Rachel Moloney | University of Oklahoma Health Sciences Center (original) (raw)

Papers by Rachel Moloney

Research paper thumbnail of Metabotropic Glutamate Receptors in Central Nervous System Diseases

Extensive research over the past thirty years has demonstrated a vital role for metabotropic glut... more Extensive research over the past thirty years has demonstrated a vital role for metabotropic glutamate (mGlu) receptors in the major functions of the central nervous system (CNS). A wealth of preclinical studies provide evidence that pharmacological targeting of mGlu receptors can effectively attenuate the development of symptoms and progression of many CNS disorders in animal models. In this review we summarize the current knowledge on the involvement of mGlu receptors in the pathophysiology of neuropsychiatric disorders (schizophrenia, depression, anxiety and cognitive disorders, pain perception and addiction), as well as neurodegenerative (Alzheimer's, Huntington's and Parkinson's diseases) and neurodevelopmental (fragile X syndrome and autism spectrum disorder) diseases. We further emphasis the therapeutic potential of mGlu receptors' pharmacological modulators in these diseases, describe the results of clinical trials with these compounds and discuss the potenti...

Research paper thumbnail of Enhancing Glutamatergic Transmission During Adolescence Reverses Early-Life Stress-induced Deficits in the Rewarding Effects of Cocaine in Rats

Neuropharmacology, Jan 14, 2015

Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet... more Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological process including reward function and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25-46) animals were treated with the glutamate transpor...

Research paper thumbnail of Prenatal Stress-Induced Alterations in Major Physiological Systems Correlate with Gut Microbiota Composition in Adulthood

Psychoneuroendocrinology, 2015

Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher pre... more Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota.

Research paper thumbnail of Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

Neurobiology of Stress, 2015

Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect ... more Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need. Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.

Research paper thumbnail of Gut Microbiota Depletion from Early Adolescence in Mice: Implications for Brain and Behaviour

Brain, Behavior, and Immunity, 2015

Background: There is growing appreciation for the importance of bacteria in shaping brain develop... more Background: There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. Methods: Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. Results: Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. Conclusions: Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.

Research paper thumbnail of Strain-Dependent Variations in Visceral Sensitivity: Relationship to Stress, Anxiety and Spinal Glutamate Transporter Expression

Genes, brain, and behavior, Jan 8, 2015

Responses to painful stimuli differ between populations, ethnic groups, genders and even among in... more Responses to painful stimuli differ between populations, ethnic groups, genders and even among individuals of a family. However, data regarding visceral pain is still lacking. Thus we investigated differences in visceral nociception across inbred and outbred mouse strains using colorectal distension (CRD). Anxiety and depression-like behaviour were assessed using the open field and forced swim test (FST) as well as the corticosterone stress response. Possible mechanistic targets (excitatory amino acid transporter (EAAT-1), brain derived neurotrophic factor (BDNF) and 5HT1A receptor) were also assessed using qRT-PCR. Adult, male, inbred and outbred mouse strains were used in all assays (Inbred strains; CBA/J Hsd, C3H/HeNHsd, BALB/c OlaHsd, C57 BL/6JOlaHsd, DBA/2J RccHsd, CAST/EiJ, SM/J, A/J OlaHsd, 129P2/OlaHsd, FVB/NHan Hsd, and outbred strains: Swiss Webster, CD-1). mRNA expression levels of EAAT-1, BDNF and 5HT1A receptor (HTR1A) were quantified in the lumbosacral spinal cord and ...

Research paper thumbnail of Microbiota Regulation of the Mammalian Gut–Brain Axis

Advances in Applied Microbiology, 2015

The realization that the microbiota-gut-brain axis plays a critical role in health and disease ha... more The realization that the microbiota-gut-brain axis plays a critical role in health and disease has emerged over the past decade. The brain-gut axis is a bidirectional communication system between the central nervous system (CNS) and the gastrointestinal tract. Regulation of the microbiota-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The routes of this communication are not fully elucidated but include neural, humoral, immune, and metabolic pathways. A number of approaches have been used to interrogate this axis including the use of germ-free animals, probiotic agents, antibiotics, or animals exposed to pathogenic bacterial infections. Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiota-brain interactions is an exciting area of research which may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior, and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia. Finally, the concept of psychobiotics, bacterial-based interventions with mental health benefit, is also emerging.

Research paper thumbnail of Inadequate dietary calcium and vitamin D intakes in renal-transplant recipients in Ireland

Journal of Renal Nutrition, 2007

To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attendi... more To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attending at a large teaching hospital in Ireland for follow-up. Outpatient renal-transplant follow-up clinic. Fifty-nine adult renal transplant recipients (58% male) with a mean age of 46 years, a median transplant duration of 6 years, and a mean estimated glomerular filtration rate (eGFR) of 50 mL/min per 1.73 m2. Fifty-three percent were at National Kidney Foundation stage 3 chronic kidney disease, and 14% had stage 4 chronic kidney disease. This cross-sectional, observational study used a tailored food frequency questionnaire specific for calcium and vitamin D intake in Irish adults, which was completed during a face-to-face interview with each subject. The main outcome measure was the average daily dietary and supplemented calcium and vitamin D intake. The median interquartile range (IQR) dietary calcium intake was 820 mg/day (range, 576-1,177 mg/day), and was similar in men and women (recommended intake > or = 1,000 mg/day in adult men and nonmenopausal adult women, > or = 1,500 mg/day in menopausal women). Five participants received calcium supplementation. Overall, 59% of men and 64% of women had total calcium intakes below the recommended amounts. The median IQR estimated dietary vitamin D intake was 5.2 microg/day (range, 2.4-6.4 microg/day) in women, and 4.6 microg/day (range, 2.2-6.6 microg/day) in men (recommended intake, > or = 10 microg/day). Six subjects received vitamin D supplementation. Total vitamin D intakes were suboptimal in 91% of men and 87% of women. Dietary calcium and vitamin D intakes significantly correlated with each other, but neither was significantly related to eGFR category, and was similarly low in both presumed menopausal women and in the initial year posttransplantation. These findings suggest that dietary and total calcium and vitamin D intakes in adult renal-transplant patients are in many cases inadequate.

Research paper thumbnail of The microbiome: stress, health and disease

Mammalian Genome, 2014

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of k... more Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome-brain-gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.

Research paper thumbnail of Inadequate Dietary Calcium and Vitamin D Intakes in Renal-Transplant Recipients in Ireland

Journal of Renal Nutrition, 2007

To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attendi... more To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attending at a large teaching hospital in Ireland for follow-up. Outpatient renal-transplant follow-up clinic. Fifty-nine adult renal transplant recipients (58% male) with a mean age of 46 years, a median transplant duration of 6 years, and a mean estimated glomerular filtration rate (eGFR) of 50 mL/min per 1.73 m2. Fifty-three percent were at National Kidney Foundation stage 3 chronic kidney disease, and 14% had stage 4 chronic kidney disease. This cross-sectional, observational study used a tailored food frequency questionnaire specific for calcium and vitamin D intake in Irish adults, which was completed during a face-to-face interview with each subject. The main outcome measure was the average daily dietary and supplemented calcium and vitamin D intake. The median interquartile range (IQR) dietary calcium intake was 820 mg/day (range, 576-1,177 mg/day), and was similar in men and women (recommended intake > or = 1,000 mg/day in adult men and nonmenopausal adult women, > or = 1,500 mg/day in menopausal women). Five participants received calcium supplementation. Overall, 59% of men and 64% of women had total calcium intakes below the recommended amounts. The median IQR estimated dietary vitamin D intake was 5.2 microg/day (range, 2.4-6.4 microg/day) in women, and 4.6 microg/day (range, 2.2-6.6 microg/day) in men (recommended intake, > or = 10 microg/day). Six subjects received vitamin D supplementation. Total vitamin D intakes were suboptimal in 91% of men and 87% of women. Dietary calcium and vitamin D intakes significantly correlated with each other, but neither was significantly related to eGFR category, and was similarly low in both presumed menopausal women and in the initial year posttransplantation. These findings suggest that dietary and total calcium and vitamin D intakes in adult renal-transplant patients are in many cases inadequate.

Research paper thumbnail of Early-life stress induces visceral hypersensitivity in mice

Neuroscience letters, Jan 23, 2012

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating ... more Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed...

Research paper thumbnail of Toll-Like Receptor 4 Regulates Chronic Stress-Induced Visceral Pain in Mice

Biological Psychiatry, 2013

Background: Functional gastrointestinal disorders, which have visceral hypersensitivity as a core... more Background: Functional gastrointestinal disorders, which have visceral hypersensitivity as a core symptom, are frequently comorbid with stress-related psychiatric disorders. Increasing evidence points to a key role for toll-like receptor 4 (TLR4) in chronic pain states of somatic origin. However, the central contribution of TLR4 in visceral pain sensation remains elusive.

Research paper thumbnail of Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities

Frontiers in Psychiatry, 2015

Visceral pain is a global term used to describe pain originating from the internal organs, which ... more Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities.The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.

Research paper thumbnail of Metabotropic Glutamate Receptors in Central Nervous System Diseases

Extensive research over the past thirty years has demonstrated a vital role for metabotropic glut... more Extensive research over the past thirty years has demonstrated a vital role for metabotropic glutamate (mGlu) receptors in the major functions of the central nervous system (CNS). A wealth of preclinical studies provide evidence that pharmacological targeting of mGlu receptors can effectively attenuate the development of symptoms and progression of many CNS disorders in animal models. In this review we summarize the current knowledge on the involvement of mGlu receptors in the pathophysiology of neuropsychiatric disorders (schizophrenia, depression, anxiety and cognitive disorders, pain perception and addiction), as well as neurodegenerative (Alzheimer's, Huntington's and Parkinson's diseases) and neurodevelopmental (fragile X syndrome and autism spectrum disorder) diseases. We further emphasis the therapeutic potential of mGlu receptors' pharmacological modulators in these diseases, describe the results of clinical trials with these compounds and discuss the potenti...

Research paper thumbnail of Enhancing Glutamatergic Transmission During Adolescence Reverses Early-Life Stress-induced Deficits in the Rewarding Effects of Cocaine in Rats

Neuropharmacology, Jan 14, 2015

Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet... more Adolescence marks a critical time when the brain is highly susceptible to pathological insult yet also uniquely amenable to therapeutic intervention. It is during adolescence that the onset of the majority of psychiatric disorders, including substance use disorder (SUDs), occurs. It has been well established that stress, particularly during early development, can contribute to the pathological changes which contribute to the development of SUDs. Glutamate as the main excitatory neurotransmitter in the mammalian CNS plays a key role in various physiological process including reward function and in mediating the effects of psychological stress. We hypothesised impairing glutamatergic signalling during the key adolescent period would attenuate early-life stress induced impaired reward function. To test this, we induced early-life stress in male rats using the maternal-separation procedure. During the critical adolescent period (PND25-46) animals were treated with the glutamate transpor...

Research paper thumbnail of Prenatal Stress-Induced Alterations in Major Physiological Systems Correlate with Gut Microbiota Composition in Adulthood

Psychoneuroendocrinology, 2015

Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher pre... more Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota.

Research paper thumbnail of Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

Neurobiology of Stress, 2015

Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect ... more Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need. Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.Please cite this article in press as: Moloney, R.D., et al., Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain, Neurobiology of Stress (2015), http://dx.

Research paper thumbnail of Gut Microbiota Depletion from Early Adolescence in Mice: Implications for Brain and Behaviour

Brain, Behavior, and Immunity, 2015

Background: There is growing appreciation for the importance of bacteria in shaping brain develop... more Background: There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. Methods: Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential gut-brain axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. Results: Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. Conclusions: Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition.

Research paper thumbnail of Strain-Dependent Variations in Visceral Sensitivity: Relationship to Stress, Anxiety and Spinal Glutamate Transporter Expression

Genes, brain, and behavior, Jan 8, 2015

Responses to painful stimuli differ between populations, ethnic groups, genders and even among in... more Responses to painful stimuli differ between populations, ethnic groups, genders and even among individuals of a family. However, data regarding visceral pain is still lacking. Thus we investigated differences in visceral nociception across inbred and outbred mouse strains using colorectal distension (CRD). Anxiety and depression-like behaviour were assessed using the open field and forced swim test (FST) as well as the corticosterone stress response. Possible mechanistic targets (excitatory amino acid transporter (EAAT-1), brain derived neurotrophic factor (BDNF) and 5HT1A receptor) were also assessed using qRT-PCR. Adult, male, inbred and outbred mouse strains were used in all assays (Inbred strains; CBA/J Hsd, C3H/HeNHsd, BALB/c OlaHsd, C57 BL/6JOlaHsd, DBA/2J RccHsd, CAST/EiJ, SM/J, A/J OlaHsd, 129P2/OlaHsd, FVB/NHan Hsd, and outbred strains: Swiss Webster, CD-1). mRNA expression levels of EAAT-1, BDNF and 5HT1A receptor (HTR1A) were quantified in the lumbosacral spinal cord and ...

Research paper thumbnail of Microbiota Regulation of the Mammalian Gut–Brain Axis

Advances in Applied Microbiology, 2015

The realization that the microbiota-gut-brain axis plays a critical role in health and disease ha... more The realization that the microbiota-gut-brain axis plays a critical role in health and disease has emerged over the past decade. The brain-gut axis is a bidirectional communication system between the central nervous system (CNS) and the gastrointestinal tract. Regulation of the microbiota-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. The routes of this communication are not fully elucidated but include neural, humoral, immune, and metabolic pathways. A number of approaches have been used to interrogate this axis including the use of germ-free animals, probiotic agents, antibiotics, or animals exposed to pathogenic bacterial infections. Together, it is clear that the gut microbiota can be a key regulator of mood, cognition, pain, and obesity. Understanding microbiota-brain interactions is an exciting area of research which may contribute new insights into individual variations in cognition, personality, mood, sleep, and eating behavior, and how they contribute to a range of neuropsychiatric diseases ranging from affective disorders to autism and schizophrenia. Finally, the concept of psychobiotics, bacterial-based interventions with mental health benefit, is also emerging.

Research paper thumbnail of Inadequate dietary calcium and vitamin D intakes in renal-transplant recipients in Ireland

Journal of Renal Nutrition, 2007

To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attendi... more To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attending at a large teaching hospital in Ireland for follow-up. Outpatient renal-transplant follow-up clinic. Fifty-nine adult renal transplant recipients (58% male) with a mean age of 46 years, a median transplant duration of 6 years, and a mean estimated glomerular filtration rate (eGFR) of 50 mL/min per 1.73 m2. Fifty-three percent were at National Kidney Foundation stage 3 chronic kidney disease, and 14% had stage 4 chronic kidney disease. This cross-sectional, observational study used a tailored food frequency questionnaire specific for calcium and vitamin D intake in Irish adults, which was completed during a face-to-face interview with each subject. The main outcome measure was the average daily dietary and supplemented calcium and vitamin D intake. The median interquartile range (IQR) dietary calcium intake was 820 mg/day (range, 576-1,177 mg/day), and was similar in men and women (recommended intake > or = 1,000 mg/day in adult men and nonmenopausal adult women, > or = 1,500 mg/day in menopausal women). Five participants received calcium supplementation. Overall, 59% of men and 64% of women had total calcium intakes below the recommended amounts. The median IQR estimated dietary vitamin D intake was 5.2 microg/day (range, 2.4-6.4 microg/day) in women, and 4.6 microg/day (range, 2.2-6.6 microg/day) in men (recommended intake, > or = 10 microg/day). Six subjects received vitamin D supplementation. Total vitamin D intakes were suboptimal in 91% of men and 87% of women. Dietary calcium and vitamin D intakes significantly correlated with each other, but neither was significantly related to eGFR category, and was similarly low in both presumed menopausal women and in the initial year posttransplantation. These findings suggest that dietary and total calcium and vitamin D intakes in adult renal-transplant patients are in many cases inadequate.

Research paper thumbnail of The microbiome: stress, health and disease

Mammalian Genome, 2014

Bacterial colonisation of the gut plays a major role in postnatal development and maturation of k... more Bacterial colonisation of the gut plays a major role in postnatal development and maturation of key systems that have the capacity to influence central nervous system (CNS) programming and signaling, including the immune and endocrine systems. Individually, these systems have been implicated in the neuropathology of many CNS disorders and collectively they form an important bidirectional pathway of communication between the microbiota and the brain in health and disease. Regulation of the microbiome-brain-gut axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the CNS and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotics which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus, the concept of a microbiome-brain-gut axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.

Research paper thumbnail of Inadequate Dietary Calcium and Vitamin D Intakes in Renal-Transplant Recipients in Ireland

Journal of Renal Nutrition, 2007

To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attendi... more To quantify the dietary calcium and vitamin D intake in adult renal-transplant recipients attending at a large teaching hospital in Ireland for follow-up. Outpatient renal-transplant follow-up clinic. Fifty-nine adult renal transplant recipients (58% male) with a mean age of 46 years, a median transplant duration of 6 years, and a mean estimated glomerular filtration rate (eGFR) of 50 mL/min per 1.73 m2. Fifty-three percent were at National Kidney Foundation stage 3 chronic kidney disease, and 14% had stage 4 chronic kidney disease. This cross-sectional, observational study used a tailored food frequency questionnaire specific for calcium and vitamin D intake in Irish adults, which was completed during a face-to-face interview with each subject. The main outcome measure was the average daily dietary and supplemented calcium and vitamin D intake. The median interquartile range (IQR) dietary calcium intake was 820 mg/day (range, 576-1,177 mg/day), and was similar in men and women (recommended intake > or = 1,000 mg/day in adult men and nonmenopausal adult women, > or = 1,500 mg/day in menopausal women). Five participants received calcium supplementation. Overall, 59% of men and 64% of women had total calcium intakes below the recommended amounts. The median IQR estimated dietary vitamin D intake was 5.2 microg/day (range, 2.4-6.4 microg/day) in women, and 4.6 microg/day (range, 2.2-6.6 microg/day) in men (recommended intake, > or = 10 microg/day). Six subjects received vitamin D supplementation. Total vitamin D intakes were suboptimal in 91% of men and 87% of women. Dietary calcium and vitamin D intakes significantly correlated with each other, but neither was significantly related to eGFR category, and was similarly low in both presumed menopausal women and in the initial year posttransplantation. These findings suggest that dietary and total calcium and vitamin D intakes in adult renal-transplant patients are in many cases inadequate.

Research paper thumbnail of Early-life stress induces visceral hypersensitivity in mice

Neuroscience letters, Jan 23, 2012

Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating ... more Early-life stress is a risk factor for irritable bowel syndrome (IBS), a common and debilitating functional gastrointestinal disorder that is often co-morbid with stress-related psychiatric disorders. In the rat, maternal separation (MS) stress has been shown to induce visceral hypersensitivity in adulthood and thus has become a useful model of IBS. However, development of mouse models of maternal separation has been difficult. Given the advent of transgenic mouse technology, such models would be useful to further our understanding of the pathophysiology of IBS and to develop new pharmacological treatments. Thus, the present study aimed to develop a mouse model of MS stress-induced visceral hyperalgesia as measured using manometric recordings of colorectal distension (CRD). Moreover, since the GABA(B) receptor has been reported to play a role in pain processes, we also assessed its role in visceral nociception using novel GABA(B(1b)) receptor subunit knockout mice. CRD was performed...

Research paper thumbnail of Toll-Like Receptor 4 Regulates Chronic Stress-Induced Visceral Pain in Mice

Biological Psychiatry, 2013

Background: Functional gastrointestinal disorders, which have visceral hypersensitivity as a core... more Background: Functional gastrointestinal disorders, which have visceral hypersensitivity as a core symptom, are frequently comorbid with stress-related psychiatric disorders. Increasing evidence points to a key role for toll-like receptor 4 (TLR4) in chronic pain states of somatic origin. However, the central contribution of TLR4 in visceral pain sensation remains elusive.

Research paper thumbnail of Stress-Induced Visceral Pain: Toward Animal Models of Irritable-Bowel Syndrome and Associated Comorbidities

Frontiers in Psychiatry, 2015

Visceral pain is a global term used to describe pain originating from the internal organs, which ... more Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities.The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.