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

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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 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.

Highlights

► Sustained IL-1β expression reduces adult hippocampal neurogenesis and shifts cellular fate towards astroglia; this reduction is not alleviated by voluntary running.

Introduction

During development, neural precursor cells (NPCs) give rise to several cell types of the adult brain including neurons in a process known as neurogenesis. Following development, neurogenesis persists in two specific regions in the adult: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. NPCs in the adult continue to give rise to new neurons but also have the ability to become glia under certain conditions. Adult hippocampal neurogenesis is thought to be important in learning and memory (Deng et al., 2010, Leuner et al., 2006) and is involved in injury models such as stroke, seizure, trauma, or radiation (Kaneko and Sawamoto, 2009, Monje, 2008). More recent evidence suggests that adult neurogenesis may be involved in other behaviors such as stress (Ben Menachem-Zidon et al., 2008, Goshen et al., 2008, Koo and Duman, 2008, Lagace et al., 2010) and depressive-like behavior (David et al., 2009, Sahay and Hen, 2007). Adult neurogenesis is also affected by a wide range of stimuli including environmental enrichment (Goshen et al., 2009), growth factors (Cao et al., 2004, Rossi et al., 2006, Sairanen et al., 2005, Trejo et al., 2008), and anti-depressants (David et al., 2009, Encinas et al., 2006, Malberg et al., 2000, Santarelli et al., 2003).

One important mediator of adult neurogenesis that is being closely examined is neuroinflammation. Neuroinflammation is the local CNS response to injury that involves phenotypic activation of glia, specifically microglia and astrocytes, recruitment of inflammatory cells, and the upregulation of chemokines, cytokines, and other inflammatory mediators. Neuroinflammation is a feature of stroke, brain trauma, epilepsy, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, motor neuron disease, and movement disorders (Lucas et al., 2006). In general, neuroinflammation is considered detrimental to adult hippocampal neurogenesis. For example, treatment with a non-steroidal anti-inflammatory drug partially rescues hippocampal neurogenesis after exposure to radiation (Monje et al., 2003). Previous work has focused on interleukin(IL)-6 and tumor necrosis factor alpha (TNFα) as potential candidates (Monje et al., 2003, Vallieres et al., 2002), but the exact mechanism through which neuroinflammation downregulates adult neurogenesis is unknown.

One potential candidate for effecting reduced neurogenesis is the pro-inflammatory cytokine interleukin-1 (IL-1). IL-1 is rapidly upregulated with injury and is implicated in the pathogenesis of Alzheimer’s disease, traumatic brain injury, epilepsy, stroke, and Parkinson’s disease (Allan et al., 2005). The IL-1 family consists of two agonists, cell-bound IL-1α and soluble IL-1β, that signal via the type 1 IL-1 receptor (IL-1R1). In the CNS, IL-1 can act on resident cells to induce expression of other cytokines and chemokines, activate glia, and recruit inflammatory cells (Allan et al., 2005). The IL-1 family is an ideal system to understand the effect of a pro-inflammatory cytokine on adult hippocampal neurogenesis due to a well characterized signaling cascade and a single functional receptor with a high density in the hippocampus (Cunningham et al., 1992). Several groups have shown that acute increases in IL-1β decrease adult hippocampal neurogenesis and blocking IL-1 signaling can abrogate this effect (Ben Menachem-Zidon et al., 2008, Goshen et al., 2008, Koo and Duman, 2008). These studies involved in vitro approaches and acute exposure paradigms, but the effect of chronic IL-1-dependent inflammation on adult neurogenesis in vivo is not as well understood.

To study the effect of chronic neuroinflammation on adult neurogenesis, we utilized a recently developed model of sustained interleukin-1β (IL-1β) expression, the IL-1βXAT mouse model, which mimics chronic neuroinflammation observed in neurodegenerative diseases. We have previously shown that IL-1β overexpression in our model results in chronic neuroinflammation which persists up to 12 months and causes glial activation, cellular recruitment, and deficits in learning and memory (Hein et al., 2010, Moore et al., 2009, Shaftel et al., 2007a, Shaftel et al., 2007b). We wanted to determine whether sustained IL-1β expression in the adult hippocampus of IL-1βXAT mice would decrease neurogenesis. Additionally, we also evaluated whether voluntary running would be beneficial in the context of ongoing neuroinflammation, as studies have shown that such a stimulus can increase adult hippocampal neurogenesis in conditions that adversely affect it (Naylor et al., 2008, Wu et al., 2007). These results may have important implications for therapies in chronic neuroinflammatory diseases where adult neurogenesis is reduced.

Section snippets

Animals

All protocols were approved by the Institutional Animal Care and Use Committee at the University of Rochester. Wild-type and IL-1βXAT C57BL/6 mice aged 8–12 weeks were used in these studies. The development and characterization of the IL-1βXAT mouse has been described previously (Shaftel et al., 2007b). Briefly, IL-1βXAT mice contain a ssIL-1β transgene driven by a GFAP promoter that is transcriptionally silent due to an upstream loxP flanked transcriptional stop. ssIL-1β encodes the signal

Sustained hippocampal IL-1β expression causes focal inflammation and reduces adult neurogenesis

One month after FIV(Cre) administration, we confirmed the presence of inflammatory cells in unilaterally FIV(Cre)-injected IL-1βXAT mice. We found robust expression of MHC-II staining in the ipsilateral, FIV(Cre)-injected hippocampus and did not observe any MHC-II+ cells in the contralateral, uninjected hippocampus (Fig. 1). Focal staining indicated that IL-1β-dependent inflammation was confined to the FIV(Cre)-injected area. We did not detect enhanced MHC-II staining in WT animals that

Discussion

Our data agree with previous evidence that inflammation is detrimental to hippocampal neurogenesis in the adult brain. We found that focal, sustained hippocampal inflammation causes severe depletion of developing neuroblasts and skews the fate of neural progenitors in the SGZ away from a neuronal lineage and toward an astroglial fate in the adult brain. Interestingly, if offspring from neural progenitors are allowed to mature, they are resistant to the effects of sustained expression of IL-1β.

Acknowledgments

We thank Jen-nie Miller and Dr. Stephanos Kyrkanides for providing the feline immunodeficiency viral vectors. Lee Trojanczyk, Jack Walter, Mallory Olschowka, and Renee Johnson assisted with tissue processing. Dr. Linda Callahan helped with the confocal images. M.D.W. is a student in the Department of Neurobiology & Anatomy and Medical Scientist Training Program at the University of Rochester SMD. Supported by NIH Research Award AG030149 and NIGMS T32 GM07356.

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