Psychiatry

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Acute stress increases monocyte levels and modulates receptor expression in healthy females
(Elsevier, 2021-05) van de Wouw, Marcel; Sichetti, Marzia; Long-Smith, Caitriona M.; Ritz, Nathaniel L.; Moloney, Gerard M.; Cusack, Anne-Marie; Berding, Kirsten; Dinan, Timothy G.; Cryan, John F.; Seventh Framework Programme; Science Foundation Ireland
There has been a growing recognition of the involvement of the immune system in stress-related disorders. Acute stress leads to the activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells, such as monocytes. Even though acute stress/monocyte interactions have been wellcharacterized in mice, this is not the case for humans. As such, this study aimed to investigate whether acute stress modulates blood monocyte levels in a subtype-dependent manner and whether the receptor expression of stress-related receptors is affected in humans. Blood was collected from healthy female volunteers at baseline and 1 h after the socially evaluated cold pressor test, after which blood monocyte levels and receptor expression were assessed by flow cytometry. Our results reveal a stress-induced increase in blood monocyte levels, which was independent of monocyte subtypes. Furthermore, colony stimulating factor 1 receptor (CSF-1R) and CD29 receptor expression was increased, while CD62L showed a trend towards increased expression. These results provide novel insights into how acute stress affects the innate immune system.
Adult microbiota-deficient mice have distinct dendritic morphological changes: Differential effects in the amygdala and hippocampus
(Wiley, 2016-10-31) Luczynski, Pauline; Whelan, Seán O.; O'Sullivan, Colette; Clarke, Gerard; Shanahan, Fergus; Dinan, Timothy G.; Cryan, John F.; Science Foundation Ireland; Health Research Board; European Commission; GlaxoSmithKline; Pfizer; Wyeth; Mead Johnson Nutrition; National Alliance for Research on Schizophrenia and Depression; Brain and Behavior Research Foundation; Irish Government's National Development Plan
Increasing evidence implicates the microbiota in the regulation of brain and behaviour. Germ‐free mice (GF; microbiota deficient from birth) exhibit altered stress hormone signalling and anxiety‐like behaviours as well as deficits in social cognition. Although the mechanisms underlying the ability of the gut microbiota to influence stress responsivity and behaviour remain unknown, many lines of evidence point to the amygdala and hippocampus as likely targets. Thus, the aim of this study was to determine if the volume and dendritic morphology of the amygdala and hippocampus differ in GF versus conventionally colonized (CC) mice. Volumetric estimates revealed significant amygdalar and hippocampal expansion in GF compared to CC mice. We also studied the effect of GF status on the level of single neurons in the basolateral amygdala (BLA) and ventral hippocampus. In the BLA, the aspiny interneurons and pyramidal neurons of GF mice exhibited dendritic hypertrophy. The BLA pyramidal neurons of GF mice had more thin, stubby and mushroom spines. In contrast, the ventral hippocampal pyramidal neurons of GF mice were shorter, less branched and had less stubby and mushroom spines. When compared to controls, dentate granule cells of GF mice were less branched but did not differ in spine density. These findings suggest that the microbiota is required for the normal gross morphology and ultrastructure of the amygdala and hippocampus and that this neural remodelling may contribute to the maladaptive stress responsivity and behavioural profile observed in GF mice.
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.
Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development
(Wiley, 2019-11-26) Cowan, Caitlin S. M.; Dinan, Timothy G.; Cryan, John F.; Science Foundation Ireland; Horizon 2020
The gut microbiota is a vast, complex, and fascinating ecosystem of microorganisms that resides in the human gastrointestinal tract. As an integral part of the microbiota–gut–brain axis, it is now being recognized that the microbiota is a modulator of brain and behavior, across species. Intriguingly, periods of change in the microbiota coincide with the development of other body systems and particularly the brain. We hypothesize that these times of parallel development are biologically relevant, corresponding to ‘sensitive periods’ or ‘critical windows’ in the development of the microbiota–gut–brain axis. Specifically, signals from the microbiota during these periods are hypothesized to be crucial for establishing appropriate communication along the axis throughout the life span. In other words, the microbiota is hypothesized to act like an expected input to calibrate the development of the microbiota–gut–brain axis. The absence or disruption of the microbiota during specific developmental windows would therefore be expected to have a disproportionate effect on specific functions or potentially for regulation of the system as a whole. Evidence for microbial modulation of neurocognitive development and neurodevelopmental risk is discussed in light of this hypothesis, finishing with a focus on the challenges that lay ahead for the future study of the microbiota–gut–brain axis during development.
Association between psychological distress and cancer type in patients referred to a psycho-oncology service
(Irish Medical Organisation, 2017-06) Lavelle, C.; Ismail, Muhammad Fahmi; Doherty, Kieran; Bowler, A.; Mohamad, M. M.; Cassidy, Eugene M.
Psychological distress is common in patients with cancer and psychological well-being is increasingly seen as an important component of cancer care. The aim of this study was to examine the relationship between cancer type and subjective distress. The following data were collected from a database of consecutive psycho-oncology referrals to the Liaison Psychiatry service in Cork University Hospital from 2006 to 2015: demographics, cancer diagnosis, Distress Thermometer (DT) score. 2102 out of 2384 referrals were assessed. Of those assessed, the most common cancer diagnoses were breast (23%, n=486) followed by haematological (21%, n=445). There were significant difference in DT score between the different cancer types, (χ2(13)=33.685, p=0.001, Kruskal–Wallis test). When adjusted for age, gender and whether or not the cancer was recently diagnosed, there was no significant association between cancer type and psychological distress. In conclusion, cancer type is not associated with level of distress in cancer.
Attenuation of oxytocin and serotonin 2A receptor signaling through novel heteroreceptor formation
(American Chemical Society, ACS, 2019-04-30) Chruścicka, Barbara; Wallace Fitzsimons, Shauna E.; Borroto-Escuela, Dasiel O.; Druelle, Clémentine; Stamou, Panagiota; Nally, Kenneth; Dinan, Timothy G.; Cryan, John F.; Fuxe, Kjell; Schellekens, Harriët; Science Foundation Ireland; Medicinska Forskningsrådet; Hjärnfonden; Karolinska Institutet
The oxytocin receptor (OTR) and the 5-hydroxytryptamine 2A receptor (5-HTR2A) are expressed in similar brain regions modulating central pathways critical for social and cognition-related behaviors. Signaling crosstalk between their endogenous ligands, oxytocin (OT) and serotonin (5-hydroxytryptamine, 5-HT), highlights the complex interplay between these two neurotransmitter systems and may be indicative of the formation of heteroreceptor complexes with subsequent downstream signaling changes. In this study, we assess the possible formation of OTR-5HTR2A heteromers in living cells and the functional downstream consequences of this receptor–receptor interaction. First, we demonstrated the existence of a physical interaction between the OTR and 5-HTR2Ain vitro, using a flow cytometry-based FRET approach and confocal microscopy. Furthermore, we investigated the formation of this specific heteroreceptor complex ex vivo in the brain sections using the Proximity Ligation Assay (PLA). The OTR-5HTR2A heteroreceptor complexes were identified in limbic regions (including hippocampus, cingulate cortex, and nucleus accumbens), key regions associated with cognition and social-related behaviors. Next, functional cellular-based assays to assess the OTR-5HTR2A downstream signaling crosstalk showed a reduction in potency and efficacy of OT and OTR synthetic agonists, carbetocin and WAY267464, on OTR-mediated Gαq signaling. Similarly, the activation of 5-HTR2A by the endogenous agonist, 5-HT, also revealed attenuation in Gαq-mediated signaling. Finally, altered receptor trafficking within the cell was demonstrated, indicative of cotrafficking of the OTR/5-HTR2A pair. Overall, these results constitute a novel mechanism of specific interaction between the OT and 5-HT neurotransmitters via OTR-5HTR2A heteroreceptor formation and provide potential new therapeutic strategies in the treatment of social and cognition-related diseases.
Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat
(Elsevier Ltd., 2016-10-11) Hoban, Alan E.; Moloney, Rachel D.; Golubeva, Anna V.; McVey Neufeld, Karen A.; O'Sullivan, Orla; Patterson, Elaine; Stanton, Catherine; Dinan, Timothy G.; Clarke, Gerard; Cryan, John F.; Science Foundation Ireland; Health Research Board; Department of Agriculture, Food and the Marine
Gut microbiota colonization is a key event for host physiology that occurs early in life. Disruption of this process leads to altered brain development which ultimately manifests as changes in brain function and behaviour in adulthood. Studies using germ-free mice highlight the extreme impact on brain health that results from life without commensal microbes, however the impact of microbiota disturbances occurring in adulthood is less studied. To this end, we depleted the gut microbiota of 10-week-old male Sprague Dawley rats via chronic antibiotic treatment. Following this marked, sustained depletion of the gut bacteria, we investigated behavioural and molecular hallmarks of gut-brain communication. Our results reveal that depletion of the gut microbiota during adulthood results in deficits in spatial memory as tested by Morris water maze, increased visceral sensitivity and a greater display of depressive-like behaviours in the forced swim test. In tandem with these clear behavioural alterations we found change in altered CNS serotonin concentration along with changes in the mRNA levels of corticotrophin releasing hormone receptor 1 and glucocorticoid receptor. Additionally, we found changes in the expression of BDNF, a hallmark of altered microbiota-gut-brain axis signaling. In summary, this model of antibiotic-induced depletion of the gut microbiota can be used for future studies interested in the impact of the gut microbiota on host health without the confounding developmental influence of early-life microbial alterations.
Bifidobacterium breve with a-linolenic acid alters the composition, distribution and transcription factor activity associated with metabolism and absorption of fat
(Elsevier, 2017-03-07) Patterson, Elaine; Wall, Rebecca; Lisai, Sara; Ross, R. Paul; Dinan, Timothy G.; Cryan, John F.; Fitzgerald, Gerald F.; Banni, Sebastiano; Quigley, Eamonn M.; Shanahan, Fergus; Stanton, Catherine; Science Foundation Ireland
This study focused on the mechanisms that fatty acid conjugating strains - Bifidobacterium breve NCIMB 702258 and Bifidobacterium breve DPC 6330 - influence lipid metabolism when ingested with α-linolenic acid (ALA) enriched diet. Four groups of BALB/c mice received ALA enriched diet (3% (w/w)) either alone or in combination with B. breve NCIMB 702258 or B. breve DPC 6330 (109 CFU/day) or unsupplemented control diet for six weeks. The overall n-3 PUFA score was increased in all groups receiving the ALA enriched diet. Hepatic peroxisomal beta oxidation increased following supplementation of the ALA enriched diet with B. breve (P < 0.05) and so the ability of the strains to produce c9t11 conjugated linoleic acid (CLA) was identified in adipose tissue. Furthermore, a strain specific effect of B. breve NCIMB 702258 was found on the endocannabinoid system (ECS). Liver triglycerides (TAG) were reduced following ALA supplementation, compared with unsupplemented controls (P < 0.01) while intervention with B. breve further reduced liver TAG (P < 0.01), compared with the ALA enriched control. These data indicate that the interactions of the gut microbiota with fatty acid metabolism directly affect host health by modulating n-3 PUFA score and the ECS.
Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers
(Nature Publishing Group, 2016-11-01) Allen, Andrew P.; Hutch, William; Borre, Yuliya E.; Kennedy, Paul J.; Temko, Andriy; Boylan, Geraldine B.; Murphy, Eileen F.; Cryan, John F.; Dinan, Timothy G.
The emerging concept of psychobiotics—live microorganisms with a potential mental health benefit—represents a novel approach for the management of stress-related conditions. The majority of studies have focused on animal models. Recent preclinical studies have identified the B. longum 1714 strain as a putative psychobiotic with an impact on stress-related behaviors, physiology and cognitive performance. Whether such preclinical effects could be translated to healthy human volunteers remains unknown. We tested whether psychobiotic consumption could affect the stress response, cognition and brain activity patterns. In a within-participants design, healthy volunteers (N=22) completed cognitive assessments, resting electroencephalography and were exposed to a socially evaluated cold pressor test at baseline, post-placebo and post-psychobiotic. Increases in cortisol output and subjective anxiety in response to the socially evaluated cold pressor test were attenuated. Furthermore, daily reported stress was reduced by psychobiotic consumption. We also observed subtle improvements in hippocampus-dependent visuospatial memory performance, as well as enhanced frontal midline electroencephalographic mobility following psychobiotic consumption. These subtle but clear benefits are in line with the predicted impact from preclinical screening platforms. Our results indicate that consumption of B. longum 1714 is associated with reduced stress and improved memory. Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects.
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.
A biological framework for emotional dysregulation in alcohol misuse: from gut to brain
(Springer Nature Ltd., 2020-12-07) Carbia, Carina; Lannoy, Séverine; Maurage, Pierre; López-Caneda, Eduardo; O'Riordan, Kenneth J.; Dinan, Timothy G.; Cryan, John F.; Horizon 2020; Belgian American Educational Foundation; Fonds De La Recherche Scientifique - FNRS; Fundação para a Ciência e a Tecnologia
Alcohol use disorder (AUD) has been associated with impairments in social and emotional cognition that play a crucial role in the development and maintenance of addiction. Repeated alcohol intoxications trigger inflammatory processes and sensitise the immune system. In addition, emerging data point to perturbations in the gut microbiome as a key regulator of the inflammatory cascade in AUD. Inflammation and social cognition are potent modulators of one another. At the same time, accumulating evidence implicates the gut microbiome in shaping emotional and social cognition, suggesting the possibility of a common underlying loop of crucial importance for addiction. Here we propose an integrative microbiome neuro-immuno-affective framework of how emotional dysregulation and alcohol-related microbiome dysbiosis could accelerate the cycle of addiction. We outline the overlapping effects of chronic alcohol use, inflammation and microbiome alterations on the fronto-limbic circuitry as a convergence hub for emotional dysregulation. We discuss the interdependent relationship of social cognition, immunity and the microbiome in relation to alcohol misuse- from binge drinking to addiction. In addition, we emphasise adolescence as a sensitive period for the confluence of alcohol harmful effects and emotional dysregulation in the developing gut-brain axis.
Challenges for people with intellectual disabilities in law enforcement interactions in Ireland; thematic analysis informed by 1537 person-years' experience.
(Elsevier, 2021-03-06) Gulati, Gautam; Cusack, Alan; Bogue, John; O'Connor, Anne; Murphy, Valerie; Whelan, Darius; Cullen, Walter; McGovern, Cliona; Kelly, Brendan D.; Fistein, Elizabeth; Kilcommins, Shane; Dunne, Colum P.
Background: People with intellectual disabilities (PWID) are over-represented in criminal justice systems globally. This over-representation reveals itself at once in the demographic make-up of prison populations, as well as those detained in police settings as suspects of crime. While it is well-established in international literature that individuals who find themselves in the latter scenario face particular challenges in negotiating the forensic formalities routinely followed by the police at the pre-trial stage of criminal proceedings on account of their impairments, the specific difficulties experienced by PWID as suspects within Ireland's criminal justice system has yet to be explained, or indeed, understood. In seeking to address this research lacuna, this paper yields an account of a qualitative study which was aimed at identifying the unique challenges which PWID face in their interactions with Law Enforcement Officials (LEOs) in Ireland. Aims: This study aimed to elicit perspectives across a range of disciplines with regard to barriers for PWID interacting with LEOs in Ireland, and sought viewpoints on the content of a proposed awareness programme. Methods: A survey using purposive sampling was used to elicit viewpoints from people from representative organisations for PWID, people working with voluntary organisations for PWID, healthcare professionals working with PWID and professionals from the criminal justice system (including members of An Garda Siochana, lawyers, members of the Irish judiciary and officials within the Airport Police). Data were anonymised at the point of collection. Qualitative thematic analysis was conducted to extract themes based on the data retrieved through the survey. Results: Ninety-five (n = 95) responses were received from individuals reporting a cumulative experience of 1537 person-years. Respondents identified themselves as members of one of three groups; people working in a voluntary or representative organisation for PWID (n = 42, 44.2%); people working in healthcare (n = 31, 32.6%); and people working in law enforcement (n = 22, 23.1%). Three themes were identified from the qualitative thematic analysis. The first theme, “Barriers to Communication”, identified challenges which PWID and LEO experience in their mutual interactions and communications with one another. The second theme, “Building Awareness and Skills”, identified elements of an ID awareness programme for LEOs. The third theme, “Institutional and System Change”, identified possible lines of innovation with respect to contemporary police practice and the availability of supports for both PWID and the LEOs who work with them. Originality/Value: This study represents the first dedicated qualitative inquiry conducted on a multidisciplinary level into the barriers which healthcare professionals, legal professionals and disability advocacy groups perceive to be faced by PWID in their interactions with LEOs in Ireland. Consequently, the findings from this study will act as a valuable template in the direction of informing the development of an ID awareness programme for LEOs in Ireland. In addition, these research findings are expected to usefully inform the development of national policy and protocols in areas related to health, disability and justice. In offering a rich evidence-base for future policy initiatives, the timing of this study is particularly significant. The recent ratification by Ireland of the UN Convention for the Rights of People with Disabilities (UNCRPD), together with the synchronous emergence of an evolving emphasis on human rights-based policing at a national level in Ireland, has meant that Irish policymakers have a unique opportunity to re-imagine the pre-trial formalities of Ireland's criminal process in order to demonstrate an increased sensitivity to the needs of PWID. Securing equal access to justice for such individuals, it is important to emphasise, is a legal requirement pursuant to Article 13 of the UNCRPD. To the extent therefore that this study yields unique insights into the barriers faced by PWID in their interactions with LEOs, the results of this study are potentially generalisable to other jurisdictions that have ratified the UNCRPD and are developing policy to accord with Article 13.
The changing face of Capacity legislation in Ireland: algorithms for clinicians
(Cambridge University Press, 2020-03-12) Murphy, Valerie E.; Gulati, Gautam; Whelan, Darius; Dunne, Colum P.; Kelly, Brendan D.
Capacity legislation in Ireland is evolving. The Assisted Decision-Making (Capacity) Act 2015 has been passed into law, but its main provisions are yet to be commenced. This paper compares the law and its practical implications currently and under the new legislation. Quick reference algorithms for frontline clinicians are proposed.
Choosing Healthy Eating for Infant Health (CHErIsH) study: protocol for a feasibility study
(BMJ Publishing Group, 2019-08-22) Matvienko-Sikar, Karen; Toomey, Elaine; Queally, Michelle; Flannery, Caragh; O'Neill, Kate; Dinan, Timothy G.; Doherty, Edel; Harrington, Janas M.; Hayes, Catherine; Heary, Caroline; Hennessy, Marita; Kelly, Colette; Mc Hugh, Sheena M.; McSharry, Jenny; Stanton, Catherine; Heffernan, Tony; Byrne, Molly; Kearney, Patricia M.; Health Research Board
Introduction: Childhood obesity is a public health challenge. There is evidence for associations between parents’ feeding behaviours and childhood obesity risk. Primary care provides a unique opportunity for delivery of infant feeding interventions for childhood obesity prevention. Implementation strategies are needed to support infant feeding intervention delivery. The Choosing Healthy Eating for Infant Health (CHErIsH) intervention is a complex infant feeding intervention delivered at infant vaccination visits, alongside a healthcare professional (HCP)-level implementation strategy to support delivery. Methods and analysis: This protocol provides a description of a non-randomised feasibility study of an infant feeding intervention and implementation strategy, with an embedded process evaluation and economic evaluation. Intervention participants will be parents of infants aged ≤6 weeks at recruitment, attending a participating HCP in a primary care practice. The intervention will be delivered at the infant’s 2, 4, 6, 12 and 13 month vaccination visits and involves brief verbal infant feeding messages and additional resources, including a leaflet, magnet, infant bib and sign-posting to an information website. The implementation strategy encompasses a local opinion leader, HCP training delivered prior to intervention delivery, electronic delivery prompts and additional resources, including a training manual, poster and support from the research team. An embedded mixed-methods process evaluation will examine the acceptability and feasibility of the intervention, the implementation strategy and study processes including data collection. Qualitative interviews will explore parent and HCP experiences and perspectives of delivery and receipt of the intervention and implementation strategy. Self-report surveys will examine fidelity of delivery and receipt, and acceptability, suitability and comprehensiveness of the intervention, implementation strategy and study processes. Data from electronic delivery prompts will also be collected to examine implementation of the intervention. A cost–outcome description will be conducted to measure costs of the intervention and the implementation strategy. Ethics and dissemination: This study received approval from the Clinical Research Ethics Committee of the Cork Teaching Hospitals. Study findings will be disseminated via peer-reviewed publications and conference presentations.
Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs
(Elsevier B.V., 2018-12-01) Lucking, Eric F.; O'Connor, Karen M.; Strain, Conall R.; Fouhy, Fiona; Bastiaanssen, Thomaz F. S.; Burns, David P.; Golubeva, Anna V.; Stanton, Catherine; Clarke, Gerard; Cryan, John F.; O'Halloran, Ken D.; University College Cork
Background Carotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia-insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity. Methods Adult male guinea-pigs were exposed to CIH (6.5% O2 at nadir, 6 cycles.hour−1) for 8 h.day−1 for 12 consecutive days. Findings CIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but β-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls. Interpretation Increased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota-gut-brainstem axis. The findings have relevance to human sleep-disordered breathing.
Complement genes contribute sex-biased vulnerability in diverse disorders
(Springer Nature Limited, 2020-05-11) Kamitaki, Nolan; Sekar, Aswin; Handsaker, Robert E.; de Rivera, Heather; Tooley, Katherine; Morris, David L.; Taylor, Kimberly E.; Whelan, Christopher W.; Tombleson, Philip; Olde Loohuis, Loes M.; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Boehnke, Michael; Kimberly, Robert P.; Kaufman, Kenneth M.; Harley, John B.; Langefeld, Carl D.; Seidman, Christine E.; Pato, Michele T.; Pato, Carlos N.; Ophoff, Roel A.; Graham, Robert R.; Criswell, Lindsey A.; Vyse, Timothy J.; McCarroll, Steven A.; Dinan, Timothy G.; National Human Genome Research Institute; National Institute of Mental Health; Stanley Center for Psychiatric Research, Broad Institute; National Institute for Health Research; NIHR Guy's and St Thomas' Biomedical Research Centre
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3,4,5,6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
Consultant psychiatrists's experience of the impact of the COVID19 pandemic on mental health services in Ireland
(Cambridge University Press, 2021-04-29) Kelleher, Eric; Geary, Eoin; Tawfik, Mary; Ní Mhuircheartaigh, Eimear; Gavin, Blánaid; Wall, Mary; Lyne, John; Doherty, Anne M.; McNicholas, Fiona
Objectives: The novel coronavirus 2019 (COVID-19) has spread worldwide threatening human health. To reduce transmission, a ‘lockdown’ was introduced in Ireland between March-May 2020. The aim of this study is to capture the experiences of Consultant Psychiatrists during lockdown and their perception of its impact on Mental Health Services. Methods: A questionnaire designed by the Royal College of Psychiatrists was adapted and circulated to Consultant members of the College of Psychiatrists following the easing of restrictions. The questionnaire assessed the perceived impact on referral rates, mental health act provision, availability of Information Technology (IT), consultant well-being and availability of Personal Protective Equipment (PPE). Thematic analysis was employed to analyse free-text sections. Results: Response rate was 32% (N=197/623). Consultants reported an initial decrease/significant decrease in referrals in the first month of lockdown (68%, N=95/140) followed by an increase/significant increase in the second month for both new (83%, N=100/137) and previously attending patients (65%, N=88/136). Social isolation and reduced face-to-face mental health supports were among the main reasons identified. The needs of children and older adults were highlighted. Most consultants (76%, N=98/129) felt their working day was affected and their well-being reduced (52%, N=61/119). The majority felt IT equipment availability was inadequate (67%, N=88/132). Main themes identified from free-text sections were service management, relationship between patients and healthcare service and effects on consultants’ lives. Conclusions: The COVID19 pandemic has placed increased pressure on service provision and consultant wellness. This further supports the longstanding need to increase mental health service investment in Ireland.
Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
(Nature Publishing Group, 2017) Marshall, Christian R.; Howrigan, Daniel P.; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wu, Wenting; Greer, Douglas S.; Antaki, Danny; Shetty, Aniket; Holmans, Peter A.; Pinto, Dalila; Gujral, Madhusudan; Brandler, William M.; Malhotra, Dheeraj; Wang, Zhouzhi; Fajarado, Karin V. Fuentes; Maile, Michelle S.; Ripke, Stephan; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amin, Farooq; Atkins, Joshua; Bacanu, Silviu A.; Belliveau, Richard A., Jr.; Bergen, Sarah E.; Ertalan, Marcelo; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Bulik-Sullivan, Brendan; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Cheng, Wei; Cloninger, C. Robert; Cohen, David; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E.; Dikeos, Dimitris; Dinan, Timothy G.; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farh, Kai-How; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedman, Joseph I.; Forstner, Andreas J.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodriguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Gratten, Jacob; de Haan, Lieuwe; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffinann, Per; Hofman, Andrea; Huang, Hailiang; Ikeda, Masashi; Joa, Inge; Kahler, Anna K.; Kahn, Rene S.; Kalaydjieva, Luba; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Kim, Yunjung; Knowles, James A.; Konte, Bettina; Laurent, Claudine; Lee, Phil; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Levy, Deborah L.; Liang, Kung-Yee; Lieberman, Jeffrey; Lonnqvist, Jouko; Loughland, Carmel M.; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Muller-Myhsok, Bertram; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; O'Neill, F. Anthony; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Perkins, Diana O.; Pers, Tune H.; Pietilainen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Savitz, Adam; Schall, Ulrich; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Silverman, Jeremy M.; Smoller, Jordan W.; Soderman, Erik; Spencer, Chris C. A.; Stahl, Eli A.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Thirumalai, Srinivas; Tooney, Paul A.; Veijola, Juha; Visscher, Peter M.; Waddington, John; Walsh, Dermot; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wormley, Brandon K.; Wray, Naomi R.; Wu, Jing Qin; Zai, Clement C.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H. R.; Bramon, Elvira; Buxbaum, Joseph D.; Cichon, Sven; Collier, David A.; Corvin, Aiden; Daly, Mark J.; Darvasi, Ariel; Domenici, Enrico; Esko, Tonu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jonsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Levinson, Douglas F.; Li, Qingqin S.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mowry, Bryan J.; Nothen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sklar, Pamela; St Clair, David; Walters, James T. R.; Werge, Thomas; Siillivan, Patrick F.; O'Donovan, Michael C.; Scherer, Stephen W.; Neale, Benjamin M.; Sebat, Jonathan
Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
Cross talk: the microbiota and neurodevelopmental disorders
(Frontiers Media, 2017) Kelly, John R.; Minuto, Chiara; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.; Brain and Behavior Research Foundation; Seventh Framework Programme; Health Research Board; Science Foundation Ireland
Humans evolved within a microbial ecosystem resulting in an interlinked physiology. The gut microbiota can signal to the brain via the immune system, the vagus nerve or other host-microbe interactions facilitated by gut hormones, regulation of tryptophan metabolism and microbial metabolites such as short chain fatty acids (SCFA), to influence brain development, function and behavior. Emerging evidence suggests that the gut microbiota may play a role in shaping cognitive networks encompassing emotional and social domains in neurodevelopmental disorders. Drawing upon pre-clinical and clinical evidence, we review the potential role of the gut microbiota in the origins and development of social and emotional domains related to Autism spectrum disorders (ASD) and schizophrenia. Small preliminary clinical studies have demonstrated gut microbiota alterations in both ASD and schizophrenia compared to healthy controls. However, we await the further development of mechanistic insights, together with large scale longitudinal clinical trials, that encompass a systems level dimensional approach, to investigate whether promising pre-clinical and initial clinical findings lead to clinical relevance.
Cutaneous glucocorticoid receptor sensitivity and proinflammatory cytokine levels in antidepressant-resistant depression
(Cambridge University Press, 2006-01) Fitzgerald, Peter; O'Brien, Sinead M.; Scully, Paul; Rijkers, Kim; Scott, Lucinda V.; Dinan, Timothy G.; Science Foundation Ireland; Health Research Board; Wellcome Trust, United Kingdom
ABSTRACT Background. There is evidence to indicate that peripheral glucocorticoid receptor (GR) function is reduced in major depression, and a possible molecular explanation for this is the impact of raised pro-inflammatory cytokines. The topical steroid vasoconstriction assay provides a convenient probe of peripheral GR function. The present study sought to assess the sensitivity of peripheral GRs in antidepressant-resistant major depressives and investigate the association between GR sensitivity and circulating plasma cytokines. Method. Nineteen antidepressant-resistant depressives together with age- and sex-matched healthy controls underwent the steroid vasoconstriction assay using three commercial preparations of corticosteroids containing clobetasol propionate 0.05%, betamethasone valerate 0.1%, and clobetasone butyrate 0.05%, corresponding to very potent, potent, and moderately potent steroid creams respectively. The pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assays. The severity of the depressive episode was assessed using the Hamilton Depression Scale (HAMD). Results. Depressed subjects had a significantly reduced vasoconstriction response across all three strengths of steroid. They also had significantly higher concentrations of TNF-a and IL-6. There was a significant inverse correlation between TNF-a concentration and vasoconstriction response and also between the HAMD score and vasoconstriction response. Conclusions. These findings suggest that cutaneous GR function is abnormal in antidepressantresistant depression, that circulating TNF-a may play a significant role in this abnormality and that the efficacy of topical steroids in antidepressant-resistant depressives is reduced.

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