Chronic intestinal inflammation alters hippocampal neurogenesis

Journal of Neuroinflammation

Vera Chesnokova³  Kathrin S Michelsen¹  Kolja Wawrowsky³  Michael Mahgerefteh³  Vladimir A Ljubimov³  Robert N Pechnick²  Svetlana Zonis³ 

[1] F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA;Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona 91766, CA, USA;Department of Medicine, Cedars-Sinai Medical Center, Davis Bldg., Room 3019, 8700 Beverly Blvd., Los Angeles 90048, CA, USA

关键词: p21;    Adult neurogenesis;    Hippocampus;    Chronic peripheral inflammation;    Inflammatory bowel disease;   

Others  :  1227100
DOI  :  10.1186/s12974-015-0281-0

 received in 2014-11-11, accepted in 2015-03-11,  发布年份 2015

【 摘 要 】

Background

Adult neurogenesis in the subgranular zone of the hippocampus is involved in learning, memory, and mood control. Decreased hippocampal neurogenesis elicits significant behavioral changes, including cognitive impairment and depression. Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the intestinal tract, and cognitive dysfunction and depression frequently occur in patients suffering from this disorder. We therefore tested the effects of chronic intestinal inflammation on hippocampal neurogenesis.

Methods

The dextran sodium sulfate (DSS) mouse model of IBD was used. Mice were treated with multiple-cycle administration of 3% wt/vol DSS in drinking water on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26. Mice were sacrificed on day 7 (acute phase of inflammation) or day 29 (chronic phase of inflammation) after the beginning of the treatment.

Results

During the acute phase of inflammation, we found increased plasma levels of IL-6 and TNF-α and increased expression of Iba1, a marker of activated microglia, accompanied by induced IL-6 and IL-1β, and the cyclin-dependent kinase inhibitor p21^Cip1 (p21) in hippocampus. During the chronic phase of inflammation, plasma levels of IL-6 were elevated. In the hippocampus, p21 protein levels were continued to be induced. Furthermore, markers of stem/early progenitor cells, including nestin and brain lipid binding protein (BLBP), and neuronal marker doublecortin (DCX) were all down-regulated, whereas glial fibrillary acidic protein (GFAP), a marker for astroglia, was induced. In addition, the number of proliferating precursors of neuronal lineage assessed by double Ki67 and DCX staining was significantly diminished in the hippocampus of DSS-treated animals, indicating decreased production of new neurons.

Conclusions

We show for the first time that chronic intestinal inflammation alters hippocampal neurogenesis. As p21 arrests early neuronal progenitor proliferation, it is likely that p21 induction during acute phase of inflammation resulted in the reduction of hippocampal neurogenesis observed later, on day 29, after the beginning of DSS treatment. The reduction in hippocampal neurogenesis might underlie the behavioral manifestations that occur in patients with IBD.

【 授权许可】

   
2015 Zonis et al.; licensee BioMed Central.

【 图 表 】

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