Corticostriatal BDNF signaling in alcohol seeking and preference switching

项目摘要 美国大多数成年人至少喝过一次酒。然而，在这一人群中， 只有10-15%的人发展为酒精使用障碍（AUD），这表明大多数人可能在本质上受到保护， 酒精成瘾酪氨酸受体激酶B（Trk B）介导的脑源性神经营养因子（BDNF）信号转导 受体在防止酒精摄入量上升到过度水平方面发挥作用。本研究的目的 是建立脑源性神经营养因子控制饮酒的机制和神经回路。BDNF- 表达从眶额皮质（OFC）到背侧纹状体（DS）的神经元投射的研究已经被证实， 之前罗恩实验室已经证明了这一点。OFC参与更新 和排名奖励价值和DS是必要的发展习惯或目标导向的行动- 选择策略我最近发现，全身给予TrkB激动剂可以逆转习惯性饮酒， 寻求小鼠更具目标导向的行为。因此我推测BDNF信号的作用 在DS中，特别是在OFC-DS电路中，是使行为偏离习惯性酒精寻求 以及更多目标导向的酒精寻求和替代奖励。 使用创新的分子，药理学和行为学方法，我将测试以下目标： 目的1：研究眶额皮层中表达BDNF的神经元在促进目标导向性运动中的作用。 酒精寻求我将训练在表达BDNF的神经元中表达Cre重组酶的转基因小鼠， 习惯性地自我管理酒精。我会用化学遗传学方法来激活脑源性神经营养因子- 表达OFC中的神经元，以确定BDNF阳性的OFC神经元活性是否足以转移 从习惯性到目标导向的酒精寻求。 目的2将研究在习惯性酒精中，BDNF信号在DS和OFC-DS回路中的作用 寻找我将利用药理学工具和特定回路的遗传干预来激活或抑制BDNF 信号在DS和OFC-DS电路，并确定这些操作对习惯性的影响， 与目标导向的酒精寻求行动选择策略相比。 目的3将确定BDNF信号在OFC-DS投射中对“偏好转换”的影响。 酒精摄入和社会交往之间的关系为了验证这一假设，我将使用新的行为分析， 评估酒精和社会互动寻求行为的差异，伴随着药物和 回路特异性遗传操作来改变内源性皮质纹状体BDNF信号传导。 如果成功，这项工作将提供深入了解BDNF信号保持酒精的机制， 适度饮酒，并为AUD治疗的未来治疗干预提供潜在目标。

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.