Psychiatry - Journal Articles

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    Age-associated deficits in social behaviour are microbiota-dependent
    (Elsevier, 2023) Cruz-Pereira, Joana S.; Moloney, Gerard M.; Bastiaanssen, Thomaz F. S.; Boscaini, Serena; Fitzgerald, Patrick; Clarke, Gerard; Cryan, John F.; Science Foundation Ireland; Saks-Kavanaugh Foundation; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
    Aging is associated with remodelling of immune and central nervous system responses resulting in behavioural impairments including social deficits. Growing evidence suggests that the gut microbiome is also impacted by aging, and we propose that strategies to reshape the aged gut microbiome may ameliorate some age-related effects on host physiology. Thus, we assessed the impact of gut microbiota depletion, using an antibiotic cocktail, on aging and its impact on social behavior and the immune system. Indeed, microbiota depletion in aged mice eliminated the age-dependent deficits in social recognition. We further demonstrate that although age and gut microbiota depletion differently shape the peripheral immune response, aging induces an accumulation of T cells in the choroid plexus, that is partially blunted following microbiota depletion. Moreover, an untargeted metabolomic analysis revealed age-dependent alterations of cecal metabolites that are reshaped by gut microbiota depletion. Together, our results suggest that the aged gut microbiota can be specifically targeted to affect social deficits. These studies propel the need for future investigations of other non-antibiotic microbiota targeted interventions on age-related social deficits both in animal models and humans.
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    Stress during puberty exerts sex-specific effects on depressive-like behavior and monoamine neurotransmitters in adolescence and adulthood
    (Elsevier Inc., 2022-10-07) Harris, Erin P.; Villalobos-Manriquez, Francisca; Melo, Thieza G.; Clarke, Gerard; O'Leary, Olivia F.; Health Research Board; Science Foundation Ireland
    Psychiatric disorders including major depression are twice as prevalent in women compared to men. This sex difference in prevalence only emerges after the onset of puberty, suggesting that puberty may be a sensitive period during which sex-associated vulnerability to stress-related depression might become established. Thus, this study investigated whether stress occurring specifically during the pubertal window of adolescence may be responsible for this sex difference in depression vulnerability. Male and female rats were exposed to a three-day stress protocol during puberty (postnatal days 35–37 in females, 45–47 in males) and underwent behavioral tests in adolescence or adulthood measuring anhedonia, anxiety-like behavior, locomotor activity and antidepressant-like behavior. Brainstem and striatum tissue were collected from a separate cohort of behavioral test-naïve rats in adolescence or adulthood to quantify the effect of pubertal stress on monoamine neurotransmitters. Pubertal stress increased immobility behavior in the forced swim test in both sexes in adolescence and adulthood. In adolescence, pubertal stress altered escape-oriented behaviors in a sex-specific manner: decreasing climbing in males but not females and decreasing swimming in females but not males. Pubertal stress decreased adolescent brainstem noradrenaline specifically in females and had opposing effects in adolescent males and females on brainstem serotonin turnover. Pubertal stress induced anhedonia in the saccharin preference test in adult males but not females, an effect paralleled by a male-specific decrease in striatal dopamine turnover. Pubertal stress did not significantly impact anxiety-like behavior or locomotor activity in any sex at either age. Taken together, these data suggest that although pubertal stress did not preferentially increase female vulnerability to depressive-like behaviors compared to males, stress during puberty exerts sex-specific effects on depressive-like behavior and anhedonia, possibly through discrete neurotransmitter systems.
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    The development and validation of a dashboard prototype for real-time suicide mortality data
    (Frontiers Media S.A., 2022-08) Benson, Ruth; Brunsdon, C.; Rigby, J.; Corcoran, P.; Ryan, M.; Cassidy, E.; Dodd, P.; Hennebry, D.; Arensman, Ella; Health Research Board
    Data visualisation is key to informing data-driven decision-making, yet this is an underexplored area of suicide surveillance. By way of enhancing a real-time suicide surveillance system model, an interactive dashboard prototype has been developed to facilitate emerging cluster detection, risk profiling and trend observation, as well as to establish a formal data sharing connection with key stakeholders via an intuitive interface. Individual-level demographic and circumstantial data on cases of confirmed suicide and open verdicts meeting the criteria for suicide in County Cork 2008-2017 were analysed to validate the model. The retrospective and prospective space-time scan statistics based on a discrete Poisson model were employed via the R software environment using the "rsatscan" and "shiny" packages to conduct the space-time cluster analysis and deliver the mapping and graphic components encompassing the dashboard interface. Using the best-fit parameters, the retrospective scan statistic returned several emerging non-significant clusters detected during the 10-year period, while the prospective approach demonstrated the predictive ability of the model. The outputs of the investigations are visually displayed using a geographical map of the identified clusters and a timeline of cluster occurrence. The challenges of designing and implementing visualizations for suspected suicide data are presented through a discussion of the development of the dashboard prototype and the potential it holds for supporting real-time decision-making. The results demonstrate that integration of a cluster detection approach involving geo-visualisation techniques, space-time scan statistics and predictive modelling would facilitate prospective early detection of emerging clusters, at-risk populations, and locations of concern. The prototype demonstrates real-world applicability as a proactive monitoring tool for timely action in suicide prevention by facilitating informed planning and preparedness to respond to emerging suicide clusters and other concerning trends.
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    Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex
    (Elsevier, 2021-02) Chruścicka, Barbara; Cowan, Caitlin S. M.; Wallace Fitzsimons, Shauna E.; Borroto-Escuela, Dasiel O.; Druelle, Clémentine; Stamou, Panagiota; Bergmann, Cristian A.; Dinan, Timothy G.; Slattery, David A.; Fuxe, Kjell; Cryan, John F.; Schellekens, Harriët; Science Foundation Ireland; Narodowym Centrum Nauki; Medicinska Forskningsrådet; Hjärnfonden
    The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2C in vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated G alpha q-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality.This article is part of the special issue on Neuropeptides.
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    Bifidobacterium longum counters the effects of obesity: partial successful translation from rodent to human
    (Elsevier B.V., 2021-01) Schellekens, Harriët; Torres-Fuentes, Cristina; van de Wouw, Marcel; Long-Smith, Caitriona M.; Mitchell, Avery; Strain, Conall R.; Berding, Kirsten; Bastiaanssen, Thomaz F. S.; Rea, Kieran; Golubeva, Anna V.; Arboleya, Silvia; Verpaalen, Mathieu; Pusceddu, Matteo M.; Murphy, Amy; Fouhy, Fiona; Murphy, Kiera; Ross, R. Paul; Roy, Bernard L.; Stanton, Catherine; Dinan, Timothy G.; Cryan, John F.; Science Foundation Ireland
    The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes. B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention. B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]). This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity. This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.