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.

总结 酒精使用障碍的部分特征是对饮酒失去控制， 在戒酒过程中的负面情绪大脑区域和神经递质系统 受慢性酒精暴露的影响是很好的特点，我们对特定神经回路的理解， 戒断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 表明位于丘脑旁核（PSTN）的神经元，后外侧核的一个小区域， 下丘脑在成瘾中的功能目前尚不清楚，它可能是这一回路的关键组成部分。 具体来说，我们表明，化学刺激的PSTN神经元表达的神经肽促肾上腺皮质激素- 释放因子（CRF）复制了戒断的行为学，PSTN神经元成为 在酒精依赖的小鼠经历戒断激活。本提案的第一个目的是探讨 PSTNCRF神经元的化学发生激活导致的表型的潜在机制。我们 将评估投射到杏仁核中央核的PSTN神经元的贡献（相对于 PSTN的其他靶点）和CRF信号传导的作用（与PSTN共同释放的其他神经递质相反）。 PSTN CRF神经元）。另一个目标是测试PSTN是神经元的关键节点的假设。 网络驱动乙醇戒断的行为学。我们将决定是否激活 在依赖性小鼠中，PSTN神经元的数量对于戒断症状的表达是必要的， 下游中央杏仁核神经元的激活，以及涉及哪种神经递质。最后我们 目的是了解PSTN神经元如何在乙醇戒断过程中被激活。我们将使用逆行 结合c-Fos定位和电生理记录来探讨其机制 在乙醇戒断的情况下控制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对特定的神经通路进行功能操纵，局部沉默， 基因表达和神经元定位，沿着全脑成像。此外，我们将使用一个良好的- 我们已经用新的情感测量方法改进了酒精依赖的有效小鼠模型， 扰动总之，所提出的实验旨在增强我们对神经系统的理解。 导致酒精使用障碍的动机和情绪功能障碍的回路， 开发更有效治疗的新途径。