Invited ReviewChronic peripheral inflammation, hippocampal neurogenesis, and behavior
Introduction
Pathologic conditions as varied as arthritis, diabetes mellitus, obesity, systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) create a state of chronic peripheral inflammation. They do so either by directly producing inflammation or by triggering pathological metabolic states, which in turn contribute to inflammatory processes. Inflammatory responses are not limited to the periphery; systemic inflammation also affects the central nervous system. These same conditions are associated with behavioral disturbances, such as cognitive impairment, deficits in learning and memory, and depression. Despite the important impact on the quality of life, very few studies have focused on the central mechanisms underlying these behavioral problems in chronic inflammatory states. Adult hippocampal neurogenesis is an important form of neuroplasticity, and data from animal models suggest that chronic peripheral inflammation disrupts hippocampal neurogenesis. Therefore, impaired neurogenesis as a consequence of chronic inflammation might underlie some of the behavioral manifestations of these disorders in humans. This review provides an overview of data that suggest links between chronic peripheral illness, adult hippocampal neurogenesis, and behavior.
Although many illnesses involve chronic inflammation (e.g. liver disease, cardiovascular disease and some forms of cancer), this review will focus on those conditions where sufficient data are available from animal models of chronic inflammation and behavioral correlates in humans. The authors regret that they cannot cite many original papers and some reviews due to space limitations.
Section snippets
Adult neurogenesis
For many years, the production of new neurons in mammalian brain had been considered to be restricted to early development. With the discovery and implementation of new methodologies, it is now clear that neurogenesis occurs in adult animals, including humans (Abrous et al., 2005, Eriksson et al., 1998, Zhao et al., 2008). Although neurogenesis can occur in multiple sites throughout the adult brain, however, under physiological conditions in rodents, neuronal progenitor cells (NPC) produce
Adult neurogenesis and behavior
In this review we will describe the changes attributed to the SGZ of hippocampus.
The role of neurogenesis in hippocampal function and behavior continues to be a subject of intense debate. Neurogenesis cannot be imaged or otherwise measured in living human subjects; therefore, most information on the behavioral consequences of normal and abnormal neurogenesis has been obtained from studies in laboratory animals.
A strong case can be made for the involvement of adult hippocampal neurogenesis in
Peripheral immune system-to-brain communication
Many inflammatory conditions are associated with both altered neurogenesis and behavior abnormalities as outlined below. Several mechanisms alert the brain to inflammation in the periphery. Locally produced pro-inflammatory cytokines activate primary afferent pathways, such as the vagus nerve, and circulating pro-inflammatory cytokines access the brain via the circumventricular organs and saturable transport systems (Dantzer et al., 2008b). Pro-inflammatory cytokines disrupt the blood–brain
Acute inflammation and neurogenesis
A great deal of work has been devoted to dissecting the role of cytokines in the direct and indirect regulation of neurogenesis (Borsini et al., 2015, Goshen and Yirmiya, 2009, Kohman and Rhodes, 2013). NPC constitutively express receptors for pro-inflammatory cytokines (Green et al., 2012). Despite some controversies and discrepancies arising from the use of different experimental models, most in vitro experiments have shown that pro-inflammatory cytokines suppress NPC proliferation. For
Chronic peripheral inflammation and neurogenesis
Relatively few in vivo experimental models of chronic peripheral inflammatory diseases have been studied with regard to neurogenesis, and almost all have examined neurogenesis in the SGZ of the dentate gyrus of the hippocampus. Currently available data showing the consequences of chronic inflammatory states on hippocampal neurogenesis are summarized below. Because neurogenesis has been linked to memory and learning, depression, and stress regulations, a discussion of the effects of chronic
Conclusions
We have discussed pathologic conditions that involve inflammatory responses in both the periphery and the central nervous system. To confirm causative relations between chronic systemic inflammation, neurogenesis, and behavior, several important questions need to be addressed and methodological limitations have to be considered.
Although there are substantial data showing a link between chronic inflammation and decreases in adult hippocampal neurogenesis, few preclinical studies have examined
Acknowledgments
This work was supported by NIH Grant MH79988 and NARSAD Independent Investigator Award (to V.C.).
References (97)
- et al.
Insulin-like growth factor-I and neurogenesis in the adult mammalian brain
Brain Res. Dev. Brain Res.
(2002) - et al.
Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats
Neurobiol. Aging
(2011) Neuroimmunopathology in a murine model of neuropsychiatric lupus
Brain Res. Rev.
(2007)- et al.
Effects of proinflammatory cytokines on the growth, fate, and motility of multipotential neural precursor cells
Mol. Cell. Neurosci.
(2003) - et al.
Impairment of hippocampal-dependent memory induced by juvenile high-fat diet intake is associated with enhanced hippocampal inflammation in rats
Brain Behav. Immun.
(2014) - et al.
The role of inflammatory cytokines as key modulators of neurogenesis
Trends Neurosci.
(2015) Neuroinflammation and neurodegeneration in overnutrition-induced diseases
Trends Endocrinol. Metab.
(2013)- et al.
White matter abnormalities in irritable bowel syndrome and relation to individual factors
Brain Res.
(2011) - et al.
Reduced adult neurogenesis and altered emotional behaviors in autoimmune-prone B-cell activating factor transgenic mice
Biol. Psychiatry
(2010) - et al.
Identification and treatment of symptoms associated with inflammation in medically ill patients
Psychoneuroendocrinology
(2008)