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

• 批准号: 10553674
• 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
• 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/10553674
• 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; Dissociation; Drug Addiction; Drug usage; E-learning; Electrophysiology (science); Faculty; Functional disorder; Genes; Glean; Glutamates; Human; Impairment; Infusion procedures; 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; Visualization; addiction; adverse outcome; approach behavior; behavioral response; classification algorithm; cocaine seeking; drug addict; experimental study; flexibility; genetic manipulation; in vivo; knock-down; motivated behavior; neural; neural correlate; neuromechanism; neuroregulation; neurotensin type 1 receptor; novel; optogenetics; receptor expression; recreational drug use; response; tenure track; tool; transmission process

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.

项目摘要/摘要 药物使用障碍的标志是继续毒品使用深刻的逆境。尽管 啮齿动物的研究表明，利用正价和负价处理可能会影响 这种强迫性寻求奖励行为与惩罚冲突，基本机制 调节价值处理和指导最终行为选择仍然未知。研究有 表明载脂杏仁核（BLA）优先向伏隔核（BLA-NAC）投射 编码正价，包括蔗糖和可卡因预测提示和驱动方法行为，而 对杏仁核（BLA-CEM）中央核的预测编码负价和避免驱动力。 该证据强烈表明BLA-NAC和BLA-CEM神经元可以编码价处理 在强迫性可卡因期间，在持续行为期间寻求和集体媒体决策。这 拟议的项目旨在确定指导BLA-NAC价值分配的基本神经底物 和BLA-CEM神经元（K99阶段），并检查相同的机制是否有助于编码 强迫性可卡因寻求（R00阶段）。初步数据表明神经素（NT），13个氨基酸 肽，在介导BLA的价值处理中起关键作用。具体而言，激活端子的激活 BLA中丘脑（Pvt）NT神经元的室室核增强了奖励学习和受损 惩罚学习，而pvt-bla ntergic信号的破坏产生了相反的行为 效果。在奖项的K99阶段，适用的将接受有关使用CRISPR-CAS9中介的培训 基因操纵以询问NTERGIC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，以提取不同的行为图案和 解码神经相关。该培训将使申请人能够调查NT在价上的特定作用 Valence处理过程中BLA神经元的分配和编码属性。为了测试这一点，适用的将 检查NT基因在BLA射击PVT神经元中的CRISPR介导的敲低的影响 奖励和惩罚学习（AIM 1）以及敲低对编码价值的影响的影响 在奖励和惩罚歧视任务中，bla-nac和bla-cem神经元（AIM 2）。固定后 一个独立的研究职位，申请人将通过合并这些来开始奖励的R00阶段 从K99阶段收集的方法，申请人在研究可卡因成瘾方面的专业知识与自我 管理和惩罚寻求奖励的范例，以调查PVT NTERGIC输入如何调节 强迫可卡因寻求的编码（AIM 3）。一起，培训和科学进步将是 通过完成该项目完成的实现将使申请人确保任期教师职位 在一所顶级研究大学中，提供了准备第一个R01申请进行研究所需的关键试验数据 控制融合行为和强迫性毒品的更多分布式神经病道。