Lipopolysaccharide administration induces sex-dependent behavioural and serotonergic neurochemical signatures in mice

Sens, Jonathon P.; Schneider, Eric C.; Mauch, Joseph; Schaffstein, Anna; Mohamed, Sara; Fasoli, Kathryn; Saurine, Joseph; Britzolaki, Aikaterini; Thelen, Connor; Pitychoutis, Pothitos M.

doi:10.1016/j.pbb.2016.12.016

Cited by 34 publications

(15 citation statements)

References 53 publications

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“…Several of these areas, including the striatum, are known to have prominent k-receptor populations (Unterwald et al, 1994). A decrease in self-grooming in rodents can be a marker of anhedonia, and it occurs after diverse behavioral and biologic stressors (Yalcin et al, 2008;Sens et al, 2017;Williams et al, 2018). Exogenous k-agonists are also known to produce other effects indicative of anhedonia or aversion in vivo (Zhang et al, 2004;Carlezon et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Self-grooming in rodents is a highly regulated homeostatic behavior, mediated by specific brain regions, including the striatum and other sites known to express dynorphin and k-receptors (Berridge and Whishaw, 1992;Unterwald et al, 1994;Kalueff et al, 2016). Studies have demonstrated that a decrease in grooming in the splash test can be an ethologically relevant display of anhedonia (Yalcin et al, 2008;Sens et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

Butelman

McElroy

Prisinzano

et al. 2019

J Pharmacol Exp Ther

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The kappa (k) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively shortacting small molecule k-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the k-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n 5 6-8) were examined for self-grooming behavior in the splash test (in which robust selfgrooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The k-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting k-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl) pyrrolidin-1-yl)methyl) phenoxy)benzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). k-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose-and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a k-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the k-receptor system is involved in an ethologically relevant measure of anhedonia, and that k-selective doses of these antagonists can produce effects consistent with rapid antianhedonia. SIGNIFICANCE STATEMENT Activation of the k-opioid receptor system results in grooming deficits in mice, an ethologically relevant marker of anhedonia. Shorter acting k-antagonists are able to cause effects consistent with rapid antianhedonia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

Butelman

McElroy

Prisinzano

et al. 2019

J Pharmacol Exp Ther

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“…The effect of maternal immune activation on fetal brains relies on the interplay among maternal transmissible cytokine IL-6 and cortisol as well as fetal effector immune cells, glial cells and neurons [40, 42]. The resultant interactions directly or indirectly increase 5-HTergic and DAergic activity, which peaked at 6 h and persisted until 24 h [17, 40, 43]. In our model, the short-term effect (24 h) of maternal immune activation significantly induced augmentation of DA levels in the fetal brains (Fig 11).…”

Section: Discussionmentioning

confidence: 99%

“…To detect the 5-HT and DA levels by enzyme-linked immunoassay (ELISA), the dissected brains were immediately homogenized in PBS and stored at -80°C. If high performance liquid chromatography (HPLC) was performed, the dissected brains were placed into a 0.2 N perchloric acid solution (see S1 Fig legend) [17]. All of the fetal brain tissues were confirmed as female using sex-specific amplicons (male-specific sry gene, 402 bp; specific primers, forward: , reverse: ; IL-3-specific primes, 544 bp; forward: , reverse: ).…”

Section: Methodsmentioning

confidence: 99%

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

et al. 2017

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Prenatal exposure to lipopolysaccharide (LPS), which likely occurs due to infection or contact with environmental allergens during pregnancy, is a proposed risk factor that induces anxiety- and autism spectrum disorder-like behaviors in offspring. However, the molecular and behavioral changes in offspring after maternal immune activation have not been completely identified. We hypothesized that a subcutaneous injection of LPS in a pregnant mouse would induce changes in cerebral serotonin (5-HT) in parallel to the appearance of anxiety-like behaviors in the dam’s offspring. After LPS injections (total, 100 μg/Kg), the time spent in the central region during the open field test and the number of times that the mice moved between the light and dark boxes and between the open and closed arms on the elevated plus maze test revealed anxiety-like behaviors in offspring at 5, 6 and 9 weeks of age. The mRNA expression levels of tph2 (5-HT synthesizing enzyme) and slc6a4 (5-HT transporter) were down-regulated in both adolescent (5 weeks of age) and adult (8 weeks of age) brains. Immunohistochemistry revealed that the numbers and sizes of tph2-expressing cells were notably decreased in the raphe nuclei of the midbrain of adults. Moreover, compared with controls (phosphate-buffered saline-treated offspring), the cerebral 5-HT concentration at adolescence and adulthood in LPS-induced offspring was significantly decreased. We concluded that maternal immune activation induced by exposure to a low dose of LPS decreased cerebral 5-HT levels in parallel to the down-regulation of the tph2 and slc6a4 genes and in conjunction with anxiety-like behaviors in offspring.

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“…I.p. administration of LPS to mice has been reported to enhance the peripheral and cerebral expression of cytokines and to elicit behavioral reactions in a sex-dependent manner [45,46]. Specifically, the enhancement of the circulating levels of IL-1β is more pronounced in adult female than in male mice, whereas the expression of IL-1β in the prefrontal cortex is more pronounced in male than in female mice [46].…”

Section: Discussionmentioning

confidence: 99%

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

et al. 2019

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Neuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is unknown whether IN NPY could prevent the behavioral, proinflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral sickness response (reduced locomotion and exploration) and the underlying molecular mechanisms, 3 h and 21 h after intraperitoneal injections of LPS (0.03 mg/kg) in male C57BL/6N mice. The acute behavioral sickness response was significantly dampened by pretreatment with IN NPY 3 h after LPS injection. This effect was accompanied by diminished weight loss and lowered plasma corticosterone (CORT) levels 21 h after LPS injection. In contrast, acute circulating cytokine levels and hypothalamic cytokine mRNA expression remained unaltered by IN NPY, which indicates that the peripheral and cerebral immune response to LPS was left undisturbed. Our findings are in agreement with the reported activity of NPY to dampen the response of the HPA axis to stress. We propose that IN NPYablates sickness behavior at a site beyond the peripheral and cerebral cytokine response, an action that is associated with reduced activity of the HPA axis as determined by decreased plasma CORT. These results indicate that IN NPY administration may be relevant to the management of neuropsychiatric disorders arising from immune-induced neuroendocrine dysfunction.

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Lipopolysaccharide administration induces sex-dependent behavioural and serotonergic neurochemical signatures in mice

Cited by 34 publications

References 53 publications

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

Expression of cerebral serotonin related to anxiety-like behaviors in C57BL/6 offspring induced by repeated subcutaneous prenatal exposure to low-dose lipopolysaccharide

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

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