Glutamatergic basal forebrain neurons in aversion-resistant drinking

项目摘要 酒精使用障碍的一个标志是继续寻求和消费酒精，尽管负 后果皮质纹状体投射到中脑核的神经适应性对于神经元的发育是至关重要的。 强迫性饮酒行为的发展，包括在厌恶抵抗饮酒模型中。但它 目前尚不清楚丘脑核神经元的增强活动如何改变对厌恶结果的敏感性 在消费和寻求酒精。厌恶相关回路中预先存在的个体差异 被证明可以预测未来的强迫性饮酒。然而，我们不知道任何 酒精诱导的神经适应在厌恶相关回路中的演示， 厌恶抵抗饮酒，这解释了酒精后这种强迫性表型的出现 exposure.我们的长期目标是确定厌恶相关神经回路活动的动态变化 导致了强迫性饮酒的出现在这里，我们将检查基底前脑的多巴胺能神经元， 投射到外侧缰的神经元。这些神经元被发现在一个前后连续体， 腹侧苍白球到外侧下丘脑，并通过丘脑底核的抑制性投射靶向 神经元我们假设，厌恶抵抗性饮酒的出现需要选择性抑制 这些神经元在酒精消耗过程中。 我们研究这一回路的关键第一步是确定厌恶的出现是否- 抵抗性饮酒与大脑中饮酒相关神经活动的细胞类型特异性改变相关。 丘脑能基底前脑。我们将评估这个问题，以及这些神经相关因素是否 在Aim 1中，位于神经核的下游。我们的第二个目标是检查外侧缰 抗厌恶饮酒过程中的谷氨酸活性动态。因此，我们的目标2实验将利用 荧光谷氨酸传感器结合纤维光度测定法来识别 抗厌恶性饮酒最后，在目标3中，我们将使用化学遗传学方法来评估功能性 基底前脑投射到外侧缰核在抗厌恶性饮酒中的作用 从丘脑能基底前脑区域到外侧缰核的输入最有效地调节 强迫性饮酒总之，这些实验将产生对神经回路的新见解 调解强迫性酒精使用，以及更广泛的奖励寻求的厌恶相关的约束。

Project Summary A hallmark of alcohol use disorder is continued seeking and consumption of alcohol despite negative consequences. Neuroadaptations in corticostriatal projections to nucleus accumbens are critical for the development of compulsive-like alcohol use behaviors, including in an aversion-resistant drinking model. Yet it remains unclear how potentiated activity in nucleus accumbens neurons alters sensitivity to aversive outcomes during consumption and seeking of alcohol. Pre-existing individual differences in aversion-related circuits have been shown to predict future compulsive-like alcohol consumption. Yet, we are not aware of any demonstrations of alcohol-induced neuroadaptations in aversion-related circuits that track the development of aversion-resistant drinking, and that account for the emergence of this compulsive phenotype after alcohol exposure. Our long-term goal is to identify dynamics changes in the activity of aversion-related neural circuits that drive the emergence of compulsive alcohol use. Here, we will examine glutamatergic basal forebrain neurons that project to the lateral habenula. These neurons are found in an anterior-posterior continuum from the ventral pallidum to the lateral hypothalamus and are targeted by nucleus accumbens inhibitory projection neurons. We hypothesize that the emergence of aversion-resistant drinking requires selective inhibition of these neurons during alcohol consumption. A crucial first step in our investigation of this circuit is to determine whether the emergence of aversion- resistant drinking is correlated with cell-type specific alterations in drinking-related neural activity in the glutamatergic basal forebrain. We will assess this question, and whether these neural correlates are downstream of nucleus accumbens mechanisms in Aim 1. Our second goal is to examine lateral habenula glutamate activity dynamics during aversion-resistant drinking. Therefore, our Aim 2 experiments will utilize a fluorescent glutamate sensor combined with fiber photometry to identify temporally-specific neural correlates of aversion-resistant drinking. Finally, in Aim 3 we will use chemogenetic approaches to assess the functional contributions of basal forebrain projections to lateral habenula in aversion-resistant drinking and determine which inputs to lateral habenula from regions of the glutamatergic basal forebrain most effectively modulate compulsive alcohol consumption. Together, these experiments will yield novel insights into the neural circuits mediating compulsive alcohol use, as well as aversion-related constraint of reward-seeking more broadly.