J. Thomas Curtis

Does fertility trump monogamy

Monogamous animals face an interesting dilemma: if and when to terminate a nonproductive relationship. To address this issue, we asked whether reproductive compatibility is a criterion for maintaining a monogamous pair-bond between mates. Prairie voles (Microtus ochrogaster), are small rodents that form long-term, monogamous pair-bonds evidenced by a strong preference for their familiar partners, and thus are an excellent model animal in which to study mate-fidelity. Accordingly, we examined partner-preferences by male prairie voles and related their behavior to the reproductive status of their mates. We found that, when given a choice between their familiar female partner and a stranger, male prairie voles differ in their responses depending on the pregnancy status of the partner. Males that were paired with females for two weeks displayed mate-fidelity only when mating had been initiated within ~48 hours after pairing. In contrast, males whose mates experienced a delay in the onset of sexual receptivity displayed non-selective affiliative behavior. We also found that, in addition to being appropriately timed, mating must be successful. Males that mated with ovariectomized females for whom pregnancy was precluded did not display mate-fidelity even though mating was initiated within the proper timeframe. These observations of mate-fidelity only when the partners pregnancy was sufficiently advanced relative to the duration of the pairing suggest that mating must be both successful and timely. Thus, reproductive compatibility can influence mate-fidelity.

Chronic inorganic mercury exposure induces sex-specific changes in central TNFα expression: Importance in autism?

Mercury is neurotoxic and increasing evidence suggests that environmental exposure to mercury may contribute to neuropathologies including Alzheimers disease and autism spectrum disorders. Mercury is known to disrupt immunocompetence in the periphery, however, little is known about the effects of mercury on neuroimmune signaling. Mercury-induced effects on central immune function are potentially very important given that mercury exposure and neuroinflammation both are implicated in certain neuropathologies (i.e., autism). Furthermore, mounting evidence points to the involvement of glial activation in autism. Therefore, we utilized an in vivo model to assess the effects of mercury exposure on neuroimmune signaling. In prairie voles, 10 week mercury exposure (60ppm HgCl(2) in drinking water) resulted in a male-specific increase in TNFα protein expression in the cerebellum and hippocampus. These findings are consistent with our previously reported male-specific mercury-induced deficits in social behavior and further support a role for heavy metals exposure in neuropathologies such as autism. Subsequent studies should further evaluate the mechanism of action and biological consequences of heavy metals exposure. Additionally, these observations highlight the potential of neuroimmune markers in male voles as biomarkers of environmental mercury toxicity.

α-Synuclein potentiates interleukin-1β-induced CXCL10 expression in human A172 astrocytoma cells

Neuroinflammation and neuronal degeneration observed in Parkinsons disease (PD) has been attributed in part to glial-mediated events. Increased expression of proinflammatory cytokines and abnormal accumulation of the neuronal protein, α-synuclein in the brain are also characteristic of PD. While increasing evidence suggests that astrocytes contribute to neuroinflammation and dopaminergic neuronal degeneration associated with PD, there remains much to learn about these astroglial-mediated events. Therefore, we investigated the in vitro effects of interleukin-1β (IL-1β) and α-synuclein on astroglial expression of interferon-γ inducible protein-10 (CXCL10), a proinflammatory and neurotoxic chemokine. IL-1β-induced CXCL10 protein expression was potentiated by co-exposure to α-synuclein. α-Synuclein did not significantly affect IL-1β-induced CXCL10 mRNA expression, but did mediate increased CXCL10 mRNA stability, which may explain, in part, the increased levels of secreted CXCL10 protein. Future investigations are warranted to more fully define the mechanism by which α-synuclein enhances IL-1β-induced astroglial CXCL10 expression. These findings highlight the importance of α-synuclein in modulating inflammatory events in astroglia. These events may be particularly relevant to the pathology of CNS disorders involving α-synuclein accumulation, including PD and HIV-1 associated dementia.

The opioid antagonist, β-funaltrexamine, inhibits NF-κB signaling and chemokine expression in human astrocytes and in mice

Opioid-immune crosstalk occurs when opioid drugs alter the activity of the immune system. In this study, the opioid antagonist β-funaltrexamine (β-FNA) decreases the expression and release of an inflammatory chemokine, interferon-γ inducible protein-10 (CXCL10) from normal human astrocytes stimulated by interleukin 1β (IL-1β). β-FNA decreased CXCL10 by an unknown action that did not involve the mu opioid receptor (MOR). As IL-1β acts through its receptor to activate NF-κB/MAPK signaling pathways which leads to CXCL10 expression and release, key steps in the IL-1β signaling pathways were examined following β-FNA treatment. IL-1β-induced activation of p38 mitogen-activated protein kinases (p38 MAPK) was inhibited by β-FNA as shown by decreased p38 MAPK phosphorylation in treated cells. β-FNA also decreased the levels of activated subunits of NF-κB (p50 and p65) in treated astrocytes. The impact of β-FNA was also observed in proteins that act to negatively regulate NF-κB signaling. IL-1β upregulated the expression of A20, a ubiquitin (Ub)-editing enzyme that dampens NF-κB signaling by altering ubiquination patterns on IL-1 receptor second messengers, and the increase in A20 was significantly inhibited by β-FNA treatment. Inhibition of the Ub-activating enzyme E1 by the inhibitor PYR41 also decreased CXCL10 release, like β-FNA, and concurrent treatment with both PYR41 and β-FNA inhibited CXCL10 more than did either agent alone. In mice, lipopolysaccharide-induced CXCL10 expression in the brain was inhibited by treatment with β-FNA. These findings suggest that β-FNA exerts an anti-inflammatory action in vitro and in vivo that is MOR-independent and possibly due to the alkylating ability of β-FNA.

Lactobacilli with probiotic potential in the prairie vole (Microtus ochrogaster)

AbstractBackgroundRecent research suggests integration of the intestinal microbiota in gut-brain communication which could lead to new approaches to treat neurological disorders. The highly social prairie voles are an excellent model system to study the effects of environmental factors on social behavior. For future studies on the role of probiotics in ameliorating disorders with social withdrawal symptoms, we report the characterization of intestinal Lactobacillus isolates with probiotic potential from voles.Methods and results30 bacterial strains were isolated from the vole intestine and found to be distinct but closely related to Lactobacillus johnsonii using 16S rRNA gene sequencing and Random Amplification of Polymorphic DNA fingerprinting. In vitro characterizations including acid and bile tolerance, antimicrobial effects, antibiotic susceptibility, and adherence to intestinal epithelial cells were performed to assess the probiotic potential of selected strains. Since previous studies revealed that mercury ingestion triggers social deficits in voles, mercury resistance of the probiotic candidates was evaluated which could be an important factor in preventing/treating these behavioral changes.ConclusionsThis study demonstrates that lactobacilli with probiotic potential are present in the vole intestine. The Lactobacillus isolates identified in this study will provide a basis for the investigation of probiotic effects in the vole behavioral model system.

The opioid antagonist, β-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice

Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (β-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered β-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered β-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. β-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by β-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of β-FNA is warranted.

Regional differences in serotonin content in the nucleus of the solitary tract of male rats after hypovolemia produced by polyethylene glycol

Serotonin (5-HT) has been implicated in centrally mediated compensatory responses to volume loss in rats. Accordingly, we hypothesized that slowly developing, non-hypotensive hypovolemia increases serotonin in the hindbrain nucleus of the solitary tract (NTS). We produced volume loss in adult male rats by administering hyperoncotic polyethylene glycol (PEG) and then assessed 5-HT levels in the NTS using measurements of tissue 5-HT content or 5-HT immunohistochemistry. The results show selective increases of 5-HT in the caudal NTS after PEG treatment, but no change in the primary 5-HT metabolite, 5-HIAA. Moreover, the intensity of 5-HT immunolabeled fibers in the caudal NTS was increased after PEG treatment. These findings suggest that, after PEG-induced hypovolemia, 5-HT accumulates in neural elements in the caudal NTS. We propose that this accumulation is attributable to an initial release of 5-HT that then acts at presynaptic autoreceptors to inhibit subsequent 5-HT release.

Fecal microbiota in the female prairie vole (Microtus ochrogaster)

We examined the fecal microbiota of female prairie voles. This species is socially and, likely, sexually monogamous, and thus serves as a valuable model in which to examine the interaction between the microbiota-gut-brain axis and social behavior. At present, little is known about the gastrointestinal microbiota of prairie voles; therefore, we performed a first characterization of the fecal microbiota using 16S rRNA gene amplicon sequencing. Semiconductor sequencing technology on an Ion Torrent PGM platform was used to assess the composition of fecal microbiotas from twelve female prairie voles. Following quality filtering, 1,017,756 sequencing reads were classified from phylum to genus level. At the phylum level, Firmicutes, Bacteroidetes, and Saccharibacteria were the predominant taxa, while the Bacteriodales, Erysipelotrichaceae, Ruminococcaceae, and Lachnospiraceae contributed the most dominant microbial groups and genera. Microbial community membership was most similar between vole sibling pairs, but consideration of taxon abundances weakened these associations. The interdependence of host factors such as genetics and behavior with the gastrointestinal microbiota is likely to be particularly pronounced in prairie voles. Our pilot characterization of the prairie vole intestinal microbiota revealed a microbial community composition remarkably consistent with the monogastric alimentary system of these rodents and their diet rich in complex plant carbohydrates. The highly social nature of these animals poses specific challenges to microbiome analyses that nonetheless are valuable for advancing research on the microbiota-gut-brain-behavior axis. Our study provides an important basis for future microbiome research in this emerging model organism for studying social behavior.

Early developmental exposure to inorganic mercury does not alter affiliative behavior of adult prairie voles (Microtus ochrogaster Walker 1842)

Mercury chloride exposure through drinking water in adult male prairie voles (Microtus ochrogaster) has been shown to alter their social behavior. Here, we examined the potential disruption of adult social behavior in prairie voles that were exposed to 60 ppm mercury during early development. We used a cross-fostering approach to test the effects of mercury exposure: (1) from conception until birth; (ii) from birth until weaning; and (iii) from conception until weaning, on adult affiliative behavior. Untreated and mercury-treated voles were given the option of remaining in an empty cage or affiliating with a same-sex conspecific in a 3-h choice test. We found that early developmental mercury exposure had little if any effect on the reproductive success of breeder pairs or on affiliative behavior by either sex when subjects were tested as adults. These results suggest that, at least in the context of the behavior tested, the effects of early developmental exposure to mercury do not permanently alter adult prairie vole affiliative behavior, or do so in a way that is too subtle to be detected using the current testing paradigm.

Cardiovascular control is associated with pair-bond success in male prairie voles

Social support structures reduce mortality and morbidity in humans, but the mechanisms underlying these reductions are not fully understood. The prevailing hypothesis is that social support buffers stress and reduces allostatic load, thereby increasing longevity. However, the possibility that affiliative social interactions confer health benefits independent of stress buffering is understudied. We examined autonomic function in prairie voles - arguably the premier species for modeling human social affiliation - to assess the possibility that the formation of strong social bonds alters autonomic function and contributes to health benefits. We examined cardiovascular measures in male prairie voles before and after two weeks of cohabitation with a female, during a partner preference test, and during social isolation. There were strong correlations between social contact and heart rate (HR) and heart rate variability (HRV), the latter being an index of autonomic nervous system function. Males that successfully pair-bonded with their partners displayed higher HRV prior to pairing than did unsuccessful males, suggesting higher basal parasympathetic tone in the successful males. HRV increased further still when pair-bonded males huddled quietly with their mates during the partner preference test. Non-pair-bonded males not only had lower baseline parasympathetic activity, but showed a further decrease after pairing. HR increased and HRV decreased during social isolation only in pair-bonded males. Since differences in HRV are thought to reflect the relative influences of the parasympathetic and sympathetic nervous systems on cardiac function, these results suggest that autonomic balance may contribute to social bonding and thus to its health benefits.