Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood.
Inhibition of norepinephrine signaling during a sensitive period disrupts locus coeruleus circuitry and emotional behaviors in adulthood.
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DOI：
10.1038/s41598-023-29175-x
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发表时间：
2023-02-22
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
觉醒和应激反应的缺陷是包括抑郁和焦虑在内的许多精神疾病的特征。从特定的脑干核，包括蓝斑（LC）神经元释放到皮质和边缘区域的去甲肾上腺素（NE）支持觉醒。在发展过程中，NE系统随着对动物环境的不断探索而成熟。虽然一些精神科药物针对NE系统，但其在谨慎发育时期的调节可能会产生长期后果的可能性尚未被探索。我们在小鼠身上使用了一种化学发生策略，在短暂的发育时期可逆地抑制NE信号传导，然后评估我们的干预对成年NE回路功能和情绪行为的任何长期影响。我们还测试了α2受体激动剂胍法辛的发育暴露是否概括了化学发生策略所看到的效果，胍法辛在儿科人群中常用，在妊娠和哺乳期间没有禁忌。我们的研究结果表明，出生后10-21天构成了一个敏感期，在此期间，NE信号的改变会导致成年期基线焦虑、快感缺乏增加和被动应对行为的变化。在这个敏感时期，NE信号的中断也会导致LC自身受体功能的改变，以及LC-NE靶区在基线和应激反应下的电路特异性变化。我们的研究结果表明，NE在塑造支持成人情感功能的大脑回路中起着早期的关键作用。胍法辛和类似临床使用的药物干扰这种作用可能对精神健康产生持久的影响。
Deficits in arousal and stress responsiveness are a feature of numerous psychiatric disorders including depression and anxiety. Arousal is supported by norepinephrine (NE) released from specialized brainstem nuclei, including the locus coeruleus (LC) neurons into cortical and limbic areas. During development, the NE system matures in concert with increased exploration of the animal’s environment. While several psychiatric medications target the NE system, the possibility that its modulation during discreet developmental periods can have long-lasting consequences has not yet been explored. We used a chemogenetic strategy in mice to reversibly inhibit NE signaling during brief developmental periods and then evaluated any long-lasting impact of our intervention on adult NE circuit function and on emotional behavior. We also tested whether developmental exposure to the α2 receptor agonist guanfacine, which is commonly used in the pediatric population and is not contraindicated during pregnancy and nursing, recapitulates the effect seen with the chemogenetic strategy. Our results reveal that postnatal days 10–21 constitute a sensitive period during which alterations in NE signaling lead to changes in baseline anxiety, increased anhedonia, and passive coping behaviors in adulthood. Disruption of NE signaling during this sensitive period also caused altered LC autoreceptor function, along with circuit specific changes in LC-NE target regions at baseline, and in response to stress. Our findings indicate an early critical role for NE in sculpting brain circuits that support adult emotional function. Interfering with this role by guanfacine and similar clinically used drugs can have lasting implications for mental health.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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影响因子：
8.2
作者：
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影响因子：
1.9
作者：
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Leslie, Laurel K.
DOI：
10.1097/00004583-199609000-00022
发表时间：
1996-09-01
影响因子：
13.3
作者：
Harmon, RJ;Riggs, PD
通讯作者：
Riggs, PD