Corticostriatal BDNF signaling in alcohol seeking and preference switching

皮质纹状体 BDNF 信号在酒精寻求和偏好转换中的作用

• 批准号: 10227660
• 负责人: Jeffrey Jay Moffat
• 金额: $ 6.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227660
• 关键词: Adult; Affect; Age; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; American; Animals; Axon; BDNF gene; Behavior; Behavioral; Behavioral Assay; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Cells; Cognition; Corpus striatum structure; Decision Making; Development; Disease; Dorsal; Enterobacteria phage P1 Cre recombinase; Equilibrium; Food; Future; Goals; Heavy Drinking; Heroin; Individual; Investigation; Judgment; Laboratories; Lateral; Light; Measures; Medial; Methamphetamine; Methods; Molecular; Mus; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pharmacology; Play; Population; Proteins; Receptor Protein-Tyrosine Kinases; Reinforcement Schedule; Reporting; Rewards; Rodent; Role; Self Administration; Signal Pathway; Signal Transduction; Social Interaction; Techniques; Testing; Therapeutic Intervention; Training; Transgenic Mice; United States; Update; Work; alcohol measurement; alcohol reward; alcohol seeking behavior; alcohol use disorder; base; design; deter alcohol use; drinking; drug development; efficacy evaluation; experimental study; gene therapy; genetic manipulation; innovation; insight; knock-down; neural circuit; neurodevelopment; novel; overexpression; preference; prevent; relating to nervous system; social; support network; therapeutic target; tool

PROJECT SUMMARY Most adults in the United States have consumed alcohol at least once. Within that population, however, only 10-15% develop alcohol use disorder (AUD), indicating that majority may be intrinsically protected against alcohol addiction. Brain-derived neurotrophic factor (BDNF) signaling via the tyrosine-receptor kinase B (TrkB) receptor plays a role in preventing the escalation of alcohol intake to excessive levels. The goal of this study is to establish the mechanisms and neural circuitry by which BDNF gates alcohol drinking. BDNF- expressing neuronal projections from the orbitofrontal cortex (OFC) to the dorsal striatum (DS) have been shown previously by the Ron laboratory to gate alcohol consumption in mice. The OFC is involved in updating and ranking reward values and the DS is necessary for the development of habitual or goal-directed action- selection strategies. I recently found that that systemic administration of a TrkB agonist reverts habitual alcohol seeking toward more goal-directed behavior in mice. I therefore hypothesize that the role of BDNF signaling in the DS, and specifically in OFC-DS circuitry, is to bias behavior away from habitual alcohol seeking and toward more goal-directed alcohol seeking and alternative rewards. Using innovative molecular, pharmacologic and behavioral approaches, I will test the following aims: Aim 1 will investigate the role of BDNF-expressing neurons in the OFC in promoting goal-directed alcohol seeking. I will train transgenic mice expressing Cre-recombinase in BDNF-expressing neurons to habitually self-administer alcohol. I will then use a chemogenetic strategy to specifically activate BDNF- expressing neurons in the OFC to determine whether BDNF-positive OFC neuronal activity is sufficient to shift mice from habitual to goal-directed alcohol seeking. Aim 2 will examine the role of BDNF signaling in the DS and in the OFC-DS circuit in habitual alcohol seeking. I will utilize pharmacological tools and circuit-specific genetic interventions to activate or inhibit BDNF signaling in the DS and in OFC-DS circuits and determine the effects these manipulations have on habitual versus goal-directed alcohol seeking action-selection strategies in mice. Aim 3 will establish the effects of BDNF signaling in the OFC-DS projection on “preference-switching” between alcohol intake and social interaction. To test this hypothesis, I will use novel behavioral assays to assess differences in alcohol- and social interaction-seeking behaviors accompanied with pharmacological and circuit-specific genetic manipulations to alter endogenous corticostriatal BDNF signaling. If successful, this work will provide insight into the mechanism by which BDNF signaling keeps alcohol drinking in moderation and provide potential targets for future therapeutic interventions for AUD treatment.

项目概要 大多数美国成年人至少饮酒过一次。然而，在该人群中， 只有 10-15% 的人会患上酒精使用障碍 (AUD)，这表明大多数人可能在本质上受到保护 酒精成瘾。通过酪氨酸受体激酶 B (TrkB) 的脑源性神经营养因子 (BDNF) 信号传导 受体在防止酒精摄入过量方面发挥作用。本研究的目标 目的是建立 BDNF 控制饮酒的机制和神经回路。脑源性神经营养因子- 表达从眶额皮质（OFC）到背侧纹状体（DS）的神经元投射 罗恩实验室此前已证明可以控制小鼠的饮酒量。 OFC 参与更新 对奖励值和 DS 进行排名对于习惯性或目标导向的行动的发展是必要的- 选择策略。我最近发现全身施用 TrkB 激动剂可以恢复习惯性饮酒 寻求小鼠更具目标导向的行为。因此我推测 BDNF 信号传导的作用 在 DS 中，特别是在 OFC-DS 电路中，是使行为偏离习惯性的饮酒行为 以及更有针对性的酒精寻求和替代奖励。 我将利用创新的分子、药理学和行为方法来测试以下目标： 目标 1 将研究 OFC 中表达 BDNF 的神经元在促进目标导向方面的作用 寻求酒精。我将训练在表达 BDNF 的神经元中表达 Cre 重组酶的转基因小鼠 习惯性自行饮酒。然后我将使用化学遗传学策略来特异性激活 BDNF- 在 OFC 中表达神经元以确定 BDNF 阳性 OFC 神经元活动是否足以发生转变 小鼠从习惯性饮酒转向有目标的饮酒。 目标 2 将检查习惯性饮酒中 BDNF 信号在 DS 和 OFC-DS 回路中的作用 寻求。我将利用药理学工具和特定回路的基因干预来激活或抑制 BDNF DS 和 OFC-DS 电路中的信号传导，并确定这些操作对习惯性的影响 与小鼠中目标导向的酒精寻求行动选择策略相比。 目标 3 将确定 OFC-DS 投影中 BDNF 信号传导对“偏好转换”的影响 酒精摄入量和社交互动之间的关系。为了检验这个假设，我将使用新颖的行为分析来 评估酒精和社交互动寻求行为的差异以及药理学和 电路特异性基因操作改变内源性皮质纹状体 BDNF 信号传导。 如果成功，这项工作将深入了解 BDNF 信号传导保持酒精的机制 适度饮酒并为 AUD 治疗的未来治疗干预提供潜在目标。