The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α₁- and β-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.

SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC–amygdala pathway plays an important role in the recall of taste associative memory.

动物获取响应于环境而存储的记忆的能力对于行为适应至关重要。大脑中含有去甲肾上腺素（NE）的神经元在调节各种记忆形成过程的突触可塑性中起关键作用。然而，中央网元系统在存储器检索中的作用仍不清楚。在这里，我们开发了一种利用昆虫嗅觉离子受体（IR）的新型化学发生激活策略，称为“ IR介导的神经元激活”，并将其用于选择性刺激蓝斑（LC）中的NE神经元。果蝇IR84a和IR8a亚基在转基因小鼠的LC NE神经元中表达。在适当剂量下应用苯乙酸（IR84a / IR8a复合物的特异性配体）可诱导切片制剂和体内电生理条件下表达受体的NE神经元的兴奋性反应，导致LC神经末梢NE释放明显增加地区（男性和女性）。配体诱导的LC NE神经元的激活增强了条件性味觉厌恶的恢复过程，而不会影响味觉敏感性，一般唤醒状态和运动能力。对味觉存储器检索该促进效果介导的，部分地，通过α ₁和杏仁核基底外侧核中的β-肾上腺素受体（BLA；男性）。LC NE神经元的药理抑制作用证实了这些神经元通过BLA（雄性）中的肾上腺素能受体在记忆恢复中的促进作用。我们的发现表明，LC NE系统通过对BLA的投影来控制味觉联想记忆的检索过程。

重要性声明大脑中含有去甲肾上腺素（NE）的神经元在调节各种记忆形成过程中的突触可塑性中起关键作用，但在记忆恢复中NE系统的作用尚不清楚。我们开发了一种基于昆虫嗅觉离子受体的化学生成激活系统，并将其用于选择性刺激转基因小鼠蓝绿色（LC）中的NE神经元。配体诱导的LC NE神经元激活增强了条件性味觉厌恶的恢复，这部分地是通过基底外侧杏仁核中的肾上腺素受体介导的。LC活性的药理学阻断作用证实了这些神经元在记忆恢复中的促进作用。我们的发现表明，LC-杏仁核途径在味觉联想记忆的回忆中起着重要作用。