Noradrenergic Locus Coeruleus-CA3 Activation Alleviates Neuropathic Pain and Anxiety- and Depression-Like Behaviors by Suppressing Microglial Neuroinflammation in SNI Mice

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-03-25 DOI:10.1111/cns.70360

Helin Zou, Weiyu Pu, Junli Zhou, Juan Li, Lulin Ma, Shuxian Wang, Chengxi Liu, Jing Mou, Xingfeng Liu, Tian Yu, Yiyong Wei, Haihui Xie, Song Cao

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Abstract

Objective

Neuropathic pain (NP) arises from neuroimmune interactions following nerve injury and is often accompanied by anxiety and depression. The aim of the study is to evaluate the effects of the noradrenergic locus coeruleus (LC), a key regulator of pain and emotional states, projects extensively to the hippocampus.

Method

We investigated the effects of chronic NP on LC integrity and its projections to the hippocampal CA3 region in spared nerve injury (SNI) mice with behavioral tests, immunohistochemistry, neurochemical analyses, and Gq-DREADD.

Results

Chronic NP induced LC neuronal loss, reduced hippocampal norepinephrine (NE) release, and triggered microglial activation and neuroinflammation in CA3. Selective activation of LC-CA3 noradrenergic neurons using Gq-DREADD chemogenetics alleviated NP and comorbid anxiety- and depression-like behaviors. This intervention suppressed microglial activation, decreased proinflammatory cytokines (TNF-α and IL-1β), and restored NE levels in CA3.

Conclusion

Our findings highlighted the therapeutic potential of targeting LC-CA3 projections to mitigate chronic NP and its neuropsychiatric comorbidities via modulation of hippocampal neuroinflammation.

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.