BACKGROUND Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated. Here, we therefore examined the role of Syt1 in alcohol-associated behaviors in rats. METHODS We evaluated the effect of Syt1 downregulation using an adeno-associated virus (AAV) containing a short hairpin RNA against Syt1. Cre-dependent Syt1 was also used in combination with an rAAV2 retro-Cre virus to assess circuit-specific effects of Syt1 knockdown (KD). RESULTS Alcohol-induced downregulation of Syt1 is specific to the prelimbic cortex (PL), and KD of Syt1 in the PL resulted in escalated alcohol consumption, increased motivation to consume alcohol, and increased alcohol drinking despite negative consequences ("compulsivity"). Syt1 KD in the PL altered the excitation/inhibition balance in the basolateral amygdala, while the nucleus accumbens core was unaffected. Accordingly, a projection-specific Syt1 KD in the PL-basolateral amygdala projection was sufficient to increase compulsive alcohol drinking, while a KD of Syt1 restricted to PL-nucleus accumbens core projecting neurons had no effect on tested alcohol-related behaviors. CONCLUSIONS Together, these data suggest that dysregulation of Syt1 is an important mechanism in long-term neuroadaptations observed after a history of alcohol dependence, and that Syt1 regulates alcohol-related behaviors in part by affecting a PL-basolateral amygdala brain circuit.

中文翻译：

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前肢皮层突触结合蛋白 1 的下调驱动大鼠的酒精相关行为。

背景技术酒精成瘾的特征在于涉及动机、情感和决策制定的大脑结构中的持续神经适应，包括内侧前额叶皮层、伏隔核和杏仁核。我们之前报道过，酒精依赖的诱导与神经递质释放相关基因表达的长期变化有关。具体来说，在神经递质释放和神经元功能中起关键作用的 Syt1 被下调。因此，我们在这里检查了 Syt1 在大鼠酒精相关行为中的作用。方法 我们使用含有针对 Syt1 的短发夹 RNA 的腺相关病毒 (AAV) 评估 Syt1 下调的影响。Cre 依赖性 Syt1 还与 rAAV2 逆转录病毒结合使用，以评估 Syt1 敲低 (KD) 的电路特异性效应。结果 酒精诱导的 Syt1 下调是特定于前肢皮层 (PL) 的，并且 PL 中 Syt1 的 KD 导致饮酒量增加，饮酒动机增加，尽管有负面后果，但饮酒量增加（“强迫性”）。PL 中的 Syt1 KD 改变了基底外侧杏仁核的兴奋/抑制平衡，而伏隔核核心不受影响。因此，PL-基底外侧杏仁核投射中的投射特异性 Syt1 KD 足以增加强迫性饮酒，而 Syt1 的 KD 仅限于 PL-伏隔核核心投射神经元对测试的酒精相关行为没有影响。结论 一起，