Early-life sevoflurane exposure impairs fear memory by suppressing extracellular signal-regulated kinase signaling in the bed nucleus of stria terminalis GABAergic neurons.
Early-life sevoflurane exposure impairs fear memory by suppressing extracellular signal-regulated kinase signaling in the bed nucleus of stria terminalis GABAergic neurons.
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生命早期接触七氟醚会抑制终纹 GABA 能神经元床核中细胞外信号调节激酶信号传导，从而损害恐惧记忆。
DOI：
10.1016/j.neuropharm.2021.108584
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发表时间：
2021
影响因子：
4.7
通讯作者：
Dai Ru-Ping
中科院分区：
文献类型：
--
作者：
Zhao Xiao-Pei;Zhong Feng;Luo Ru-Yi;Zhang Yan-Ling;Luo Cong;Li Hui;Dai Ru-Ping
新生儿七氟烷暴露可诱导学习和记忆的长期损害;然而，其对发育后期认知的影响及其潜在机制仍不清楚。在本研究中，我们发现，多次七氟烷暴露会损害新生小鼠（出生后第7天）和青春期前小鼠（出生后第22天）长时间滞留延迟的恐惧记忆，但不会损害年龄较大的小鼠。在恐惧记忆测试后，磷酸化细胞外信号调节激酶（p-ERK）和c-fos的表达在终纹床核（BNST）和中央杏仁核中升高，但在海马和前额皮质中没有。p-ERK的上调仅限于γ-氨基丁酸（GABA能）神经元群，并受到多次七氟烷暴露的抑制。BNST内注射ERK抑制剂也损害了长时间保留延迟的恐惧记忆。相反，BNST内注射ERK激动剂可减轻重复七氟烷暴露引起的恐惧记忆受损。在BNST而不是尾壳核中注射七氟烷会损害青春期前小鼠长时间保留延迟的恐惧记忆。最后，由设计药物（DREADD）专门激活的设计受体对BNST GABA能神经元的化学发生激活逆转了多次七氟烷暴露导致的长时间保留延迟时受损的恐惧记忆。这些研究结果表明，多次七氟烷暴露通过抑制BNST中GABA能神经元的ERK信号传导来损害青春期前小鼠长时间保留延迟的恐惧记忆。
Sevoflurane exposure in neonates induces long-term impairment of learning and memory; however, its effect on cognition in the later developmental period and the underlying mechanisms remain unclear. In the present study, we showed that multiple sevoflurane exposures impaired fear memory at long retention delays in neonatal (postnatal day 7) and preadolescent mice (postnatal day 22), but not in mice at older ages. After the fear memory test, expression of phosphorylated extracellular signaling-regulated kinase (p-ERK) and c-fos were elevated in the bed nucleus of the stria terminalis (BNST) and central amygdala, but not in the hippocampus or prefrontal cortex. The upregulation of p-ERK was restricted to populations of γ-aminobutyric acid (GABAergic) neurons and was inhibited by multiple sevoflurane exposures. Intra-BNST injection of ERK inhibitor also impaired fear memory at long retention delays. In contrast, intra-BNST injection of ERK agonist attenuated impaired fear memory caused by repeated sevoflurane exposures. Injection of sevoflurane in the BNST but not the caudate putamen impaired the fear memory at long retention delays in preadolescent mice. Finally, chemogenetic activation of BNST GABAergic neurons by designer receptors exclusively activated by designer drug (DREADD) reversed the impaired fear memory at long retention delays by multiple sevoflurane exposures. These findings suggest that multiple sevoflurane exposures impaired fear memory at long retention delays in preadolescent mice by suppressing the ERK signaling in GABAergic neurons in the BNST.