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Chronic intestinal inflammation alters hippocampal neurogenesis.

Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS, Chesnokova V - J Neuroinflammation (2015)

Bottom Line: We therefore tested the effects of chronic intestinal inflammation on hippocampal neurogenesis.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Cedars-Sinai Medical Center, Davis Bldg., Room 3019, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA. ZonisS@cshs.org.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Chronic intestinal inflammation in mice on day 29 after the beginning of DSS treatment. (A) Cumulative change of body weight (BW) in the course of dextran sodium sulfate (DSS) treatment from three independent experiments; n = 15 mice analyzed. (B) Serum IL-6 levels in control and DSS-treated mice (n = 8). (C) Immunohistochemical analysis of intestinal inflammation (H&E). Inflammation sites are marked by dotted lines. Cecum: Arrow points to the site of severe transmural inflammation with loss of entire crypts and endothelium and infiltration of inflammatory cells. Colon: Arrow points to severe submucosal inflammation with loss of crypts while the surface epithelium is still intact and to infiltration of inflammatory cells.
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Fig1: Chronic intestinal inflammation in mice on day 29 after the beginning of DSS treatment. (A) Cumulative change of body weight (BW) in the course of dextran sodium sulfate (DSS) treatment from three independent experiments; n = 15 mice analyzed. (B) Serum IL-6 levels in control and DSS-treated mice (n = 8). (C) Immunohistochemical analysis of intestinal inflammation (H&E). Inflammation sites are marked by dotted lines. Cecum: Arrow points to the site of severe transmural inflammation with loss of entire crypts and endothelium and infiltration of inflammatory cells. Colon: Arrow points to severe submucosal inflammation with loss of crypts while the surface epithelium is still intact and to infiltration of inflammatory cells.

Mentions: To induce intestinal inflammation, mice received four cycles of DSS or normal drinking water (controls) for 26 days. Body weight was monitored twice a week. Loss of 7% to 15% body weight initially was observed in DSS-treated animals, and normal weight was restored by day 26 (Figure 1A). The mice were sacrificed on day 29 after the beginning of DSS administration. Trunk blood was collected, and serum levels of TNF-α and IL-6 were measured. TNF-α was below detection in both experimental and control groups of animals. IL-6 was below the level of detection (<2.5 pg/ml) in control mice, whereas it was present in the serum of DSS-treated animals indicating the presence of systemic inflammation (Figure 1B). Signs of intestinal inflammation were assessed histologically by a trained pathologist to evaluate the extent, regeneration, crypt damage, and percentage involvement in cecum and colon as described [38,41,48]. All animals exhibited signs of intestinal inflammation as evidenced by infiltration of inflammatory cells and loss of crypts (microscopic scores 1 to 2, average histological scores 10.2 ± 1.7, n = 15) on day 29 (Figure 1C).Figure 1


Chronic intestinal inflammation alters hippocampal neurogenesis.

Zonis S, Pechnick RN, Ljubimov VA, Mahgerefteh M, Wawrowsky K, Michelsen KS, Chesnokova V - J Neuroinflammation (2015)

Chronic intestinal inflammation in mice on day 29 after the beginning of DSS treatment. (A) Cumulative change of body weight (BW) in the course of dextran sodium sulfate (DSS) treatment from three independent experiments; n = 15 mice analyzed. (B) Serum IL-6 levels in control and DSS-treated mice (n = 8). (C) Immunohistochemical analysis of intestinal inflammation (H&E). Inflammation sites are marked by dotted lines. Cecum: Arrow points to the site of severe transmural inflammation with loss of entire crypts and endothelium and infiltration of inflammatory cells. Colon: Arrow points to severe submucosal inflammation with loss of crypts while the surface epithelium is still intact and to infiltration of inflammatory cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4403851&req=5

Fig1: Chronic intestinal inflammation in mice on day 29 after the beginning of DSS treatment. (A) Cumulative change of body weight (BW) in the course of dextran sodium sulfate (DSS) treatment from three independent experiments; n = 15 mice analyzed. (B) Serum IL-6 levels in control and DSS-treated mice (n = 8). (C) Immunohistochemical analysis of intestinal inflammation (H&E). Inflammation sites are marked by dotted lines. Cecum: Arrow points to the site of severe transmural inflammation with loss of entire crypts and endothelium and infiltration of inflammatory cells. Colon: Arrow points to severe submucosal inflammation with loss of crypts while the surface epithelium is still intact and to infiltration of inflammatory cells.
Mentions: To induce intestinal inflammation, mice received four cycles of DSS or normal drinking water (controls) for 26 days. Body weight was monitored twice a week. Loss of 7% to 15% body weight initially was observed in DSS-treated animals, and normal weight was restored by day 26 (Figure 1A). The mice were sacrificed on day 29 after the beginning of DSS administration. Trunk blood was collected, and serum levels of TNF-α and IL-6 were measured. TNF-α was below detection in both experimental and control groups of animals. IL-6 was below the level of detection (<2.5 pg/ml) in control mice, whereas it was present in the serum of DSS-treated animals indicating the presence of systemic inflammation (Figure 1B). Signs of intestinal inflammation were assessed histologically by a trained pathologist to evaluate the extent, regeneration, crypt damage, and percentage involvement in cecum and colon as described [38,41,48]. All animals exhibited signs of intestinal inflammation as evidenced by infiltration of inflammatory cells and loss of crypts (microscopic scores 1 to 2, average histological scores 10.2 ± 1.7, n = 15) on day 29 (Figure 1C).Figure 1

Bottom Line: We therefore tested the effects of chronic intestinal inflammation on hippocampal neurogenesis.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Cedars-Sinai Medical Center, Davis Bldg., Room 3019, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA. ZonisS@cshs.org.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus