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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 negatively affects hippocampal neurogenesis. Mice were sacrificed on day 29 after the beginning of DSS treatment. (A) Western blot analysis of markers of neurogenesis and p21. Three independent experiments were performed, and representative blots are shown depicting pooled samples derived from DSS-treated and control mice; (B) intensities of protein bands were quantified from nine individual samples run together, normalized to GAPDH and presented as a fold change relative to control animals; (C) mRNA levels of proinflammatory cytokines, markers of neurogenesis, and p21 in the hippocampus of DSS-treated mice. Data are shown as mean ± SEM of three independent experiments. All samples from three experiments (n = 9) were run together in triplicates and normalized against GAPDH. Results are expressed in fold change vs. control taken as 1 (broken line); *p < 0.05, **p < 0.01. BLBP, brain lipid binding protein; Cont, control; DCX, doublecortin; DSS, dextran sodium sulfate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein.
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Fig2: Chronic intestinal inflammation negatively affects hippocampal neurogenesis. Mice were sacrificed on day 29 after the beginning of DSS treatment. (A) Western blot analysis of markers of neurogenesis and p21. Three independent experiments were performed, and representative blots are shown depicting pooled samples derived from DSS-treated and control mice; (B) intensities of protein bands were quantified from nine individual samples run together, normalized to GAPDH and presented as a fold change relative to control animals; (C) mRNA levels of proinflammatory cytokines, markers of neurogenesis, and p21 in the hippocampus of DSS-treated mice. Data are shown as mean ± SEM of three independent experiments. All samples from three experiments (n = 9) were run together in triplicates and normalized against GAPDH. Results are expressed in fold change vs. control taken as 1 (broken line); *p < 0.05, **p < 0.01. BLBP, brain lipid binding protein; Cont, control; DCX, doublecortin; DSS, dextran sodium sulfate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein.

Mentions: At the conclusion of the experiment on day 29, RNA and protein were isolated from the whole hippocampi. We analyzed mRNA levels of pro-inflammatory cytokines, as well as neuronal markers in the hippocampi of DSS-treated mice. Western blot analysis of the neuronal markers showed decreased levels of nestin and BLBP, both markers of stem/early progenitor cells, whereas levels of GFAP were up-regulated in DSS-treated mice, indicative of activated astroglia. p21 was also induced compared to the controls, and DCX protein levels were decreased, indicating that neurogenesis was reduced in DSS-treated mice (Figure 2A,B). Real-time PCR results indicated that IL-1β and TNF-α mRNA levels were increased more than twofold accompanied by a fourfold increase in p21 mRNA levels, whereas nestin, a marker of stem/early progenitor cells, and DCX, a marker of newly developing neurons, were both down-regulated. At the same time, GFAP mRNA expression was induced (Figure 2C).Figure 2


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 negatively affects hippocampal neurogenesis. Mice were sacrificed on day 29 after the beginning of DSS treatment. (A) Western blot analysis of markers of neurogenesis and p21. Three independent experiments were performed, and representative blots are shown depicting pooled samples derived from DSS-treated and control mice; (B) intensities of protein bands were quantified from nine individual samples run together, normalized to GAPDH and presented as a fold change relative to control animals; (C) mRNA levels of proinflammatory cytokines, markers of neurogenesis, and p21 in the hippocampus of DSS-treated mice. Data are shown as mean ± SEM of three independent experiments. All samples from three experiments (n = 9) were run together in triplicates and normalized against GAPDH. Results are expressed in fold change vs. control taken as 1 (broken line); *p < 0.05, **p < 0.01. BLBP, brain lipid binding protein; Cont, control; DCX, doublecortin; DSS, dextran sodium sulfate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Chronic intestinal inflammation negatively affects hippocampal neurogenesis. Mice were sacrificed on day 29 after the beginning of DSS treatment. (A) Western blot analysis of markers of neurogenesis and p21. Three independent experiments were performed, and representative blots are shown depicting pooled samples derived from DSS-treated and control mice; (B) intensities of protein bands were quantified from nine individual samples run together, normalized to GAPDH and presented as a fold change relative to control animals; (C) mRNA levels of proinflammatory cytokines, markers of neurogenesis, and p21 in the hippocampus of DSS-treated mice. Data are shown as mean ± SEM of three independent experiments. All samples from three experiments (n = 9) were run together in triplicates and normalized against GAPDH. Results are expressed in fold change vs. control taken as 1 (broken line); *p < 0.05, **p < 0.01. BLBP, brain lipid binding protein; Cont, control; DCX, doublecortin; DSS, dextran sodium sulfate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic protein.
Mentions: At the conclusion of the experiment on day 29, RNA and protein were isolated from the whole hippocampi. We analyzed mRNA levels of pro-inflammatory cytokines, as well as neuronal markers in the hippocampi of DSS-treated mice. Western blot analysis of the neuronal markers showed decreased levels of nestin and BLBP, both markers of stem/early progenitor cells, whereas levels of GFAP were up-regulated in DSS-treated mice, indicative of activated astroglia. p21 was also induced compared to the controls, and DCX protein levels were decreased, indicating that neurogenesis was reduced in DSS-treated mice (Figure 2A,B). Real-time PCR results indicated that IL-1β and TNF-α mRNA levels were increased more than twofold accompanied by a fourfold increase in p21 mRNA levels, whereas nestin, a marker of stem/early progenitor cells, and DCX, a marker of newly developing neurons, were both down-regulated. At the same time, GFAP mRNA expression was induced (Figure 2C).Figure 2

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