Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons
Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons
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DOI：
10.1523/jneurosci.1720-20.2020
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发表时间：
2020-10-21
影响因子：
5.3
通讯作者：
Kobayashi, Kazuto
中科院分区：
文献类型：
--
作者：
Fukabori, Ryoji;Iguchi, Yoshio;Kobayashi, Kazuto
动物恢复记忆的能力是对环境的反应，这对行为适应至关重要。脑中含有去甲肾上腺素（NE）的神经元在调节突触可塑性中起关键作用，这些突触可塑性是记忆形成的各种过程的基础。然而，中枢NE系统在记忆提取中的作用仍不清楚。在这里，我们开发了一种新的化学发生激活策略，利用昆虫嗅觉离子型受体（IR），被称为“IR介导的神经元激活”，并使用它选择性刺激NE神经元的蓝斑（LC）。果蝇IR 84 a和IR 8a亚基在转基因小鼠的LC NE神经元中表达。应用苯乙酸（IR 84 a/IR 8a复合物的特异性配体）以适当的剂量诱导表达受体的NE神经元在切片制备和体内电生理条件下的兴奋性反应，导致LC神经末梢区域（雄性和雌性）的NE释放显著增加。配体诱导的LC NE神经元激活增强了条件性味觉厌恶的提取过程，而不影响味觉敏感性、一般觉醒状态和运动活动。这种对味觉记忆提取的增强作用部分是通过杏仁核基底外侧核（BLA;雄性）中的α（1）-和β-肾上腺素能受体介导的。LC NE神经元的药理学抑制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。我们的研究结果表明，LC NE系统，通过投射到BLA，控制味觉联想记忆的提取过程。
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 alpha(1)- and beta-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.