Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running

Abstract

Acute neuroinflammation reduces adult hippocampal neurogenesis but the role of chronic neuroinflammation, which may be more representative of ongoing processes in CNS disorders, remains relatively unknown. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that has been shown to acutely impair neurogenesis. To further investigate the relationship between sustained IL-1β expression and adult neurogenesis, a mouse model with an IL-1β excisionally activated transgene, IL-1βXAT, was utilized. Upon exposure to Cre recombinase, IL-1β overexpression in this model results in chronic neuroinflammation, which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory. We hypothesized that adult neurogenesis would be reduced by sustained hippocampal IL-1β overexpression and rescued by voluntary running, which has been shown to enhance neurogenesis. Hippocampal inflammation in the IL-1βXAT model severely impaired doublecortin (DCX) positive cells at 1 month and 3 months after IL-1β induction. Furthermore, BrdU labeling demonstrated a shift in cell lineage from neuronal to astroglial in the context of sustained hippocampal IL-1β overexpression. Deletion of the IL-1 receptor prevented the decrease in DCX+ cells. Voluntary running did not attenuate the effects of IL-1β expression demonstrated by DCX staining. These results suggest that chronic neuroinflammation severely impairs adult hippocampal neurogenesis and voluntary running is not beneficial as a therapy to rescue these effects.

The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression

“…Notably, inhibition of IL-1β blocked a decrease in neurogenesis caused by acute stress and anhedonic and anti-neurogenic effects of chronic stress (Goshen et al, 2008;Koo and Duman, 2008). Sustained hippocampal IL-1β expression has a detrimental effect on adult neurogenesis (Wu et al, 2012). Recently, Zunszain et al (2012) reported that a kynurenine 3-monooxygenase inhibitor reversed IL-1β-induced impaired neurogenesis (Zunszain et al, 2012), suggesting that IL-1β regulates hippocampal neurogenesis via the kynurenine pathway.…”

Modulation of learning and memory by cytokines: Signaling mechanisms and long term consequences

“…Chronic exposure to IL-1 consistently impairs neurogenesis (Goshen et al, 2008; Koo & Duman, 2008; Seguin, Brennan, Mangano, & Hayley, 2009; Wu et al, 2012; Zunszain et al, 2012). The effects of IL-1 on neurogenesis are mediated via SAPK/JNK pathway (X.…”

Intra-Hippocampal Transplantation of Neural Precursor Cells with Transgenic Over-Expression of IL-1 Receptor Antagonist Rescues Memory and Neurogenesis Impairments in an Alzheimer’s Disease Model

“…In particular, at pathophysiological levels IL-1 can produce detrimental effects on hippocampal-dependent memory processes (Rachal Pugh et al, 2001;Yirmiya and Goshen, 2011), which may be related to its effects on several mechanisms of neural plasticity, including suppression of neurogenesis Koo and Duman, 2008;Wu et al, 2012) and the production of brain-derived neurotrophic factor (BDNF) (Barrientos et al, 2003;Barrientos et al, 2004;Tong et al, 2008).…”