A model of ethanol self-administration in head-fixed mice

IF 2.7 Q2 SUBSTANCE ABUSE
Amy L. Ward, Kion T. Winston, Sophie Buchmaier, Cynara J. Cooper, Rachel E. Clarke, Michael R. Martino, Kelsey M. Vollmer, Jacqueline E. Paniccia, Marcus S. Bell, Elizabeth M. Doncheck, Roger I. Grant, Joshua Boquiren, Jade Baek, Logan M. Manusky, Annaka M. Westphal, Lisa M. Green, Bayleigh E. Pagoota, James M. Otis, Jennifer A. Rinker
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引用次数: 0

Abstract

Background

Significant advances in neurotechnology, such as the application of two-photon (2P) imaging of biosensors in vivo, have enabled unparalleled longitudinal and high-resolution access to neural circuits that coordinate behavior in rodents. Integration of these techniques would be groundbreaking for the study of alcohol use disorder (AUD). AUD is rooted in significant neural adaptations that could be functionally monitored and manipulated at the single-cell level across the development of dependence in rodents. However, 2P imaging and related methodologies often require or are facilitated by head fixation, and a lack of head-fixed models has hindered their integration for the study of alcohol dependence.

Methods

We developed a head-fixed model in which animals learned to self-administer ethanol across ~14 days. Active lever responding resulted in a tone cue and ethanol reward, whereas responding on the inactive lever resulted in neither cue nor ethanol reward. Following acquisition, animals extinguished lever pressing across a minimum of 10 days. Finally, animals were tested separately for both cue- and ethanol-induced reinstatement of lever pressing.

Results

Here we show, for the first time, that in our head-fixed ethanol self-administration model, male and female mice reliably pressed an active, but not inactive, lever for an oral ethanol reward. Ethanol rewards positively correlated with blood ethanol concentrations at pharmacologically relevant levels. Furthermore, mice extinguished ethanol self-administration when the ethanol reward and cue were omitted, suggesting active lever pressing was ethanol-directed. Following extinction, presentation of the ethanol-associated cue or priming with ethanol itself invigorated reinstatement of ethanol seeking, modeling relapse in a manner that replicates decades of work in freely moving rodent studies.

Conclusions

Overall, our head-fixed ethanol self-administration model will allow for incorporation of novel technologies that require or are greatly facilitated by head fixation, improving our ability to study and understand the neural adaptations and computations that underlie alcohol dependence.

Abstract Image

头颅固定小鼠乙醇自我给药模型。
背景:神经技术的重大进步,如生物传感器在体内双光子成像的应用,使得对协调啮齿动物行为的神经回路的纵向和高分辨率访问成为可能。这些技术的整合将对酒精使用障碍(AUD)的研究具有开创性意义。AUD根植于重要的神经适应,可以在啮齿动物依赖发展的单细胞水平上进行功能监测和操纵。然而,2P成像和相关方法通常需要头部固定或由头部固定促进,头部固定模型的缺乏阻碍了它们在酒精依赖研究中的整合。方法:我们建立了一个头部固定的模型,在这个模型中,动物学会了在14天内自我给药乙醇。积极杠杆反应产生音调提示和乙醇奖励,而不活跃杠杆反应既不产生提示也不产生乙醇奖励。在获得后,动物至少在10天内停止按压杠杆。最后,分别对动物进行线索和乙醇诱导的杠杆按压恢复实验。结果:我们首次发现,在我们的头部固定的乙醇自我给药模型中,雄性和雌性小鼠可靠地按下了一个活跃的杠杆,而不是不活跃的杠杆,以获得口服乙醇奖励。乙醇奖励与血乙醇浓度在药理学相关水平上正相关。此外,当乙醇奖励和提示被忽略时,小鼠熄灭了乙醇自我给药,这表明主动杠杆按压是由乙醇引导的。在灭绝之后,乙醇相关线索的呈现或乙醇本身的启动激活了乙醇寻找的恢复,以复制数十年来在自由移动的啮齿动物研究中工作的方式模拟复发。结论:总的来说,我们的头部固定乙醇自我给药模型将允许结合需要或通过头部固定大大促进的新技术,提高我们研究和理解酒精依赖背后的神经适应和计算的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.40
自引率
0.00%
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0
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