BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice

IF 3 Q2 SUBSTANCE ABUSE
Marie A. Doyle, Gregory J. Salimando, Megan E. Altemus, Justin K. Badt, Michelle N. Bedenbaugh, Alexander S. Vardy, Danielle N. Adank, Anika S. Park, Danny G. Winder
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引用次数: 0

Abstract

Background

Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST) and Crh+ neurons in this region play a key role in chronic ethanol-induced increases in volitional intake, hypothesized to be driven by emergent negative affective behaviors. Excitatory N-methyl-d-aspartate receptors (NMDARs) are a major target of ethanol, and chronic ethanol exposure has been shown to regulate NMDAR function and expression. Specifically, GluN2D subunit-containing NMDARs have emerged as a target of interest due to their limited distribution and potential roles in affective behavior.

Methods

Male and female mice underwent a home cage chronic drinking forced abstinence model (CDFA) to assess the impact of 1 day or 2 weeks of ethanol abstinence on BNST synaptic transmission and BNST Grin gene expression. Constitutive and conditional BNST GluN2D knockout mice were used to assess the impact of GluN2D deletion on continuous access ethanol intake as well as negative affect behaviors, using the open field, elevated zero maze, and forced swim tasks.

Results

We report here that excitatory transmission undergoes time-dependent upregulation in BNST Crh+ cells. Further, knockdown of dorsal BNST (dBNST) GluN2D expression significantly decreases ethanol intake in female, but not male, mice. While BNST Grin2b expression was significantly increased in protracted abstinence following CDFA, no differences in Grin2d expression were observed in the dBNST or dBNST Crh+ neurons. Finally, we find that deletion of GluN2D fails to alter negative affect in ethanol-naïve female mice.

Conclusions

These data suggest a role for BNST GluN2D-containing NMDARs in ethanol drinking but not ethanol abstinence, highlighting sex differences and behavioral specificity. Overall, these data further suggest roles for BNST synaptic signaling in volitional ethanol intake that are partially independent of actions on affective behavior.

Abstract Image

Abstract Image

BNST 含 GluN2D 的 NMDARs 会导致雌性小鼠摄入乙醇,但不会导致其产生负面情绪行为。
背景:酒精使用障碍(AUD)是一种慢性、复发性疾病,与焦虑和抑郁高度共存。纹状体末端床核(BNST)和该区域的Crh+神经元在慢性乙醇诱导的意志摄入量增加中起着关键作用,据推测,乙醇诱导的意志摄入量增加是由新出现的负性情感行为驱动的。兴奋性 N-甲基-d-天冬氨酸受体(NMDARs)是乙醇的一个主要靶点,慢性乙醇暴露已被证明能调节 NMDAR 的功能和表达。特别是含 GluN2D 亚基的 NMDARs,由于其有限的分布和在情感行为中的潜在作用,已成为一个受关注的靶点:方法:对雌雄小鼠进行家笼慢性饮酒强迫戒断模型(CDFA),以评估1天或2周的乙醇戒断对BNST突触传递和BNST Grin基因表达的影响。我们利用连续性和条件性BNST GluN2D基因敲除小鼠来评估GluN2D基因缺失对连续摄入乙醇以及负性情绪行为的影响,包括开放场地、高架零迷宫和强迫游泳任务:结果:我们在此报告了兴奋性传递在 BNST Crh+ 细胞中发生的时间依赖性上调。此外,敲除背侧 BNST(dBNST)GluN2D 的表达会显著降低雌性小鼠的乙醇摄入量,而雄性小鼠则不会。虽然 BNST Grin2b 的表达在 CDFA 后的长期戒断中显著增加,但在 dBNST 或 dBNST Crh+ 神经元中并未观察到 Grin2d 表达的差异。最后,我们发现删除 GluN2D 无法改变乙醇成瘾雌性小鼠的负性情绪:这些数据表明,含 BNST GluN2D 的 NMDARs 在乙醇饮酒中发挥作用,但在乙醇戒断中不发挥作用,凸显了性别差异和行为特异性。总之,这些数据进一步表明,BNST 突触信号在乙醇自愿摄入中的作用部分独立于对情感行为的作用。
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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CiteScore
5.40
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