Orbitofrontal circuit mechanisms underlying alcohol use disorder

酒精使用障碍背后的眶额回路机制

• 批准号: 10684275
• 负责人: Vijay Mohan K Namboodiri
• 金额: $ 40.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684275
• 关键词: Alcohol consumption; Alcohols; Animals; Association Learning; Behavior; Brain; Calcium; Cells; Chronic; Corpus striatum structure; Cues; Decision Making; Development; Dorsal; Evolution; Extinction; Functional disorder; Head; Home; Hour; Image; Imaging Techniques; Investigation; Label; Learning; Longitudinal Studies; Mediating; Memory; Mental disorders; Mus; Nature; Neurons; Output; Population; Process; Quinine; Relapse; Research; Resistance; Resolution; Rewards; Role; Self Administration; Site; Sucrose; Technology; Testing; Time; Ventral Striatum; Ventral Tegmental Area; Water; alcohol behavior; alcohol cue; alcohol memory; alcohol response; alcohol reward; alcohol seeking behavior; alcohol use disorder; drug of abuse; drug reward; insight; interest; learning extinction; motivated behavior; mouse model; neuronal circuitry; optogenetics; preference; response; serial imaging; therapeutically effective; two-photon

PROJECT SUMMARY The orbitofrontal cortex (OFC) is a major hub in the brain that interacts with numerous other brain circuits to control many behaviors related to learning, memory and decision-making. OFC has also emerged as a significant node of dysfunction in alcohol use disorder (AUD). Nevertheless, how different OFC outputs contribute to AUD remains largely unknown. One major challenge in such an investigation is that AUD develops over long time- scales and is a chronic relapsing condition. Another challenge is that distinct projection outputs of OFC have different functions. Thus, investigation into the neuronal mechanisms underlying AUD will benefit from a longitu- dinal study of projection-specific neurons that spans the long timescale representative of AUD. Recent advances in two-photon microendoscopic calcium imaging allows the longitudinal tracking of the same projection-specific OFC neurons across months. In this proposal, we will use this cutting-edge technology to study the function of two OFC circuits—projections to dorsal striatum (targeting the densest projection near the border between dorsal and ventral striatum) and the ventral tegmental area (VTA) in alcohol related behaviors. These downstream targets are themselves critical regulators of natural reward or alcohol related behaviors, and these projections have been demonstrated to have at least some non-overlapping functions in natural reward learning. The central question of interest in this proposal is whether the encoding adaptations during initial alcohol use in neuronal ensembles within these OFC circuits predict their subsequent encoding and control of aversion-resistant operant alcohol seeking or cue-induced reinstatement. In aim 1, we will image alcohol related neuronal activity weekly in the above OFC outputs while C57/BL6 mice have intermittent access to 20% alcohol in a two-bottle choice paradigm (IA20%2BC) for 7-8 weeks. We will test the hypothesis that OFC→dorsal striatum, but not OFC→VTA, neurons strengthen their responses to alcohol, as animals begin preferring alcohol. In aim 2, we will longitudinally track the same neurons from initial alcohol consumption to subsequent tests of aversion-resistant seeking. Spe- cifically, we will investigate the role of the above circuits during operant self-administration of alcohol with or without quinine adulteration, and test the hypothesis that the same OFC→dorsal striatum neurons that encode initial escalation of alcohol preference also encode and mediate aversion-resistant seeking. In aim 3, we will longitudinally track neurons from initial alcohol use to subsequent extinction and cue-induced reinstatement of operant alcohol seeking. We will test the hypothesis that OFC→VTA neuronal activity predicts and mediates cue-induced reinstatement of operant alcohol seeking. Overall, these studies will yield insights on the extent of overlap of neuronal encoding of alcohol consumption/preference, aversion-resistant operant seeking, and cue- induced reinstatement.

项目总结 眶前叶皮质(OFC)是大脑中的一个主要中枢，它与许多其他脑回路相互作用，以 控制许多与学习、记忆和决策有关的行为。OFC也已成为一项重要的 酒精使用障碍的功能障碍结节(AUD)。然而，不同的OFC输出如何对澳元做出贡献 在很大程度上仍不为人所知。这种调查的一个主要挑战是澳元会随着时间的推移而发展- 规模大，是一种慢性复发的情况。另一个挑战是OFC的不同预测输出具有 不同的功能。因此，对AUD背后的神经元机制的研究将受益于一项纵向的研究。 对代表AUD的长时间标度的投射特定神经元的深入研究。最新进展 在双光子显微内窥镜下钙离子成像允许纵向跟踪相同的投影 几个月的OFC神经元。在这份提案中，我们将利用这一前沿技术来研究 两个OFC环路-至背侧纹状体的投射(定位于背侧交界处附近密度最高的投射 和腹侧纹状体)和腹侧被盖区(VTA)。这些下游的 目标本身就是自然奖励或酒精相关行为的关键调节者，而这些预测 已被证明在自然奖赏学习中至少有一些不重叠的功能。中环 在这项提议中感兴趣的问题是，在最初的酒精使用期间，神经元中的编码适应 这些OFC回路中的集合预测了它们随后对抗厌恶操纵子的编码和控制 酒精寻求或暗示诱导复活。在目标1中，我们将每周对酒精相关的神经元活动进行成像 当C57/BL6小鼠在两瓶的选择中间歇性地获得20%的酒精时，上述OFC输出 模型(IA20%2BC)，7-8周。我们将检验这样的假设，即OFC→背侧纹状体，而不是OFC→VTA， 随着动物开始偏爱酒精，神经元加强了对酒精的反应。在目标2中，我们将纵向 追踪相同的神经元，从最初的饮酒到随后的抗厌恶寻求测试。SPE- 实际上，我们将研究上述回路在酒精可操作性自我给药过程中的作用。 没有掺入奎宁，并检验了这样的假设，即编码的相同的→背侧纹状体神经元 酒精偏好的初始升级也编码并调节了抗厌恶寻求。在《目标3》中，我们将 纵向追踪神经元从最初的酒精使用到随后的消失和线索诱导的恢复 有效的酒精寻觅。我们将检验这样一种假设，即Ofc→室旁核神经元活动预测和调节 提示诱导的可操作性酒精寻求的复苏性。总体而言，这些研究将对 酒精消费/喜好、抗厌恶操作者寻找和线索-的神经元编码重叠 诱导复职。