Orbitofrontal circuit mechanisms underlying alcohol use disorder

项目摘要 眶额皮层（OFC）是大脑中的一个主要中枢，它与许多其他大脑回路相互作用， 控制许多与学习、记忆和决策有关的行为。OFC也已成为一个重要的 酒精使用障碍（AUD）的功能障碍节点。然而，不同的OFC产出如何对澳元做出贡献， 仍然是未知的。在这样的调查中，一个主要的挑战是澳元的发展需要很长一段时间- 规模和是一种慢性复发性疾病。另一个挑战是，OFC的不同预测输出 不同的功能。因此，对AUD潜在神经机制的研究将受益于长期的研究。 投射特异性神经元的纵向研究，其跨越AUD的长时间尺度代表。最新进展 在双光子显微内窥镜钙成像允许纵向跟踪相同的投影特异性 眶额皮层神经元。在本提案中，我们将利用这一尖端技术来研究 两个OFC回路-向背侧纹状体的投射（靶向背侧和背侧之间的边界附近的背侧投射） 和腹侧纹状体）和腹侧被盖区（VTA）在酒精相关行为中的作用。这些下游 目标本身是自然奖励或酒精相关行为的关键调节器，这些预测 在自然奖励学习中至少有一些不重叠的功能。中央 这个建议中的一个有趣的问题是，在神经元中最初使用酒精期间的编码适应是否 这些OFC回路中的合奏预测了它们随后对厌恶抗性操作词的编码和控制， 酒精寻求或线索诱导的恢复。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/BL 6小鼠间歇性地接触两瓶选择中的20%酒精时， 模型（IA20%2BC）7-8周。我们将检验OFC→背侧纹状体而不是OFC→VTA的假设， 当动物开始喜欢酒精时，神经元会加强对酒精的反应。在目标2中，我们将纵向 从最初的酒精消费到随后的厌恶寻求测试，跟踪相同的神经元。斯佩 接下来，我们将研究上述回路在酒精操作性自我给药过程中的作用， 没有奎宁掺假，并测试假设，相同的OFC→背侧纹状体神经元编码 酒精偏好初始升级也编码和介导厌恶抵抗寻求。在目标3中，我们 纵向跟踪神经元从最初的酒精使用到随后的灭绝和线索诱导的恢复， 酒精寻求我们将检验OFC→VTA神经元活动预测和介导 线索诱导的操作性酒精寻求恢复。总的来说，这些研究将有助于了解 酒精消费/偏好的神经元编码重叠，厌恶抵抗操作寻求，和线索- 诱导恢复。

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.