Department of Pharmacology, Northwestern University, Chicago, IL, USA.
Department of Pharmacology, Northwestern University, Chicago, IL, USA; Department of Neuroscience and Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA.
Neurobiol Learn Mem. 2021 Sep;183:107459. doi: 10.1016/j.nlm.2021.107459. Epub 2021 May 18.
Alcohol use disorder (AUD) frequently co-occurs with dissociative disorders and disorders with dissociative symptoms, suggesting a common neurobiological basis. It has been proposed that facilitated information processing under the influence of alcohol, resulting in the formation of dissociated memories, might be an important factor controlling alcohol use. Access to such memories is facilitated under the effect of alcohol, thus further reinforcing alcohol use. To interrogate possible mechanisms associated with these phenotypes, we used a mouse model of dissociative amnesia, combined with a high-alcohol preferring (HAP) model of AUD. Dissociated memory was induced by activation of hippocampal extrasynaptic GABA type A receptor delta subunits (GABAR-δ), which control tonic inhibition and to which ethanol binds with high affinity. Increased ethanol preference was associated with increased propensity to form dissociated memories dependent on GABAR-δ in the dorsal hippocampus (DH). Furthermore, the DH level of GABAR-δ protein, but not mRNA, was increased in HAP mice, and was inversely correlated to the level of miR-365-3p, suggesting an miRNA-mediated post-transcriptional mechanism contributing to elevated GABAR-δ. The observed changes of DH GABAR-δ were associated with a severe reduction of excitatory projections stemming from GABAR-δ-containing pyramidal neurons in the subiculum and terminating in the mammillary body. These results suggest that both molecular and circuit dysfunction involving hippocampal GABAR-δ receptors might contribute to the co-occurrence of ethanol preference and dissociated information processing.
酒精使用障碍（AUD）常与分离性障碍和具有分离症状的障碍共病，提示其具有共同的神经生物学基础。有人提出，酒精影响下促进信息处理，导致分离记忆的形成，可能是控制饮酒的一个重要因素。在酒精的作用下，这些记忆更容易被获取，从而进一步强化了饮酒行为。为了探究与这些表型相关的可能机制，我们使用了分离性遗忘症的小鼠模型，结合了高酒精偏好（HAP）的 AUD 模型。通过激活海马 extrasynaptic GABA 型 A 受体 δ 亚基（GABAR-δ）诱导分离记忆，GABAR-δ 控制着紧张性抑制，而乙醇与它具有高亲和力。增加的乙醇偏好与依赖于背侧海马（DH）中的 GABAR-δ 形成分离记忆的倾向增加有关。此外，HAP 小鼠的 DH 中 GABAR-δ 蛋白水平增加，但 mRNA 水平没有增加，并且与 miR-365-3p 水平呈负相关，提示 miRNA 介导的转录后机制可能导致 GABAR-δ 升高。DH GABAR-δ 的观察到的变化与来自含有 GABAR-δ 的海马锥体细胞的兴奋性投射严重减少有关，这些投射终止于乳头体。这些结果表明，涉及海马 GABAR-δ 受体的分子和回路功能障碍可能共同导致乙醇偏好和分离信息处理的共病。
