Anatomy and Neuroscience - Journal Articles

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Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala
(BioMed Central Ltd., 2017) O'Loughlin, Elaine; Pakan, Janelle M. P.; Yilmazer-Hanke, Deniz; McDermott, Kieran W.; Health Research Board
Background: Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders such as autism and schizophrenia, as well as seizure development. The amygdala is a brain region involved in the regulation of emotions, and amygdalar maldevelopment due to infection-induced MIA may lead to amygdala-related disorders. MIA priming of glial cells during development has been linked to abnormalities seen in later life; however, little is known about its effects on amygdalar biochemical and cytoarchitecture integrity. Methods: Time-mated C57BL6J mice were administered a single intraperitoneal injection of 50 mu g/kg lipopolysaccharide (LPS) on embryonic day 12 (E12), and the effects of MIA were examined at prenatal, neonatal, and postnatal developmental stages using immunohistochemistry, real-time quantitative PCR, and stereological quantification of cytoarchitecture changes. Results: Fetal brain expression of pro-inflammatory cytokines (IL-1 beta, TNF alpha, and IL-6) was significantly upregulated at 4 h postinjection (E12) and remained elevated until the day of birth (P0). In offspring from LPS-treated dams, amygdalar expression of pro-inflammatory cytokines was also increased on day 7 (P7) and expression was sustained on day 40 (P40). Toll-like receptor (TLR-2, TLR-4) expression was also upregulated in fetal brains and in the postnatal amygdala in LPS-injected animals. Morphological examination of cells expressing ionized calcium-binding adaptor molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) suggested long-term microglial activation and astrogliosis in postnatal amygdalar regions. Conclusions: Our results showed that LPS-induced MIA at E12 induces a pro-inflammatory cytokine profile in the developing fetal brain that continues up to early adulthood in the amygdala. Inflammation elicited by MIA may activate cells in the fetal brain and lead to alterations in glial (microglia and astrocyte) cells observed in the postnatal amygdala. Moreover, increased pro-inflammatory cytokines and their effects on glial subpopulations may in turn have deleterious consequences for neuronal viability. These MIA-induced changes may predispose offspring to amygdala-related disorders such as heightened anxiety and depression and also neurodevelopmental disorders, such as autism spectrum disorders.
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.
Anti-TLR2 antibody triggers oxidative phosphorylation in microglia and increases phagocytosis of β-amyloid
(BioMed Central Ltd., 2018-08-31) Rubio-Araiz, Ana; Finucane, Orla M.; Keogh, Samuel; Lynch, Marina A.; Science Foundation Ireland
Microglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to the accumulation of amyloid-β (Aβ) in Alzheimer’s disease (AD). Therefore, improving phagocytosis should be beneficial in limiting the amyloidosis that characterises AD.
The antimicrobial capacity of embalming solutions: a comparative study
(John Wiley & Sons, Inc., 2018-12-29) Balta, Joy Y.; Cryan, John F.; O'Mahony, Siobhain M.
Aims: Infectious health risks are associated with handling human cadavers and to decrease such risks, cadavers are embalmed using different chemicals. The aim of this study is to quantify the amount of microorganisms present in different regions of human cadavers before embalming, after embalming and over a period of eight months. Methods and Results: Human cadavers were embalmed using Thiel, formalin, Genelyn and the Imperial College London soft-preservation (ICL-SP) solution with two cadavers per technique. Sterile swabs were used to collect samples from different regions. Samples were collected every two months. All cadavers had a high number of microbial colonies before embalming. While no colonies were detected on formalin and Genelyn embalmed cadavers post embalming, the number of colonies decreased significantly in Thiel embalmed cadavers and nearly stayed the same in ICL-SP embalmed cadavers. Conclusions: Formalin embalmed cadavers showed the strongest disinfecting abilities followed by Thiel embalmed cadavers, then Genelyn embalmed cadavers and finally by ICL-SP cadavers. Significance and Impact of Study: This study highlights how under researched this area is and the evident variation in the antimicrobial abilities of different embalming solutions on the cadaver as a whole and within different regions of the same cadaver.
Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate
(Wiley, 2018-01-10) Donovan, Maria D.; Abduljalil, Khaled; Cryan, John F.; Boylan, Geraldine B.; Griffin, Brendan T.; Irish Research Council for Science, Engineering and Technology; Health Research Board; Science Foundation Ireland; Seventh Framework Programme
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
Aroma compound diacetyl suppresses glucagon-like peptide-1 production and secretion in STC-1 cells
(Elsevier, 2017-01-21) McCarthy, Triona; Bruen, Christine; O'Halloran, Fiona; Schellekens, Harriët; Kilcawley, Kieran N.; Cryan, John F.; Giblin, Linda; Teagasc; Enterprise Ireland
Diacetyl is a volatile flavour compound that has a characteristic buttery aroma and is widely used in the flavour industry. The aroma of a food plays an important role in food palatability and thus intake. This study investigates the effect of diacetyl on the satiety hormone, glucagon-like peptide (GLP-1), using the enteroendocrine cell line, STC-1. Diacetyl decreased proglucagon mRNA and total GLP-1 from glucose stimulated STC-1 cells. This dampening effect on GLP-1 appears to be mediated by increasing intracellular cAMP levels, increasing synthesis of the G protein coupled receptor, GPR120, and its recruitment to the cell surface. Voltage gated Ca2+ channels, K+ATP channels and the α-gustducin taste pathway do not appear to be involved. These findings demonstrate that components contributing to food palatability suppress GLP-1. This ability of diacetyl to reduce satiety signals may contribute to overconsumption of some palatable foods.
Assessing radiological images of human cadavers: Is there an effect of different embalming solutions?
(Elsevier Ltd., 2017-10-12) Twomey, Maria; Balta, Joy Y.; Moloney, Fiachra; O'Connor, Owen J.; Murphy, Kevin P.; Cronin, Michael; Cryan, John F.; Maher, Michael M.; O'Mahony, Siobhain M.
The aim of this study is to investigate the impact of different embalming solutions including formalin, Genelyn, Thiel and Imperial College London- Soft Preserving solutions on the quality of radiological images taken from cadavers embalmed with the above mentioned techniques. Two cadavers per embalming technique were imaged pre and post-embalming using three different imaging modalities including ultrasound, plain radiography and computed tomography (CT). Imaging criteria and a qualitative grading system for each imaging modality were adapted from the European Guidelines on Quality Criteria for Computed Tomography, the European Guidelines on Quality Criteria for Diagnostic Radiographic Images, and according to the AIUM Practice Guideline for the performance of ultrasound. Qualitative analysis was performed independently by three readers on a Picture Archiving and Communication System (PACS). The readers were blinded to both the embalmment status and the embalming agent used to preclude bias. On comparison of images pre and post-embalming, brain CT images showed a significant deterioration in image quality post-embalming, while there was no significant change in chest and abdomen/pelvic images and some improvement was observed in Genelyn embalmed cadavers. No changes were observed when using ultrasound to image the spleen and aorta, while a significant improvement in image quality was observed when examining the kidney in all embalmed cadavers with a small improvement when imaging the liver. No significant difference was observed on plain radiography post-embalming, while a minor deterioration was observed mainly in the chest area. Different embalming techniques had varying effects on image quality, in human cadavers, with the range of imaging modalities investigated in this study. Thus, no ideal embalming solution was identified, which would improve the quality of images on all imaging modalities. Further research is required to compare the quality of radiological images at different stages of decomposition taking into consideration antemortal pathologies with a larger number of donors.
The association between caesarean section and cognitive ability in childhood
(Springer, 2019-10-22) Hanrahan, Michael; McCarthy, Fergus P.; O'Keeffe, Gerard W.; Khashan, Ali S.
Purpose: Global rates of caesarean section (CS) rates have increased rapidly in recent years. This is a growing public health concern as it has been proposed that CS may impact cognitive outcomes in childhood. However, the evidence for this association is limited and inconsistent. Therefore, the aim of this study was to investigate the relationship between obstetric mode of delivery and longitudinal cognitive outcomes in childhood. Methods: We examined this question using data from a longitudinal cohort study of 8845 participants from the Millennium Cohort Study, a nationally representative UK cohort, who completed a range of verbal and visual-spatial cognitive assessments at ages 3, 5, 7 and 11 years. Results: We found a statistically significant association between planned CS and visual-spatial cognitive delay in the pattern construction assessment at age 5 (OR 1.31, 95% CI 0.99–1.72) and age 7 (OR 1.42, 95% CI 1.12–1.81). Additionally planned CS was also associated with increased odds of “early childhood delay” (OR 1.70, 95% CI 1.15–2.50) and borderline increased odds of “persistent delay” (OR 1.37, 95% CI 0.99–1.89) in visual-spatial cognitive tests. Mode of delivery was not associated with verbal ability or with patterns of delay at any age point in verbal cognitive tests. Conclusion: We have reported a small association between planned CS and visual-spatial cognitive delay in childhood. However, while this result should be interpreted with caution, it highlights the need to further explore this potential relationship and the causal basis of such an association.
Association between preeclampsia and attention deficit hyperactivity disorder: a population-based and sibling-matched cohort study
(Wiley, 2020-02-13) Maher, Gillian M.; Dalman, Christina; O'Keeffe, Gerard W.; Kearney, Patricia M.; McCarthy, Fergus P.; Kenny, Louise C.; Khashan, Ali S.; Health Research Board
Objective: Examine the association between preeclampsia and attention deficit hyperactivity disorder (ADHD), using a large Swedish‐based registry cohort. Methods: This study comprised 2,047,619 children, with 114,934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: 1. Preeclampsia (using ICD‐9/ICD‐10) 2.Preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: 1. If a diagnosis of ADHD was present in the National Patient Register or 2.If an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling‐matched analysis further controlled for shared genetic and familial confounding. Results: In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling‐matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88). Conclusions: Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling‐matched analysis can only adjust for factors that are constant between pregnancies, therefore residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most‐at‐risk babies following delivery.
Association between preeclampsia and autism spectrum disorder: a population-based study
(John Wiley & Sons Ltd., 2019-09-17) Maher, Gillian M.; O'Keeffe, Gerard W.; Dalman, Christina; Kearney, Patricia M.; McCarthy, Fergus P.; Kenny, Louise C.; Khashan, Ali S.; Health Research Board; Science Foundation Ireland
Background: The environmental contribution of autism spectrum disorder (ASD) is approximately 17%–50%, highlighting the importance of investigating factors potentially contributing to the likelihood of its development, and of gaining a greater understanding of the pathogenesis surrounding ASD. The objective of this study was to examine the association between preeclampsia and ASD using a population‐based cohort study. Methods: All singleton live births in Sweden from 1982 to 2010 were included, using data from Swedish National Registers. Exposures of interest included: (a) preeclampsia (classified according to ICD‐8, ICD‐9 and ICD‐10) and (b) preeclampsia and small for gestational age (SGA) combined, used as a proxy for preeclampsia with placental dysfunction. ASD status was based on ICD‐9 and ICD‐10. The cohort consisted of 2,842,230 children, with 54,071 cases of ASD. Follow‐up began from the child's first birthday, and data were censored at first diagnosis of ASD, death, migration or end of study period (31st December 2016). We conducted multivariate Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors, selected a priori. We further controlled for shared genetic and familial confounding using sibling‐matched analysis. Results: In the adjusted Cox proportional hazards regression analysis, preeclampsia was associated with a 25% increase in the likelihood of ASD (Hazard Ratio (HR): 1.25, 95% CI:1.19, 1.30) compared with those unexposed to preeclampsia, while in the sibling‐matched analysis the HR was 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling‐matched analysis. Conclusions: Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ASD. The stronger association with preeclampsia/SGA than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD.
The association between preeclampsia and childhood development and behavioural outcomes
(Springer Nature Switzerland AG, 2020-04-11) Maher, Gillian M.; O'Keeffe, Gerard W.; O'Keeffe, Linda M.; Matvienko-Sikar, Karen; Dalman, Christina; Kearney, Patricia M.; McCarthy, Fergus P.; Khashan, Ali S.; Health Research Board
Objectives: To examine the associations between preeclampsia and longitudinal child developmental and behavioural outcomes using data from a nationally representative study of children living in Ireland. Methods: We used maternal-reported data from the Growing Up in Ireland longitudinal study of children. Data on preeclampsia and preeclampsia + small for gestational age (SGA) were collected when children were 9-months old. Data on child development and behavioural outcomes were collected at 9-months using the Ages and Stages Questionnaire (ASQ), and at 3 years, 5 years and 7–8 years using the Strengths and Difficulties Questionnaire (SDQ). Multivariate logistic regression analysis was used to examine the association between preeclampsia exposure and failure of ASQ domains, and abnormal SDQ domains. Linear spline multilevel models were used to examine the association between preeclampsia and preeclampsia + SGA and repeated measures of SDQ. All models controlled for several perinatal and sociodemographic factors. Results: A total of 10,692 children were included in the study at baseline, representing a weighted total of 70,791. Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of emotional (≥ 5) and hyperactivity (≥ 7) domains at age 5 years only. In the linear spline model, mean SDQ score was higher at each time point in exposed groups. Conclusions for Practice: While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall, some associations between preeclampsia-exposure and subtle behavioural issues did persist. Further research is needed to replicate these findings, and determine the clinical significance of changes in SDQ scores.
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.

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