Activation of the parasubthalamic nucleus in alcohol dependence

酒精依赖中副丘脑核的激活

• 批准号: 9899906
• 负责人: Candice Contet
• 金额: $ 43.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-10 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899906
• 关键词: Affect; Affective; Affective Symptoms; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Amygdaloid structure; Animals; Area; Automobile Driving; Behavioral; Behavioral Symptoms; Brain imaging; Brain region; Cell Nucleus; Cells; Central Medial Thalamic Nucleus; Chemicals; Chronic; Corticotropin-Releasing Hormone; Data; Development; Electrophysiology (science); Emotional; Enkephalins; Ethanol; Ethanol dependence; Event; Exhibits; FOS gene; Female; Fibrinogen; Functional disorder; Gene Expression; Gene Silencing; Genetic; Genetic Engineering; Glutamates; Goals; Heavy Drinking; Hypothalamic structure; In Situ Hybridization; Insula of Reil; Lateral; Location; Maps; Measures; Mediating; Mediator of activation protein; Molecular; Motivation; Mus; Nature; Neural Pathways; Neurons; Neuropeptides; Neurotensin; Neurotransmitters; Pathway interactions; Phenotype; Posterior Hypothalamus; Pre-Clinical Model; Relapse; Research Personnel; Research Project Grants; Role; Self Administration; Signal Transduction; Source; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Tachykinin; Testing; Time; Viral Vector; Withdrawal; Withdrawal Symptom; Work; addiction; alcohol abstinence; alcohol exposure; alcohol use disorder; behavior test; behavioral phenotyping; design; dorsal raphe nucleus; drinking; excitatory neuron; experience; experimental study; follow-up; male; mouse model; multidisciplinary; negative affect; neural circuit; neurochemistry; neuronal excitability; neurotransmitter release; novel; postsynaptic; recruit; sex; symptomatology; tool; transmission process

SUMMARY Alcohol use disorders are in part characterized by the loss of control over alcohol drinking and the emergence of negative emotionality during abstinence from alcohol. While the brain regions and neurotransmitter systems affected by chronic alcohol exposure are well characterized, our understanding of the specific neural circuits driving drinking escalation and negative affect during withdrawal remains limited. We have generated data indicating that neurons located in the parasubthalamic nucleus (PSTN), a small region of the posterior lateral hypothalamus whose function in addiction is currently unknown, may be a critical component of this circuitry. Specifically, we show that chemogenetic stimulation of PSTN neurons expressing the neuropeptide corticotropin- releasing factor (CRF) replicates the behavioral symptomatology of withdrawal and that PSTN neurons become activated in ethanol-dependent mice experiencing withdrawal. A first aim of this proposal is to explore the mechanisms underlying the phenotypes resulting from the chemogenetic activation of PSTN CRF neurons. We will evaluate the contribution of PSTN neurons projecting to the central nucleus of the amygdala (as opposed to other targets of the PSTN) and the role of CRF signaling (as opposed to other neurotransmitters co-released by PSTN CRF neurons). Another goal is to test the hypothesis that the PSTN is a critical node of the neuronal network driving the behavioral symptomatology of ethanol withdrawal. We will determine whether the activation of PSTN neurons is necessary to the expression of withdrawal symptoms in dependent mice, whether it drives the activation of downstream central amygdala neurons, and which neurotransmitter is implicated. Finally, we aim to understand how PSTN neurons become activated during ethanol withdrawal. We will use retrograde tracing combined with c-Fos mapping as well as electrophysiological recordings to investigate the mechanisms controlling the activity of PSTN neurons in the context of ethanol withdrawal. Throughout the project, we will leverage state-of-the-art genetic tools for the functional manipulation of specific neural pathways, local silencing of gene expression and neuronal mapping, along with whole-brain imaging. In addition, we will use a well- validated mouse model of ethanol dependence that we have refined with novel measures of affective perturbation. Altogether, the proposed experiments are designed to enhance our understanding of the neural circuitry that contributes to motivational and emotional dysfunction in alcohol use disorders and may provide novel avenues for the development of more efficacious treatments.

概括 酒精使用障碍的部分原因是失去对酒精饮酒的控制和出现 戒酒期间的负面情绪。而大脑区域和神经递质系统 受到慢性酒精暴露影响的特征是我们对特定神经回路的理解 撤离期间驾驶饮酒升级和负面影响仍然有限。我们已经生成了数据 表明位于副丘脑核（PSTN）中的神经元，后侧的一个小区域 下丘脑的成瘾功能目前未知，可能是该电路的关键组成部分。 具体而言，我们表明，表达神经肽皮质激素的PSTN神经元的化学发生刺激 - 释放因子（CRF）复制了戒断的行为症状，并且PSTN神经元成为 在乙醇依赖性小鼠中被激活。该提议的第一个目的是探索 由PSTN CRF神经元的化学发生激活产生的表型的机制。我们 将评估投射到杏仁核中央核的PSTN神经元的贡献（相反 PSTN的其他靶标）和CRF信号的作用（与其他神经递质相反， PSTN CRF神经元）。另一个目标是检验pstn是神经元的关键节点的假设 驱动乙醇提取行为症状的网络。我们将确定是否激活 PSTN神经元的表达在依赖小鼠中的表达是必要的，它是否驱动 下游中央杏仁核神经元的激活与神经递质的激活有关。最后，我们 旨在了解PSTN神经元如何在乙醇提取期间激活。我们将使用逆行 跟踪与C-FOS映射以及电生理记录一起研究机制 在乙醇提取的背景下控制PSTN神经元的活性。在整个项目中，我们将 利用最先进的遗传工具来操纵特定神经途径，局部沉默 基因表达和神经元映射，以及全脑成像。此外，我们将使用一个很好的 经过验证的乙醇依赖的小鼠模型，我们已经通过新颖的情感度量进行了改进 扰动。总共拟议的实验旨在增强我们对神经的理解 导致酒精使用障碍中动机和情感功能障碍的电路，可能会提供 开发更有效治疗的新途径。