Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing endogenous cannabinoids (eCB) with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain's eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, eCB-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences the CDFA behavioral phenotype and dBNST neuronal activity. Lastly, we used an anterograde strategy for transynaptic targeting of Cre expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the eCB system for treating negative affective disorders.

中文翻译：

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内源性大麻素对终纹回路岛床核的控制调节与戒酒相关的负面情感行为。


负面情绪是与一系列神经和精神疾病相关的核心症状，目前的治疗只能部分针对负面情绪，这凸显了对更好、更有针对性的治疗方案的需求。这项研究的重点是与长期戒酒相关的负面情感症状，这是复发的主要原因之一。使用慢性饮酒后强制戒酒 (CDFA) 的小鼠模型，长期戒酒会增加终纹背床核 (dBNST) 中的 c-fos 表达和自发性谷氨酸能神经传递，该区域与两种疾病的负面影响密切相关人类和啮齿动物。此外，JZL184 在药理上增强内源性大麻素 (eCB) 可以防止戒断引起的 dBNST 神经元活性增加，强调了针对大脑 eCB 系统的药物的治疗潜力。接下来，我们使用视紫红质通道辅助绘图策略来识别可能导致 CDFA 诱导的负面影响的 dBNST 兴奋性输入。我们确定岛叶皮层（岛叶）是一个参与调节内感受的区域，是 dBNST 的密集、功能性、eCB 敏感输入。使用化学遗传学策略局部模拟 eCB 信号传导，我们证明岛叶强烈影响 CDFA 行为表型和 dBNST 神经元活动。最后，我们使用顺行策略来跨突触靶向 Cre 表达，并结合 Gq-DREADD 来选择性招募接受岛叶投射的 dBNST 神经元。这些神经元的化学遗传学募集模仿了 CDFA 中观察到的行为和 c-fos 反应。 总的来说，这项研究支持岛-BNST 神经回路在负性情感障碍中的作用，并强调了 eCB 系统治疗负性情感障碍的治疗潜力。