Glutamatergic basal forebrain neurons in aversion-resistant drinking

项目摘要 酒精使用障碍的一个特征是尽管消极的情况下仍继续寻找和消费酒精 后果。皮质纹状体向伏隔核投射的神经适应对 强迫性饮酒行为的发展，包括抗厌恶饮酒模式。然而，它 目前尚不清楚伏隔核神经元的增强活动如何改变对厌恶结果的敏感性 在饮酒和寻找酒精的过程中。厌恶相关回路中预先存在的个体差异 已被证明可以预测未来的强迫症，如饮酒。然而，我们还不知道有任何 酒精诱导的神经适应在跟踪发展的厌恶相关回路中的演示 抗厌恶饮酒，这就解释了在饮酒之后出现这种强迫表型的原因 曝光。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 这推动了强迫性饮酒的出现。在这里，我们将检查谷氨酸能基底前脑 投射到外侧缰核的神经元。这些神经元位于前-后连续体中，从 腹侧苍白球至下丘脑外侧，是伏隔核抑制性投射的靶点 神经元。我们假设，抗厌恶饮酒的出现需要选择性地抑制 这些神经元在饮酒期间。 在我们对这个回路的研究中，关键的第一步是确定厌恶情绪的出现是否- 抵抗饮酒与饮酒相关神经活动的细胞类型特异性改变相关 谷氨酸能基底前脑。我们将评估这个问题，以及这些神经关联是否 目标1中伏核下游的机制。我们的第二个目标是检查外侧缰核 抗厌恶饮酒中谷氨酸活性的动态变化。因此，我们的目标2实验将利用 荧光谷氨酸传感器与纤维光度法相结合识别时间特异性神经相关 抗厌恶的饮酒。最后，在目标3中，我们将使用化学发生学方法来评估功能 抗厌恶饮酒中基底前脑投射对外侧缰核的作用 从谷氨酸能基底前脑区域到外侧缰核的哪一种输入最有效地调制 强迫性饮酒。总之，这些实验将对神经回路产生新的见解 调节强迫性酒精使用，以及更广泛的与厌恶相关的寻求奖励的限制。

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.