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: 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
• 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

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.

项目总结/文摘