The pivotal role of PACAP/PAC1R signaling from the anterior insular cortex to the locus coeruleus on anxiety-related behaviors of mice

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-10-11 DOI:10.1016/j.neuint.2024.105879
Thi Thu Nguyen , Kohei Hashiguchi , James A. Waschek , Atsuro Miyata , Yuki Kambe
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Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific receptor (PAC1R) are widely present in the central nervous system (CNS), and PACAP/PAC1R signaling has been implicated in anxiety-related behaviors. The locus coeruleus (LC), with its extensive noradrenergic (NA) projections throughout the CNS, is also implicated in anxiety. Although the LC exhibits a high expression of PAC1R, the precise role of PACAP/PAC1R signaling in the LC's involvement in anxiety remains unclear. Histochemical analysis confirmed high levels of PAC1R mRNA in the LC and showed that PAC1R gene transcripts were highly localized to NA neurons. Targeted deletion of PAC1R from these cells led to a hyperactive/low anxiety phenotype in the open field and elevated-plus maze tests. Retrograde neurocircuit tracing indicated PACAP neurons from the anterior insular cortex (aIC) and a few other regions projected axons to the LC. The selective activation of PACAP neurons in the aIC led to significantly increased anxiety behavior without a change in overall locomotor activity. Moreover, shRNA PACAP knockdown in the aIC in wild-type mice led to a selective decrease in anxiety. The present results identify an aIC to LC neurocircuit controlling anxiety that critically requires PACAP/PAC1R signaling.
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PACAP/PAC1R信号从前部岛叶皮层传导至小鼠神经节对小鼠焦虑相关行为的关键作用
神经肽垂体腺苷酸环化酶激活多肽(PACAP)及其特异性受体(PAC1R)广泛存在于中枢神经系统(CNS)中,PACAP/PAC1R 信号传导与焦虑相关行为有关。在整个中枢神经系统中具有广泛去甲肾上腺素能(NA)投射的小脑位置(LC)也与焦虑有关。虽然 LC 中 PAC1R 的表达量很高,但 PACAP/PAC1R 信号在 LC 参与焦虑中的确切作用仍不清楚。组织化学分析证实了 LC 中高水平的 PAC1R mRNA,并显示 PAC1R 基因转录物高度定位在 NA 神经元中。从这些细胞中靶向缺失 PAC1R 会导致在开阔地和高架迷宫测试中出现多动/低焦虑表型。逆行神经回路追踪表明,来自前岛皮质(aIC)和其他一些区域的PACAP神经元将轴突投射到LC。选择性激活 aIC 中的 PACAP 神经元会导致焦虑行为显著增加,而整体运动活动并无变化。此外,在野生型小鼠的 aIC 中敲除 shRNA PACAP 可选择性地减少焦虑。本研究结果确定了控制焦虑的 aIC 至 LC 神经环路,该神经环路关键需要 PACAP/PAC1R 信号。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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