Chronic intestinal inflammation alters hippocampal neurogenesis

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.

Chronic peripheral inflammation, hippocampal neurogenesis, and behavior

“…Adult hippocampal neurogenesis is stimulated by environmental enrichment and exercise(Kempermann et al, 2003; van Praag et al, 1999), and neurogenesis is suppressed by acute and chronic inflammation (Ben-Hur et al, 2003; Borsini et al, 2015 ; Monje et al, 2003; Zonis et al, 2013; Zonis et al, 2015). The microenvironment in the neurogenic niche is important, and is mediated by a range of critical factors, including the oxygen supply, nutrition, hormones, and trophic factors, but also, to a large extent, by the cellular and humoral activity of the immune system (Kohman and Rhodes, 2013; Yirmiya and Goshen, 2011).…”

“…Recently, we characterized the effects of chronic intestinal inflammation on hippocampal neurogenesis using a mouse model of IBD (Zonis et al, 2015). Repeated administration of cycles of dextran sodium sulfate in the drinking water produces colonic epithelial cell lesions; acute intestinal inflammation is seen 7–14 days after start of treatment, and chronic intestinal inflammation develops later.…”

“…During the acute phase of colitis, plasma levels of IL-6 are increased, accompanied by activation of resident hippocampal microglia, as well as increased levels of IL-1β, TNF-α, and p21 in the hippocampus. As p21 is expressed in NPC and in early neuroblasts (Pechnick et al, 2011), it is plausible to consider that cytokine-induced p21 expression might be responsible for the decreased neurogenesis, given that nestin and brain lipid binding protein, both markers of NPC, as well as DCX, an early neuronal marker, are all decreased (Zonis et al, 2015). In mice, approximately 3 weeks are required for the new neurons to mature (Kempermann et al, 2003).…”

(Putative) sex differences in neuroimmune modulation of memory

“…Both acute (Valero et al, 2014) and chronic (Zonis et al, 2015) inflammation, as well as chronic stressors (McKim et al, 2016), lead to dysregulation of adult neurogenesis. Studies of inflammatory signaling and neurogenesis show conflicting results: immune challenges can increase proliferation (Seguin et al, 2009), decrease proliferation (Islam et al, 2009), maintain neurogenesis by increasing survival of new cells (Ziv et al, 2006), decrease survival of newborn neurons (McKim et al, 2016), or impair integration of new cells into neural circuits (Jakubs et al, 2008).…”

Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis

“…For example, in animals, induction of colitis caused an increase in pro-inflammatory cytokines, reduced neurogenesis in hippocampus [15] and behavioral abnormalities such as cognition impairment, and depression- and anxiety-like behavior which persisted after the colonic inflammation had resolved [16, 17]. In humans, the gut-brain interaction during colitis has been suggested to be responsible for inflammation-mediated changes in gray matter in patients with IBD [18].…”