Psychiatry

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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.
Schizophrenia patients with a history of childhood trauma have a pro-inflammatory phenotype
(Cambridge University Press, 2012) Dennison, Una; McKernan, Declan P.; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland; GlaxoSmithKline, United Kingdom
Background. Increasing evidence indicates that childhood trauma is a risk factor for schizophrenia and patients with this syndrome have a pro-inflammatory phenotype. We tested the hypothesis that the pro-inflammatory phenotype in schizophrenia is associated with childhood trauma and that patients without a history of such trauma have a similar immune profile to healthy controls. Method. We recruited 40 schizophrenia patients and 40 controls, all of whom completed the Childhood Trauma Questionnaire (CTQ). Using enzyme-linked immunosorbent assay (ELISA) techniques, we measured peripheral levels of interleukin (IL)-1b, IL-6, IL-8 and tumour necrosis factor (TNF)-a. These immune parameters were compared in schizophrenia with childhood trauma, schizophrenia without childhood trauma and healthy controls. Results. Patients with childhood trauma had higher levels of IL-6 and TNF-a than patients without trauma and healthy controls, and TNF-a levels correlated with the extent of the trauma. Patients with no trauma had similar immune profiles to controls. Conclusions. Childhood trauma drives changes, possibly epigenetic, that generate a pro-inflammatory phenotype.
Dynamic 5-HT2C receptor editing in a mouse model of obesity
(PLOS, 2012-03-20) Schellekens, Harriët; Clarke, Gerard; Jeffery, Ian B.; Dinan, Timothy G.; Cryan, John F.; Bartolomucci, Alessandro; Science Foundation Ireland; Enterprise Ireland; European Commission; American Neurogastroenterology and Motility Society
The central serotonergic signalling system has been shown to play an important role in appetite control and the regulation of food intake. Serotonin exerts its anorectic effects mainly through the 5-HT1B, 5-HT2C and 5-HT6 receptors and these are therefore receiving increasing attention as principal pharmacotherapeutic targets for the treatment of obesity. The 5-HT2C receptor has the distinctive ability to be modified by posttranscriptional RNA editing on 5 nucleotide positions (A, B, C, D, E), having an overall decreased receptor function. Recently, it has been shown that feeding behaviour and fat mass are altered when the 5-HT2C receptor RNA is fully edited, suggesting a potential role for 5-HT2C editing in obesity. The present studies investigate the expression of serotonin receptors involved in central regulation of food intake, appetite and energy expenditure, with particular focus on the level of 5-HT2C receptor editing. Using a leptin-deficient mouse model of obesity (ob/ob), we show increased hypothalamic 5-HT1A receptor expression as well as increased hippocampal 5-HT1A, 5-HT1B, and 5-HT6 receptor mRNA expression in obese mice compared to lean control mice. An increase in full-length 5-HT2C expression, depending on time of day, as well as differences in 5-HT2C receptor editing were found, independent of changes in total 5-HT2C receptor mRNA expression. This suggests that a dynamic regulation exists of the appetite-suppressing effects of the 5-HT2C receptor in both the hypothalamus and the hippocampus in the ob/ob mice model of obesity. The differential 5-HT1A, 5-HT1B and 5-HT6 receptor expression and altered 5-HT2C receptor editing profile reported here is poised to have important consequences for the development of novel anti-obesity therapies.
Towards a cognitive neurobiology of brain-gut axis disorders
(University College Cork, 2014) Kennedy, Paul J.; Dinan, Timothy G.; Cryan, John F.; Clarke, Gerard; Science Foundation Ireland; Health Research Board; University College Cork
The past two decades have seen substantial gains in our understanding of the complex processes underlying disturbed brain-gut communication in disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Despite a growing understanding of the neurobiology of brain-gut axis dysfunction, there is a relative paucity of investigations into how the various factors involved in dysregulating the brain-gut axis, including stress, immune activation and pain, could impact on fundamental brain processes such as cognitive performance. To this end, we proposed a cognitive neurobiology of brain-gut axis dysfunction and took a novel approach to examine how disturbed brain-gut interactions may manifest as altered cognitive performance in IBS and IBD, both cross-sectionally and prospectively. We have demonstrated that, disorders of the brain-gut axis are characterised by stable deficits in specific cognitive domains. Specifically, patients with IBS exhibit a consistent hippocampal mediated visuospatial memory impairment. In addition we have found evidence to suggest a similar visuospatial impairment in IBD. However, our most consistent finding within this population was that patients with Crohn’s disease exhibit impaired selective attention/ response inhibition on the classic Stroop interference test. These cognitive deficits may serve to perpetuate and sustain brain-gut axis dysfunction. Furthermore, this research has shed light on some of the underlying neurobiological mechanisms that may be mediating cognitive dysfunction in IBS. Our findings may have significant implications for the individual who suffers from a brain-gut axis disorder and may also inform future treatment strategies. Taken together, these findings can be incorporated into existing neurobiological models of brain-gut axis dysfunction, to develop a more comprehensive model accounting for the cognitive-neurobiology of brain-gut axis disorders. This has furthered our understanding of disease pathophysiology and may ultimately aid in both the diagnosis and treatment of these highly prevalent, but poorly understood disorders.
Devil's Claw to suppress appetite - ghrelin receptor modulation potential of a Harpagophytum procumbens root extract
(Public Library of Science, 2014) Torres-Fuentes, Cristina; Theeuwes, Wessel F.; McMullen, Michael K.; McMullen, Anna K.; Dinan, Timothy G.; Cryan, John F.; Schellekens, Harriët; Enterprise Ireland; Science Foundation Ireland
Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.
Sex offender risk assessment and management in Ireland
(University College Cork, 2014) Walker, Mary; O'Rourke, Margaret; An Garda Síochána, Ireland; British Psychological Society
This research examined sex offender risk assessment and management in Ireland. It focused on the statutory agencies with primary responsibility (Garda Síochána and the Probation Service). The goal was to document the historical, contextual and current systems, in addition to identifying areas of concern/improvements. The research was a mixed-methods approach. Eight studies were conducted. This incorporated documentary reviews of four Commission to Inquire Reports, qualitative interviews/focus groups with Garda staff, Probation Service staff, statutory agencies, community stakeholders, various Non-Governmental Organisations (NGOs) and sex offenders. Quantitative questionnaires were also administered to Garda staff. In all over 70 interviews were conducted and questionnaires were forwarded to 270 Garda members. The overall findings are: Sex offender management in Ireland has become formal only since 2001. Knowledge, skills and expertise is in its infancy and is still evolving. Mixed reviews and questions regarding fitness for purpose of currently used risk assessments tools were noted. The Sex Offender Act 2001 requires additional elements to ensure safe sex offender monitoring and public protection. A judicial review of the Sex Offender Act 2001 was recommended by many respondents. Interagency working under SORAM was hugely welcomed. The sharing of information has been welcomed by managing agencies as the key benefit to improving sex offender management. Respondents reported that in practice, sex offender management in Ireland is fragmented and unevenly implemented. The research concluded that an independent National Sex Offender Authority should be established as an oversight and regulatory body for policy, strategy and direction in sex offender management. Further areas of research were also highlighted: ongoing evaluation and audits of the joint agency process and systems in place; recidivism studies tracking the risk assessment ratings and subsequent offending; and an evaluation of the current status of sex offender housing in Ireland.
Stress-induced visceral pain in rodents: neurochemical, hormonal, immune and epigenetic mechanisms
(University College Cork, 2014) Moloney, Rachel D.; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland
Visceral pain is a debilitating disorder which affects up to 25% of the population at any one time. It is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. Currently the treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The work presented in this thesis aimed to redress this issue and look in more detail at the molecular mechanisms of visceral pain in preclinical models. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here a mouse model of early-life stress-induced visceral hypersensitivity was validated. Moreover, mouse strain differences were also apparent in visceral sensitivity suggesting a possible genetic component to the underlying pathophysiology. Furthermore, gender and sex hormones were also implicated in stress sensitivity and visceral pain. Using the rat model of maternal separation, some of the epigenetic mechanisms underpinning visceral hypersensitivity, specifically the contribution of histone acetylation were unravelled. Glutamate has been well established in somatic pain processing, however, its contribution to visceral pain has not been extensively characterised. It was found that glutamate uptake is impaired in viscerally hypersensitive animals, an effect which could be reversed by treatment with riluzole, a glutamate uptake activator. Moreover, negative modulation of the metabotropic glutamate (mGlu) receptor 7 was sufficient to reverse visceral hypersensitivity in a stress sensitive rat strain, the Wistar Kyoto rat. Furthermore, toll-like receptor 4 (TLR4) was implicated in chronic stress-induced visceral hypersensitivity. Taken together, these findings have furthered our knowledge of the pathophysiology of visceral pain. In addition, we have identified glutamate transporters, mGlu7 receptor, histone acetylation and TLR4 as novel targets, amenable to pharmacological manipulation for the specific treatment of visceral pain.
An examination of the impact of dietary lipids on behaviour and neurochemistry
(University College Cork, 2015) Pusceddu, Matteo M.; Dinan, Ted G.; Cryan, John F.
The molecular and cellular basis of stress pathology remains an important research question in biological science. A better understanding of this may enable the development of novel approaches for the treatment of stress-related disorders. There is a considerable body of scientific evidence suggesting that dietary lipids, phospholipids and omega-3 polyunsaturated fatty acids (n-3 PUFAs), have therapeutic potential for certain psychiatric disorders. Thus, we proposed n-3 PUFAs as a novel strategy for the prevention or amelioration of stress-related disorders. We hypothesised that these compounds would improve behavioural and neurobiological responses and alter gut microbial composition. Furthermore, we proposed a new mechanism of action exerted by n-3 PUFAs using an in vitro model of stress. Lastly, we explored the protective effects of both phospholipids and n-3 PUFAs against neuroinflammation, which has been shown to contribute to the development of stress-related disorders. We provide further evidence that glucocorticoids, inflammation and early-life stress induce vulnerability to psychopathologies. Specifically, we have demonstrated that corticosterone (CORT) alters cortical neuron and astrocyte percentage composition, reduces brain-derived-neuronal factor (BDNF) expression, and induces glucocorticoid receptor (GR) down-regulation in mixed cortical cultures. Interestingly, we found that lipopolysaccharide (LPS) treatment resulted in an over-expression of pro-inflammatory cytokines in cortical astrocyte cultures. Moreover, we demonstrate that early-life stress induces changes to the monoaminergic and immune systems as well as altered neuroendocrine response to stressors later in life. In addition, we found that early-life stress alters the gut microbiota in adulthood. These data demonstrate that n-3 PUFAs can attenuate CORT-induced cellular changes, but not those caused by LPS, within the cerebral cortex. Similarly, phospholipids were unable to reverse LPS-induced inflammation in cultured astrocytes. In addition, this thesis proposes that n-3 PUFAs may prevent the development or lessen the symptoms of mental illnesses, ameliorating anxiety- and depressive-like symptoms as well as cognitive effects, particularly when administered during neurodevelopment. Such effects may be mediated by GR activation as well as by modification of the gut microbiota composition. Taken together, our findings suggest that n-3 PUFAs have therapeutic potential for stress-related disorders and we provide evidence for the mechanisms by which they may exert these effects. These findings contribute to an exciting and growing body of research suggesting that nutritional interventions may have an important role to play in the treatment of stress-related psychiatric conditions.
The gut microbiota in depression
(University College Cork, 2016) Kelly, John; Dinan, Timothy G.; Clarke, Gerard; Science Foundation Ireland
The accruing data linking the gut microbiota to the development and function of the central nervous system has been proposed as a paradigm shift in neuroscience. Neuroimmune, neuroendocrine and neural communication pathways exist between host and microbe. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. Dysfunctional neuro-immune and neuro-endocrine pathways are implicated in stress-related psychiatric disorders. To this end, we proposed that the gut microbiota, by modulating these pathways, plays an influential role in the pathophysiology of depression. We demonstrated that depression is associated with altered gut microbiota composition with decreased richness and diversity. Furthermore, we have shown that transferring the gut microbiota from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. Although we provide evidence that the gut microbiota is altered in depression and that this alteration could have a role in prominent features of depression, an interventional study based on targeting the gut microbiota in healthy males using Lactobacillus rhamnosus (JB-1) was not superior to placebo in modifying self-reported stress, HPA axis response to an acute stressor, inflammation, cognition or neurophysiological measures. Taken together, these findings have furthered our understanding of the pathophysiology of depression. By incorporating the gut microbiota into existing neurobiological models of depression a more comprehensive model has been developed. The successful translation of this work could lead to stratification based on gut microbiome composition and could deliver further diagnostic accuracy to improve patient phenotyping for treatment selection in future studies in psychiatric populations. Furthermore, our findings advance the possibility of targeting the gut microbiome in the treatment and prevention of stress related disorders and offer an important future strategy in psychiatry.
Food for thought: The role of nutrition in the microbiota-gut–brain axis
(Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism, 2016-01-21) Oriach, Clara Seira; Robertson, Ruairi C.; Stanton, Catherine; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland; Health Research Board; Marine Institute; Teagasc; Enterprise Ireland; Department of Agriculture, Food and the Marine
Recent research has provided strong evidence for the role of the commensal gut microbiota in brain function and behaviour. Many potential pathways are involved in this bidirectional communication between the gut microbiota and the brain such as immune mechanisms, the vagus nerve and microbial neurometabolite production. Dysbiosis of gut microbial function has been associated with behavioural and neurophysical deficits, therefore research focused on developing novel therapeutic strategies to treat psychiatric disorders by targeting the gut microbiota is rapidly growing. Numerous factors can influence the gut microbiota composition such as health status, mode of birth delivery and genetics, but diet is considered among the most crucial factors impacting on the human gut microbiota from infancy to old age. Thus, dietary interventions may have the potential to modulate psychiatric symptoms associated with gut–brain axis dysfunction. Further clinical and in vivo studies are needed to better understand the mechanisms underlying the link between nutrition, gut microbiota and control of behaviour and mental health.
Regulation of prefrontal cortex myelination by the microbiota
(Nature Publishing Group, 2016-04-05) Hoban, Alan E.; Stilling, Roman M.; Ryan, Feargal J.; Shanahan, Fergus; Dinan, Timothy G.; Claesson, Marcus J.; Clarke, Gerard; Cryan, John F.; Science Foundation Ireland; Irish Research Council; Department of Agriculture, Food and the Marine; Enterprise Ireland; National Alliance for Research on Schizophrenia and Depression; Health Research Board
The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.
Obesity takes its toll on visceral pain: High-fat diet induces toll-like receptor 4-dependent visceral hypersensitivity
(PLoS, 2016-05-09) Tramullas, Mónica; Finger, Beate C.; Dinan, Timothy G.; Cryan, John F.; Science Foundation Ireland; Health Research Board; Seventh Framework Programme
Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.
Impact of exercise on innate immunity in multiple sclerosis progression and symptomatology
(Frontiers Media, 2016-06-02) Barry, Alison; Cronin, Owen; Ryan, Aisling M.; Sweeney, Brian; Yap, Siew M.; O'Toole, Orna; Allen, Andrew P.; Clarke, Gerard; O'Halloran, Ken D.; Downer, Eric J.; University College Cork; Trinity College Dublin
Multiple Sclerosis (MS), an idiopathic progressive immune-mediated neurological disorder of the central nervous system (CNS), is characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. It accounts for functional deterioration and lasting disability among young adults. A body of literature demonstrates that physical activity counteracts fatigue and depression and may improve overall quality of life in MS patients. Furthermore, much data indicates that exercise ameliorates chronic neuroinflammation and its related pathologies by tipping cytokine profiles toward an anti-inflammatory signature. Recent data has focused on the direct impact of exercise training on the innate immune system by targeting toll-like receptors (TLRs), signaling pattern recognition receptors that govern the innate immune response, shedding light on the physiological role of TLRs in health and disease. Indeed, TLRs continue to emerge as players in the neuroinflammatory processes underpinning MS. This review will highlight evidence that physical activity and exercise are potential immunomodulatory therapies, targeting innate signaling mechanism(s) to modulate MS symptom development and progression.
Kynurenine pathway metabolism and the microbiota-gut-brain axis
(Elsevier Ltd., 2016-07-05) Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Science Foundation Ireland; Health Research Board; Brain and Behavior Research Foundation; Seventh Framework Programme
It has become increasingly clear that the gut microbiota influences not only gastrointestinal physiology but also central nervous system (CNS) function by modulating signalling pathways of the microbiota-gut-brain axis. Understanding the neurobiological mechanisms underpinning the influence exerted by the gut microbiota on brain function and behaviour has become a key research priority. Microbial regulation of tryptophan metabolism has become a focal point in this regard, with dual emphasis on the regulation of serotonin synthesis and the control of kynurenine pathway metabolism. Here, we focus in detail on the latter pathway and begin by outlining the structural and functional dynamics of the gut microbiota and the signalling pathways of the brain-gut axis. We summarise preclinical and clinical investigations demonstrating that the gut microbiota influences CNS physiology, anxiety, depression, social behaviour, cognition and visceral pain. Pertinent studies are drawn from neurogastroenterology demonstrating the importance of tryptophan and its metabolites in CNS and gastrointestinal function. We outline how kynurenine pathway metabolism may be regulated by microbial control of neuroendocrine function and components of the immune system. Finally, preclinical evidence demonstrating direct and indirect mechanisms by which the gut microbiota can regulate tryptophan availability for kynurenine pathway metabolism, with downstream effects on CNS function, is reviewed. Targeting the gut microbiota represents a tractable target to modulate kynurenine pathway metabolism. Efforts to develop this approach will markedly increase our understanding of how the gut microbiota shapes brain and behaviour and provide new insights towards successful translation of microbiota-gut-brain axis research from bench to bedside.
Estrous cycle influences excitatory amino acid transport and visceral pain sensitivity in the rat: Effects of early-life stress
(BioMed Central, 2016-07-14) Moloney, Rachel D.; Sajjad, Jahangir; Foley, Tara; Felice, Valeria D.; Dinan, Timothy G.; Cryan, John F.; O'Mahony, Siobhain M.; Science Foundation Ireland; Health Research Board
Background: Early-life stress (ELS) is a recognized risk factor for chronic pain disorders, and females appear to be more sensitive to the negative effects of stress. Moreover, estrous cycle-related fluctuations in estrogen levels have been linked with alternating pain sensitivity. Aberrant central circuitry involving both the anterior cingulate cortex (ACC) and the lumbosacral spinal cord has also been implicated in the modulation of visceral pain in clinical and preclinical studies. Here we further investigate changes in visceral pain sensitivity and central glutamatergic systems in rats with respect to estrous cycle and ELS. Methods: We investigated visceral sensitivity in adult female Sprague-Dawley rats, which had undergone maternal separation (MS) in early life or remained non-separated (NS), by performing colorectal distension (CRD). We also assessed excitatory amino acid uptake through excitatory amino acid transporters (EAATs) in the lumbosacral spinal cord and ACC. Results: NS animals in proestrus and estrus exhibited reduced EAAT uptake and decreased threshold to CRD. Moreover, total pain behaviors were increased in these stages. MS rats exhibited lower pain thresholds and higher total pain behaviors to CRD across all stages of the estrous cycle. Interestingly, cortical EAAT function in MS rats was inhibited in the low estrogen state—an effect completely opposite to that seen in NS rats. Conclusions: This data confirms that estrous cycle and ELS are significant factors in visceral sensitivity and fluctuations in EAAT function may be a perpetuating factor mediating central sensitization.
Probiotic modulation of the microbiota-gut-brain axis and behaviour in zebrafish
(Nature Publishing Group, 2016-07-15) Borrelli, Luca; Aceto, Serena; Agnisola, Claudio; De Paolo, Sofia; Dipineto, Ludovico; Stilling, Roman M.; Dinan, Timothy G.; Cryan, John F.; Menna, Lucia F.; Regione Campania
The gut microbiota plays a crucial role in the bi-directional gut–brain axis, a communication that integrates the gut and central nervous system (CNS) activities. Animal studies reveal that gut bacteria influence behaviour, Brain-Derived Neurotrophic Factor (BDNF) levels and serotonin metabolism. In the present study, we report for the first time an analysis of the microbiota–gut–brain axis in zebrafish (Danio rerio). After 28 days of dietary administration with the probiotic Lactobacillus rhamnosus IMC 501, we found differences in shoaling behaviour, brain expression levels of bdnf and of genes involved in serotonin signalling/metabolism between control and treated zebrafish group. In addition, in microbiota we found a significant increase of Firmicutes and a trending reduction of Proteobacteria. This study demonstrates that selected microbes can be used to modulate endogenous neuroactive molecules in zebrafish.
MicroRNAs as biomarkers for major depression: A role for let-7b and let-7c
(Nature Publishing Group, 2016-08-02) Gururajan, Anand; Naughton, Maura; Scott, Karen A.; O'Connor, R. M.; Moloney, Gerard M.; Clarke, Gerard; Dowling, J.; Walsh, A.; Ismail, F.; Shorten, George; Scott, Lucinda V.; McLoughlin, D. M.; Cryan, John F.; Dinan, Timothy G.; Health Research Board; Science Foundation Ireland; Seventh Framework Programme; Brain and Behavior Research Foundation
There is a growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of depression, particularly with respect to predicting response to specific therapeutic strategies. MicroRNAs are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level and emerging evidence from a range of studies has highlighted their biomarker potential. Here we compared healthy controls (n=20) with patients diagnosed with major depression (n=40) and who were treatment-resistant to identify peripheral microRNA biomarkers, which could be used for diagnosis and to predict response to electroconvulsive therapy (ECT) and ketamine (KET) infusions, treatments that have previously shown to be effective in treatment-resistant depression (TRD). At baseline and after treatment, blood samples were taken and symptom severity scores rated using the Hamilton Depression Rating Scale (HDRS). Samples were analyzed for microRNA expression using microarray and validated using quantitative PCR. As expected, both treatments reduced HDRS scores. Compared with controls, the baseline expression of the microRNA let-7b was less by ~40% in TRD patients compared with controls. The baseline expression of let-7c was also lower by ~50% in TRD patients who received ECT. Bioinformatic analysis revealed that let-7b and let-7c regulates the expression of 27 genes in the PI3k-Akt-mTOR signaling pathway, which has previously been reported to be dysfunctional in depression. The expression of miR-16, miR-182, miR-451 and miR-223 were similar to that in controls. Baseline microRNA expression could not predict treatment response and microRNAs were unaffected by treatment. Taken together, we have identified let-7b and let-7c as candidate biomarkers of major depression.
N-3 polyunsaturated fatty acids through the lifespan: implication for psychopathology
(Oxford University Press, 2016-09-08) Pusceddu, Matteo M.; Kelly, Philip; Stanton, Catherine; Cryan, John F.; Dinan, Timothy G.
Objective: The impact of lifetime dietary habits and their role in physical, mental, and social well-being has been the focus of considerable recent research. Omega-3 polyunsaturated fatty acids as a dietary constituent have been under the spotlight for decades. Omega-3 polyunsaturated fatty acids constitute key regulating factors of neurotransmission, neurogenesis, and neuroinflammation and are thereby fundamental for development, functioning, and aging of the CNS. Of note is the fact that these processes are altered in various psychiatric disorders, including attention deficit hyperactivity disorder, depression, and Alzheimer’s disease. Design: Relevant literature was identified through a search of MEDLINE via PubMed using the following words, “n-3 PUFAs,” “EPA,” and “DHA” in combination with “stress,” “cognition,” “ADHD,” “anxiety,” “depression,” “bipolar disorder,” “schizophrenia,” and “Alzheimer.” The principal focus was on the role of omega-3 polyunsaturated fatty acids throughout the lifespan and their implication for psychopathologies. Recommendations for future investigation on the potential clinical value of omega-3 polyunsaturated fatty acids were examined. Results: The inconsistent and inconclusive results from randomized clinical trials limits the usage of omega-3 polyunsaturated fatty acids in clinical practice. However, a body of literature demonstrates an inverse correlation between omega-3 polyunsaturated fatty acid levels and quality of life/ psychiatric diseases. Specifically, older healthy adults showing low habitual intake of omega-3 polyunsaturated fatty acids benefit most from consuming them, showing improved age-related cognitive decline. Conclusions: Although further studies are required, there is an exciting and growing body of research suggesting that omega-3 polyunsaturated fatty acids may have a potential clinical value in the prevention and treatment of psychopathologies.
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.
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.

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