary to prepare the first R01 application to study more distributed neural pathways that govern motivated behavior and compulsive drug-seeking.

项目概要/摘要物质使用障碍的一个标志是尽管产生了严重的不良后果，但仍然继续使用药物。对啮齿动物的研究表明，利用正价和负价处理可以影响这种与惩罚相冲突的强迫性寻求奖励行为模式，其潜在机制调节价处理和指导最终行为选择的机制仍然未知。显示基底外侧杏仁核（BLA）优先投射到伏隔核（BLA-NAc）编码正价，包括蔗糖和可卡因预测线索并驱动接近行为，同时杏仁核中央核（BLA-CeM）的投射编码负价并驱动回避。这一证据强烈表明 BLA-NAc 和 BLA-CeM 神经元可以编码价处理在强迫性寻求可卡因期间，并在持续行为期间集体调解决策。拟议项目旨在确定指导 BLA-NAc 之间价态分配的基本神经底物和 BLA-CeM 神经元（K99 相），并检查相同的机制是否有助于编码初步数据表明，神经降压素 (NT) 是一种 13 种氨基酸。肽，在介导 BLA 的价态加工中发挥着关键作用，具体来说，是末端的激活。 BLA 中的丘脑室旁核 (PVT) NT 神经元增强奖赏学习并受损惩罚学习，而 PVT-BLA NTergic 信号的破坏会产生相反的行为在奖励的 K99 阶段，申请人将接受使用 CRISPR-Cas9 介导的培训。基因操作以询问 NTergic 的贡献而不影响谷氨酸和应用机器基于学习的计算机视觉工具和分类算法来提取不同的行为模式和该培训将使申请人能够研究 NT 在价态中的具体作用。价处理过程中 BLA 神经元的分配和编码特性为了测试这一点，申请人将进行测试。检查 CRISPR 介导的 BLA 投射 PVT 神经元中 Nt 基因敲低的影响奖励和惩罚学习（目标 1）以及敲低对价编码特性的影响 BLA-NAc 和 BLA-CeM 神经元在奖励和惩罚辨别任务中（目标 2）。一个独立的研究职位，申请人将通过结合这些来开始该奖项的 R00 阶段从 K99 阶段收集的方法以及申请人在研究可卡因成瘾方面的专业知识以及自我管理和惩罚奖励寻求范式，以研究 PVT NTergic 输入如何调节编码强迫性可卡因寻求（目标 3）。通过完成该项目所取得的成就将使申请人能够获得终身教授职位在顶尖研究型大学，并提供准备第一个 R01 申请研究所需的关键试点数据控制动机行为和强迫性药物寻求的更加分布式的神经通路。