Exploring striatal circuits underlying behavioral flexibility during punishment of cocaine seeking

探索可卡因寻求惩罚期间行为灵活性背后的纹状体回路

• 批准号: 10709530
• 负责人: Adelis Marie Cruz
• 金额: $ 3.94万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10709530
• 关键词: Acetylcholine; Animal Model; Area; Automobile Driving; Behavior; Behavioral; Cholinergic Antagonists; Collaborations; Compulsive Behavior; Corpus striatum structure; Desire for food; Development; Dorsal; Drug Addiction; Environment; Event; Exhibits; FOS gene; Faculty; Fellowship; Food; Foundations; Goals; Growth; Immunohistochemistry; Impairment; Individual; Interneurons; Intralaminar Nuclear Group; Knowledge; Learning; Lesion; Measures; Mediating; Mentors; Microdialysis; Modeling; Outcome; Pattern; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Postdoctoral Fellow; Punishment; Rattus; Recurrent disease; Reinforcement Schedule; Research; Research Personnel; Research Project Grants; Resistance; Reversal Learning; Rewards; Role; Stains; Technical Expertise; Testing; Thalamic structure; Training; Update; Work; addiction; behavior measurement; behavioral response; career; cell type; cholinergic; cocaine seeking; cocaine self-administration; experience; flexibility; frontal lobe; in vivo calcium imaging; interest; neural; neural circuit; neuromechanism; neurotransmission; optogenetics; pharmacologic; pre-doctoral; response; skills; targeted treatment; tenure track; tool; treatment strategy

Abstract A hallmark of drug addiction is the uncontrollable urge to seek drug despite negative consequences— drug seeking individuals become resistant to punishment. Punishment resistance has also been observed in an animal model of addiction. In this model, some rats continue to seek cocaine despite a footshock outcome (i.e., punishment), whereas other rats instead reduce their cocaine seeking to avoid footshock. The propensity to reduce cocaine seeking to avoid a negative consequence may require behavioral flexibility, an adaptive form of learning that allows changes in behavior in response to new features in the environment. Previous work using measures of behavioral flexibility, such as reversal learning and strategy shifting, have shown that striatal circuits are essential for expressing behavioral flexibility. Specifically, frontal cortex areas such as the orbitofrontal cortex (OFC) and thalamic areas such as the parafascicular thalamus (PF) target the dorsal striatum (DS) and help track events in the environment that are important for updating behavior. One striatal cell type that is important for the role of PF and OFC in behavioral flexibility are cholinergic interneurons (CIN). However, the role of be- havioral flexibility and its neural substrates in punishment resistance is poorly understood. The proposed work will test the hypothesis that punishment-resistant cocaine seeking results from reduced behavioral flexibility when faced with negative consequences. Specific Aim 1 (F99, dissertation phase) will identify a DS CIN mechanism that supports behavioral flexibility during punishment of cocaine seeking in rats, using immunohistochemistry, behavioral pharmacological, and optogenetics. Specific Aim 2 (K00, postdoctoral phase) proposes a research direction that will focus on the role of OFC in driving vs suppressing punishment-resistant cocaine seeking, which serves as an extension of the dissertation work that will be completed in Aim 1. I will acquire technical skills related to a measure of neurotransmission, such as in vivo calcium imaging, to fully investigate OFC activity patterns related to cocaine seeking in the face of negative outcomes. In addition, Aim 2 describes the qualities I will seek in a postdoctoral mentor and research environment that can support my research interests, technical training goals, and growth as an independent neuroscientist. Overall, the proposed research in this training fel- lowship aims to define the neural mechanisms underlying reduced behavioral flexibility, which will contribute to identifying targeted treatment strategies for drug addiction.

摘要 吸毒成瘾的一个标志是尽管有负面后果，但仍有无法控制的寻求毒品的冲动- 寻求毒品的人变得抗拒惩罚。在一个国家，也观察到了对惩罚的抵制。 成瘾的动物模型在该模型中，尽管有足电击结果，一些大鼠仍继续寻求可卡因（即， 惩罚），而其他大鼠则减少可卡因，以避免脚震。的倾向 减少可卡因寻求避免负面后果可能需要行为灵活性，这是一种适应性形式， 允许行为改变以响应环境中的新特征的学习。以前的工作使用 行为灵活性的测量，如逆转学习和策略转移，已经表明纹状体回路 是表达行为灵活性的关键。具体来说，额叶皮层区域，如眶额皮层， (OFC)而丘脑区域，如束旁丘脑（PF），则以背侧纹状体（DS）为目标， 跟踪环境中对更新行为很重要的事件。一种重要的纹状体细胞类型 PF和OFC在行为灵活性中的作用是胆碱能中间神经元（CIN）。然而，be的作用- 对惩罚抵抗中的脑柔韧性及其神经基质的了解很少。拟议工作 将测试这一假设，即当行为灵活性降低时， 面对负面后果。具体目标1（F99，论文阶段）将确定DS CIN机制 在大鼠寻求可卡因的惩罚过程中支持行为灵活性，使用免疫组织化学， 行为药理学和光遗传学具体目标2（K 00，博士后阶段）提出了一项研究 方向，将重点放在OFC在驱动与抑制惩罚抵抗可卡因寻求中的作用， 作为论文工作的延伸，将在目标1中完成。我将获得技术技能 与神经传递的测量相关，例如体内钙成像，以充分研究OFC活性 在面对负面结果时寻求可卡因的模式。此外，目标2描述了我 我将寻求博士后导师和研究环境，可以支持我的研究兴趣，技术 培训目标和成长为一个独立的神经科学家。总的来说，本次培训中提出的研究- 研究的目的是确定行为灵活性降低的神经机制，这将有助于 确定有针对性的药物成瘾治疗策略。