Adult hippocampal neurogenesis is involved in memory and learning, and disrupted neurogenesis is implicated in cognitive impairment and mood disorders, including anxiety and depression. Some long-term peripheral illnesses and metabolic disorders, as well as normal aging, create a state of chronic peripheral inflammation. These conditions are associated with behavioral disturbances linked to disrupted adult hippocampal neurogenesis, such as cognitive impairment, deficits in learning and memory, and depression and anxiety. Pro-inflammatory cytokines released in the periphery are involved in peripheral immune system-to-brain communication by activating resident microglia in the brain. Activated microglia reduce neurogenesis by suppressing neuronal stem cell proliferation, increasing apoptosis of neuronal progenitor cells, and decreasing survival of newly developing neurons and their integration into existing neuronal circuits. In this review, we summarize evolving evidence that the state of chronic peripheral inflammation reduces adult hippocampal neurogenesis, which, in turn, produces the behavioral disturbances observed in chronic inflammatory disorders. As there are no data available on neurogenesis in humans with chronic peripheral inflammatory disease, we focus on animal models and, in parallel, consider the evidence of cognitive disturbance and mood disorders in human patients.

No abstract

BackgroundAdult 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.MethodsThe 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.ResultsDuring 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 p21Cip1 (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.ConclusionsWe 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.

The subgranular zone (SGZ) of the dentate gyrus of the hippocampus is a brain region where robust neurogenesis continues throughout adulthood. Cyclin-dependent kinases (CDKs) have a primary role in controlling cell division and cellular proliferation. p21 Cip1 (p21) is a CDK inhibitor that restrains cell cycle progression. Confocal microscopy revealed that p21 is abundantly expressed in the nuclei of cells in the SGZ and is colocalized with NeuN, a marker for neurons. Doublecortin (DCX) is a cytoskeletal protein that is primarily expressed by neuroblasts. By using FACS analysis it was found that, among DCX-positive cells, 42.8% stained for p21, indicating that p21 is expressed in neuroblasts and in newly developing neurons. p21-null (p21 ؊/؊ ) mice were examined, and the rate of cellular proliferation, as measured by BrdU incorporation, was increased in the SGZ of p21 ؊/؊ compared with WT mice. In addition, the levels of both DCX and NeuN protein were increased in p21 ؊/؊ mice, further demonstrating increased hippocampal neuron proliferation. Chronic treatment with the tricyclic antidepressant imipramine (10 mg/kg per day i.p. for 21 days) markedly decreased hippocampal p21 mRNA and protein levels, produced antidepressant-like behavioral changes in the forced swim test, and stimulated neurogenesis in the hippocampus. These results suggest that p21 restrains neurogenesis in the SGZ and imipramine-induced stimulation of neurogenesis might be a consequence of decreased p21 expression and the subsequent release of neuronal progenitor cells from the blockade of proliferation. Because many antidepressants stimulate neurogenesis, it is possible that their shared common mechanism of action is suppression of p21.antidepressant ͉ neurogenesis ͉ depression ͉ cyclin-dependent kinase inhibitor I n the central nervous system, developing neurons are derived from quiescent multipotent or neural stem cells and progenitors (1). In the hippocampus, the neural progenitor cells are located in the subgranular zone (SGZ) of the dentate gyrus, at the border between the hilus and the granular cell layer (GCL) (2, 3). Newborn cells proliferate in SGZ, migrate into the GCL, develop the morphological and functional properties of granule cell neurons, and become integrated into existing neuronal circuitry (4). This suggests an important role of intrinsic stimulatory and inhibitory factors in the regulation of proliferation of neuronal precursor cells.In mammalian cells, the control of cellular proliferation primarily is achieved in the G 1 phase of the cell cycle. Cyclindependent kinases (CDKs) tightly control the cell cycle process. Cell cycle progression is negatively regulated by two families of CDK inhibitors: Ink4/ARF type (p16, p15, p18, and p19) and Cip/Kip type (p21, p27, and p57). p21 Cip1 (p21) acts in the G 1 phase of the cell cycle and delays or blocks the progression of the cell into the S phase (5). p21 maintains cell quiescence, and chronic activation of p21 can drive the cell into irreversible cell growth arrest and senescen...

Fig. 6. GH induces EMT, suppresses apoptosis, and increases motility. Western blot analysis of PTEN and EMT factors in (A) hNCC and (B) HCT116 cells treated with indicated doses of GH for 24 h. (C) Western blot analysis of cleaved caspase 3 in cells treated with GH (500 ng/mL) for 24 h. Experiments were performed at least three times, and representative results shown. (D) Migration of hNCC and HCT116 cells treated with GH (500 ng/mL) and harvested 48 h after plating. (E) Migration of HCT116 cocultured for 48 h with hCF infected with lentivector or lentiGH. In D and E, for quantification, the number of migrated cells per 1,000 cells in five randomly chosen fields in each duplicate transwell were counted and means calculated. Results are presented as mean ± SEM of three independent experiments; *P < 0.05. (F) Number of colonies and arbitrary colony size formed in soft agar by HCT116 cells cocultured with hCF infected with lentivector or lentiGH, and tested for anchorage independent growth. Colony size was determined using ImageJ software. Results are presented as mean ± SEM of duplicates from two independent experiments; **P < 0.01 vs. control. In D-F, the differences between groups were analyzed using two-tailed unpaired Student t test.