Silent information regulator sirtuin 1-mediated neuronal excitation-inhibition imbalance in the central amygdala is involved in peripheral nerve injury-induced depression-related behavior in mice.

IF 5.5 1区医学 Q1 ANESTHESIOLOGY

PAIN® Pub Date : 2025-07-23 DOI:10.1097/j.pain.0000000000003744

Jia-Tao Lin,Xiao-Bao Ding,Wei Dong,Wei-Feng Wu,Yu-Wen Lin,Chen-Rui Zhou,Chu-Di Zhang,Chen Chen,Yi-Man Sun,Qiang Liu,Yan-Ping Liu,Cheng-Hua Zhou,Yu-Qing Wu

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Abstract

Chronic pain often coexists with depression. We have found that histone deacetylase Silent information regulator sirtuin 1 (SIRT1) is involved in peripheral nerve injury-induced depression-related behavior in mice. However, the underlying mechanism is still unclear. In this study, using a mouse spared nerve injury (SNI) model, we found that SIRT1 was downregulated in both glutamatergic and GABAergic neurons in the central amygdala (CeA) of mice with peripheral nerve injury-induced depression-related behavior. SIRT1 overexpression in CeA glutamatergic or GABAergic neurons effectively alleviated peripheral nerve injury-induced depression-related behavior in mice. Moreover, peripheral nerve injury induced significant neuronal excitation-inhibition (E-I) imbalance in CeA, manifested by the increased glutamatergic neuronal excitability and decreased GABAergic neuronal excitability in SNI mice. SIRT1 overexpression in CeA glutamatergic neurons decreased glutamatergic neuronal activity without influence on GABAergic neuronal activity, while SIRT1 overexpression in CeA GABAergic neurons increased GABAergic neuronal activity and reduced glutamatergic neuronal activity in SNI mice. Moreover, optogenetic induction of neuronal E-I imbalance in CeA by activating glutamatergic neurons or inhibiting GABAergic neurons reversed the improvement of peripheral nerve injury-induced depression-related behavior by SIRT1 overexpression. These findings suggest that the dysfunction of SIRT1 is related to the development of peripheral nerve injury-induced depression-related behavior by decreasing GABAergic neuronal excitability and enhancing glutamatergic neuronal excitability, leading to the neuronal E-I imbalance in CeA. These results demonstrate that SIRT1 is a key regulator in peripheral nerve injury-induced depression-related behavior.

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沉默信息调节器sirtuin 1介导的中央杏仁核神经元兴奋抑制失衡参与小鼠周围神经损伤诱导的抑郁相关行为。

慢性疼痛常常与抑郁症共存。我们发现组蛋白去乙酰化酶沉默信息调节因子SIRT1 （SIRT1）参与小鼠周围神经损伤诱导的抑郁相关行为。然而，其潜在机制尚不清楚。在本研究中，我们使用小鼠免除神经损伤（SNI）模型，发现周围神经损伤诱导的抑郁相关行为小鼠中央杏仁核（CeA）谷氨酸能和gaba能神经元中SIRT1均下调。SIRT1在CeA谷氨酸能或gaba能神经元中的过表达可有效减轻小鼠周围神经损伤诱导的抑郁相关行为。此外，周围神经损伤引起了明显的CeA神经元兴奋抑制（E-I）失衡，表现为SNI小鼠谷氨酸能神经元兴奋性升高，gaba能神经元兴奋性降低。SIRT1在CeA谷氨酸能神经元中的过表达降低了谷氨酸能神经元的活性，但不影响gaba能神经元的活性，而SIRT1在CeA gaba能神经元中的过表达增加了gaba能神经元的活性，降低了SNI小鼠的谷氨酸能神经元的活性。此外，通过激活谷氨酸能神经元或抑制gaba能神经元，光遗传诱导CeA神经元E-I失衡逆转了SIRT1过表达对周围神经损伤诱导的抑郁相关行为的改善。这些发现提示SIRT1功能障碍与周围神经损伤诱导的抑郁相关行为的发生有关，其机制是通过降低gaba能神经元兴奋性和增强谷氨酸能神经元兴奋性，导致CeA神经元E-I失衡。这些结果表明SIRT1是周围神经损伤诱导的抑郁相关行为的关键调节因子。

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来源期刊

PAIN® 医学-临床神经学

CiteScore

12.50

自引率

8.10%

发文量

242

审稿时长

9 months

期刊介绍： PAIN® is the official publication of the International Association for the Study of Pain and publishes original research on the nature,mechanisms and treatment of pain.PAIN® provides a forum for the dissemination of research in the basic and clinical sciences of multidisciplinary interest.