Exploring striatal circuits underlying behavioral flexibility during punishment of cocaine seeking

摘要 吸毒成瘾的一个标志是，不顾负面后果，无法控制地寻求毒品的冲动-- 寻求毒品的人变得抗拒惩罚。惩罚抵抗也被观察到在一个 上瘾的动物模型。在这个模型中，一些大鼠继续寻找可卡因，尽管结果是脚部电击(即， 而其他老鼠则减少吸食可卡因，以避免脚部电击。倾向于…… 减少可卡因寻求避免负面后果可能需要行为灵活性，一种适应形式的 允许根据环境中的新特征改变行为的学习。以前的工作使用 行为灵活性的衡量标准，如反转学习和策略转移，已经表明纹状体回路 对于表达行为灵活性是必不可少的。具体地说，额叶皮质区域，如眼眶额叶皮质 (OFC)和丘脑区域，如束旁丘脑(PF)靶向背侧纹状体(DS)和HELP 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的作用是- 行为灵活性及其神经基础在惩罚抵抗中的作用尚不清楚。拟议中的工作 将检验这样一种假设，即抗拒惩罚的可卡因寻求是由于以下情况下行为灵活性降低所致 面临着负面后果。具体目标1(F99，论文阶段)将确定DS CIN机制 这支持了在惩罚大鼠寻求可卡因的过程中的行为灵活性，使用免疫组织化学， 行为药理学和光遗传学。具体目标2(K00，博士后阶段)提出一项研究 方向将集中在OFC在驾驶和抑制抗拒惩罚的可卡因寻求方面的作用，这 作为将在目标1中完成的论文工作的延伸。我将获得技术技能 与神经传递的测量有关的，例如体内钙成像，以全面研究OFC的活动 在消极结果面前寻求可卡因的相关模式。此外，目标2描述了我的品质 我会在博士后导师和研究环境中寻找能够支持我的研究兴趣、技术 培养目标，并成长为一名独立的神经科学家。总体而言，本次培训中拟议的研究-- Lowship旨在定义行为灵活性降低背后的神经机制，这将有助于 确定针对药物成瘾的针对性治疗策略。

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.