1. Academic Validation
  2. Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness

Protective role of aconitate decarboxylase 1 in neuroinflammation-induced dysfunctions of the paraventricular thalamus and sleepiness

  • Commun Biol. 2024 Nov 10;7(1):1484. doi: 10.1038/s42003-024-07215-0.
Jianjun Chang 1 Zijie Li 1 Hui Yuan 2 Xuejiao Wang 1 Jingyi Xu 3 Pingting Yang 4 Ling Qin 5
Affiliations

Affiliations

  • 1 Department of Physiology, School of Life Sciences, China Medical University, Shenyang, China.
  • 2 Laboratory of Hearing Research, School of Life Sciences, China Medical University, Shenyang, China.
  • 3 Department of Rheumatology and Immunology, The First Hospital of China Medical University, Shenyang, China.
  • 4 Department of Rheumatology and Immunology, The First Hospital of China Medical University, Shenyang, China. yangpingtingting@163.com.
  • 5 Laboratory of Hearing Research, School of Life Sciences, China Medical University, Shenyang, China. qinlingling@yahoo.com.
Abstract

Sleepiness is commonly associated with neuroinflammation; however, the underlying neuroregulatory mechanisms remain unclear. Previous research suggests that the paraventricular thalamus (PVT) plays a crucial role in regulating sleep-wake dynamics; thus, neurological abnormalities in the PVT may contribute to neuroinflammation-induced sleepiness. To test this hypothesis, we performed electroencephalography recordings in mice treated with lipopolysaccharide (LPS) and found that the mice exhibited temporary sleepiness lasting for 7 days. Using the Fos-TRAP method, fiber photometry recordings, and immunofluorescence staining, we detected temporary PVT neuron hypoactivation and microglia activation from day 1 to day 7 post-LPS treatment. Combining the results of bulk and single-cell RNA Sequencing, we found upregulation of aconitate decarboxylase 1 (Acod1) in PVT microglia post-LPS treatment. To investigate the role of Acod1, we manipulated Acod1 gene expression in PVT microglia via stereotactic injection of short hairpin RNA adenovirus. Knockdown of Acod1 exacerbated inflammation, neuronal hypoactivation, and sleepiness. Itaconate is a metabolite synthesized by the Enzyme encoded by Acod1. Finally, we confirmed that exogenous administration of an itaconate derivative, 4-octyl itaconate, could inhibit microglia activation, alleviate neuronal dysfunction, and relieve sleepiness. Our findings highlight PVT's role in inflammation-induced sleepiness and suggest Acod1 as a potential therapeutic target for neuroinflammation.

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