Astrocytic IL-6 mediates locomotor activity, exploration, anxiety, learning and social behavior

Erta, María; Giralt, Mercedes; Esposito, Flavia; Fernández-Gayol, Olaya; Hidalgo, Juan

doi:10.1016/j.yhbeh.2015.06.016

Cited by 45 publications

(34 citation statements)

References 58 publications

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“…Recent studies highlight a link between immune dysfunction and behavioral impairments [105]. For example, the relation between IL-6 and several altered behaviors has already been established in the literature [106][107][108]. Signs of neuroinflammation and altered inflammatory responses are seen in ASD subjects throughout life [109].…”

Section: Neuroimmune Alterations In Asd: From Patients To the Vpa Animentioning

confidence: 99%

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Deckmann

Schwingel

Fontes-Dutra

et al. 2018

Neuroimmunomodulation

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Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

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Section: Neuroimmune Alterations In Asd: From Patients To the Vpa Animentioning

confidence: 99%

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Deckmann

Schwingel

Fontes-Dutra

et al. 2018

Neuroimmunomodulation

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“…However, estradiol replacement therapy does not alter IL-6 levels in postmenopausal women (Edwards and Mills, 2008), and higher, lower, or similar levels of IL-6 have been measured in healthy men versus women (Giraldo et al., 2008). Sex differences in the role of CNS produced IL-6 have already been indicated (Erta et al., 2015). We have previously demonstrated that estrous females have higher GLP-1R-induced IL-6 mRNA levels in the hypothalamus when circulating estrogen levels are highest (López-Ferreras et al., 2018).…”

Section: Discussionmentioning

confidence: 86%

“…Central IL-6 is linked to stress-related disorders, such as depression and anxiety (Erta et al., 2015, Hodes et al., 2016), and the lPBN has well-established neuroanatomical links to emotionality regulating regions, such as the amygdala (Bernard et al., 1996, Gauriau and Bernard, 2002). Therefore, we evaluated the potential impact of IL-6 loss in the lPBN on anxiety-like behavior using two well-validated rodent tests of anxiety: the open field and the elevated plus maze (EPM).…”

Section: Resultsmentioning

confidence: 99%

“…Using recent advances in molecular and genetic tools, we were able to both localize IL-6 mRNA to neurons, astrocytes, and microglial cell bodies in lPBN and then selectively reduce IL-6 mRNA levels in the lPBN. This approach represents a significant refinement to many previous reports because localizing IL-6 to a specific brain region proved challenging because of a lack of reliable antibodies, and most manipulations of IL-6 involved whole body or, more recently, tissue/cell-specific manipulations, which are not compatible with understanding the diverse, and possibly divergent, function of IL-6 in different CNS nuclei (Erta et al., 2015, Matthews et al., 2010, Quintana et al., 2013, Wallenius et al., 2002b). Our complementary set of results clearly indicates that IL-6 acts in the lPBN to reduce the intake of chow and high-fat/high-sugar diet, and to increase BAT thermogenesis by increasing the HPT axis activity and sympathetic outflow.…”

Section: Discussionmentioning

confidence: 99%

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Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism

et al. 2019

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SummaryChronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuroanatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (lPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating lPBN neurons. IL-6 microinjection into lPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of lPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of lPBN IL-6. These results indicate that lPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with lPBN IL-6.

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“…EtOH has also been reported to activate the NLRP3-inflammasome in astroglial cells, which stimulates caspase-1 cleavage and IL-1β and IL-18 production (Alfonso-Loeches et al 2016). IL-6 is a major cytokine in the CNS that is secreted by various brain cells and has a number of physiological functions (Erta et al 2012), including behavior regulation (Erta et al 2015). Moreover, IL-6 expression was previously reported to be induced by HIV-1 Tat, gpl20, and Nef (Del Como et al 2014; Liu and Kumar 2015; Nookala and Kumar 2014).…”

Section: Discussionmentioning

confidence: 99%

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats

Huang

Zheng

et al. 2017

J. Neurovirol.

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Binge drinking affects the onset and progression of human immunodeficiency virus (HIV)-associated neurological disorders. The HIV-1 transgenic (HIV-1Tg) rat was created with a gag- and pol-deleted HIV-1 viral genome to mimic HIV-infected patients receiving combination anti-retroviral therapy (cART). Docosahexaenoic acid (DHA) is a marine compound that modulates inflammatory responses. Using HIV-1Tg rats subjected to binge exposure to ethanol (EtOH), this study examined whether DHA could reduce the detrimental neurological effects of EtOH and HIV proteins. Young adult male HIV-1Tg and F344 control rats received 4 mL/kg/day saline as a control (Saline group), 20 mg/kg/day DHA (DHA group), 4.8 g/kg/day 52% w/v EtOH (EtOH group), or 4.8 g/kg/day 52% w/v EtOH and 20 mg/kg/d DHA (DHA + EtOH group) by gavage for 5 weeks (n = 6 per group). EtOH was administrated on days 5, 6, and 7 of each week. Locomotor activity (LMA) was assessed using open field tests before and 45, 90, 135, and 180 min after each treatment. Repeated binge EtOH exposure gradually decreased LMA measured before daily treatments in HIV-1Tg and F344 rats, an effect that was reversed by DHA only in the HIV-1Tg rats. Decreased LMA of rats after treatment and under the influence of EtOH was less pronounced, and the reversal effect of DHA did not reach statistical significance. The plasma endotoxin level was significantly higher in HIV-1Tg rats than in F344 rats. IL-6 and IL-18 expression in the striatum was significantly higher in the HIV-1Tg EtOH group than in the F344 EtOH group. DHA significantly decreased the high levels of IL-6, IL-18, and NF-κB expression observed in the HIV-1Tg EtOH group. DHA appears to ameliorate inflammation and consequently lessen the reductions in LMA produced by the combination of EtOH and HIV-1 viral proteins.

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Astrocytic IL-6 mediates locomotor activity, exploration, anxiety, learning and social behavior

Cited by 45 publications

References 58 publications

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism

Effects of docosahexaenoic acid on locomotor activity in ethanol-treated HIV-1 transgenic rats

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