Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence
Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence
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DOI：
10.1038/s41386-018-0257-8
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发表时间：
2019-02-01
影响因子：
7.6
通讯作者：
Winder, Danny G.
中科院分区：
文献类型：
--
作者：
Centanni, Samuel W.;Morris, Bridget D.;Winder, Danny G.
负面情绪是与一系列神经和精神疾病相关的核心症状领域，目前的治疗方法只能部分针对它，这凸显了对更好、更具针对性的治疗方案的需求。本研究关注与长期戒酒相关的负面情感症状，戒酒是复发的主要原因之一。利用一种慢性饮酒后强制戒酒（CDFA）的小鼠模型，长期戒酒会增加终纹床核背侧部（dBNST）的c - fos表达和自发性谷氨酸能神经传递，该区域在人类和啮齿动物的负面情绪中都有重要作用。此外，用JZL184药物增强内源性大麻素（eCB）可防止戒酒引起的dBNST神经元活动增加，这凸显了针对大脑eCB系统的药物的治疗潜力。接下来，我们使用了一种视紫红质通道辅助的定位策略，以确定可能导致CDFA诱导的负面情绪的dBNST兴奋性输入。我们确定岛叶皮质（insula），一个参与调节内感受的区域，是对dBNST密集、功能性、对eCB敏感的输入。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，我们使用一种顺行策略对Cre表达进行跨突触靶向，并结合Gq - DREADD选择性地募集接受岛叶投射的dBNST神经元。对这些神经元进行化学遗传学募集模拟了在CDFA中观察到的行为和c - fos反应。总体而言，这项研究支持岛叶 - BNST神经回路在负面情感障碍中的作用，并凸显了eCB系统在治疗负面情感障碍方面的治疗潜力。
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.