Glutamatergic basal forebrain neurons in aversion-resistant drinking

厌恶性饮酒中的谷氨酸能基底前脑神经元

基本信息

批准号：
10555313
负责人：
Jocelyn M Richard
金额：
$ 42.97万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555313
关键词：
Affect Alcohol consumption Alcohols Anterior Behavior Brain Cells Chemosensitization Chronic Consumption Corpus striatum structure Development Diagnostic Fiber Fluorescent in Situ Hybridization Future Globus Pallidus Glutamate Receptor Glutamates Goals Habenula Hypothalamic structure Individual Differences Investigation Lateral Learning Measures Mediating Messenger RNA Modeling Motivation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurons Nucleus Accumbens Outcome Phenotype Photometry Play Preoptic Areas Quinine Rattus Regulation Reporter Research Resistance Rewards Rodent Role Signal Transduction Testing activity marker alcohol availability alcohol exposure alcohol seeking behavior alcohol use disorder basal forebrain brain pathway cell type drinking experimental study genetic approach genetic manipulation glutamatergic signaling in vivo insight neural neural circuit neural correlate neuroadaptation neurochemistry neuromechanism neuroregulation novel recruit response sensor single molecule

项目摘要

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.

项目摘要尽管负面结果。对伏隔核的皮质纹状体投影中的神经适应至关重要强迫性饮酒行为的发展，包括在抗厌恶的饮酒模型中。但是尚不清楚伏隔神经元中的增强活性如何改变对厌恶结果的敏感性在消费和寻求酒精期间。与厌恶相关的电路中存在的个体差异具有被证明可以预测未来的强迫性饮酒。但是，我们不知道有什么在跟踪的厌恶相关电路中，酒精引起的神经适应的演示抗厌恶的饮酒，这解释了酒精后这种强迫表型的出现接触。我们的长期目标是确定与厌恶相关的神经回路活动的动态变化这推动了强迫饮酒的出现。在这里，我们将检查谷氨酸能的基础前脑将其投射到外侧Habenula的神经元。这些神经元是在前后连续性中发现的腹侧下丘脑的腹侧粒子，由伏隔核抑制投影靶向神经元。我们假设抗厌恶饮酒的出现需要选择性抑制这些神经元在饮酒期间。我们研究该电路的关键第一步是确定厌恶的出现 - 抗性饮酒与饮酒相关神经活动的细胞类型特异性变化有关谷氨酸能基础前脑。我们将评估这个问题，以及这些神经相关性是否是 AIM 1中伏隔核机制的下游。我们的第二个目标是检查横向habenula 抗厌恶性饮酒期间的谷氨酸活性动力学。因此，我们的目标2实验将使用荧光谷氨酸传感器与纤维光度法结合，以鉴定时间特异性的神经相关性抗厌恶的饮酒。最后，在AIM 3中，我们将使用化学发生方法评估功能基础前脑预测对抗厌恶性饮酒中侧向Habenula的贡献并确定最有效地调节了谷氨酸能基础前脑区域的外侧Habenula的输入强迫性饮酒。这些实验将共同对神经回路产生新的见解更广泛地介导强迫性饮酒，以及与厌恶相关的奖励。