RESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social behaviour, increased repetitive behaviour, anxiety and gastrointestinal symptoms. The aetiology of ASD is complex and involves an interplay of genetic and environmental factors. Emerging pre-clinical and clinical studies have documented a potential role for the gut microbiome in ASD, and consequently, the microbiota represents a potential target in the development of novel therapeutics for this neurodevelopmental disorder. In this study, we investigate the efficacy of the live biotherapeutic strain, Blautia stercoris MRx0006, in attenuating some of the behavioural deficits in the autism-relevant, genetic mouse model, BTBR T+ Itpr3tf/J (BTBR). We demonstrate that daily oral administration with MRx0006 attenuates social deficits while also decreasing repetitive and anxiety-like behaviour. MRx0006 administration increases the gene expression of oxytocin and its receptor in hypothalamic cells in vitro and increases the expression of hypothalamic arginine vasopressin and oxytocin mRNA in BTBR mice. Additionally at the microbiome level, we observed that MRx0006 administration decreases the abundance of Alistipes putredinis, and modulates the faecal microbial metabolite profile. This alteration in the metabolite profile possibly underlies the observed increase in expression of oxytocin, arginine vasopressin and its receptors, and the consequent improvements in behavioural outcomes. Taken together, these findings suggest that the live biotherapeutic MRx0006 may represent a viable and efficacious treatment option for the management of physiological and behavioural deficits associated with ASD.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Animais , Ansiedade , Arginina Vasopressina , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Clostridiales , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos , Ocitocina , RNA Mensageiro/metabolismoRESUMO
We have shown previously that prebiotic (Bimuno galacto-oligosacharides, B-GOS®) administration to neonatal rats increased hippocampal NMDAR proteins. The present study has investigated the effects of postnatal B-GOS® supplementation on hippocampus-dependent behavior in young, adolescent, and adult rats and applied electrophysiological, metabolomic and metagenomic analyses to explore potential underlying mechanisms. The administration of B-GOS® to suckling, but not post-weaned, rats reduced anxious behavior until adulthood. Neonatal prebiotic intake also reduced the fast decay component of hippocampal NMDAR currents, altered age-specific trajectories of the brain, intestinal, and liver metabolomes, and reduced abundance of fecal Enterococcus and Dorea bacteria. Our data are the first to show that prebiotic administration to rats during a specific postnatal period has long-term effects on behavior and hippocampal physiology. The study also suggests that early-life prebiotic intake may affect host brain function through the reduction of stress-related gut bacteria rather than increasing the proliferation of beneficial microbes.
RESUMO
We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno™ galacto-oligosaccharides (B-GOS®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS® administered rats compared to non-supplemented controls. The intake of B-GOS® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.
Assuntos
Atenção/fisiologia , Córtex Cerebral/metabolismo , Suplementos Nutricionais , N-Metilaspartato/metabolismo , Neurônios/metabolismo , Prebióticos/administração & dosagem , Animais , Córtex Cerebral/efeitos dos fármacos , Função Executiva/fisiologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/efeitos dos fármacos , Neurotransmissores/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Triglicerídeos/administração & dosagemRESUMO
The manipulation of the enteric microbiota with specific prebiotics and probiotics, has been shown to reduce the host's inflammatory response, alter brain chemistry, and modulate anxiety behaviour in both rodents and humans. However, the neuro-immune and behavioural effects of prebiotics on sickness behaviour have not been explored. Here, adult male CD1 mice were fed with a specific mix of non-digestible galacto-oligosaccharides (Bimuno®, BGOS) for 3 weeks, before receiving a single injection of lipopolysaccharide (LPS), which induces sickness behaviour and anxiety. Locomotor and marble burying activities were assessed 4h after LPS injection, and after 24h, anxiety in the light-dark box was assessed. Cytokine expression, and key components of the serotonergic (5-Hydroxytryptamine, 5-HT) and glutamatergic system were evaluated in the frontal cortex to determine the impact of BGOS administration at a molecular level. BGOS-fed mice were less anxious in the light-dark box compared to controls 24h after the LPS injection. Elevated cortical IL-1ß concentrations in control mice 28 h after LPS were not observed in BGOS-fed animals. This significant BGOS×LPS interaction was also observed for 5HT2A receptors, but not for 5HT1A receptors, 5HT, 5HIAA, NMDA receptor subunits, or other cytokines. The intake of BGOS did not influence LPS-mediated reductions in marble burying behaviour, and its effect on locomotor activity was equivocal. Together, our data show that the prebiotic BGOS has an anxiolytic effect, which may be related to the modulation of cortical IL-1ß and 5-HT2A receptor expression. Our data suggest a potential role for prebiotics in the treatment of neuropsychiatric disorders where anxiety and neuroinflammation are prominent clinical features.
Assuntos
Ansiedade/dietoterapia , Comportamento de Doença/efeitos dos fármacos , Interleucina-1beta/metabolismo , Prebióticos/administração & dosagem , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Microbioma Gastrointestinal , Hipocampo/metabolismo , Inflamação/induzido quimicamente , Inflamação/dietoterapia , Inflamação/psicologia , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina/metabolismoRESUMO
Compelling data suggest that perturbations in microbial colonization of the gut in early-life, influences neurodevelopment and adult brain function. If this is the case, then ensuring the growth of beneficial bacteria at an early age will lead to optimal brain development and maturation. We have tested whether feeding neonatal rats daily (from post-natal days 3-21) with a galacto-oligosaccharide prebiotic (Bimuno®, BGOS) or a control solution, alters the levels of hippocampal N-Methyl-D-Aspartate receptor (NMDAR) subunits (GluN1, GluN2A, GluN2B), synaptic proteins (synaptophysin, MAP2, and GAP43) and brain-derived-neurotrophic factor (BDNF), at post-natal days 22 and 56. The administration of BGOS significantly elevated GluN2A subunits, synaptophysin and BDNF in the hippocampus of 22 day old rats. The effect was also observed on day 56 (26 days after the feeding ceased). The levels of all other proteins (GluN1, GluN2B, MAP2, GAP43) remained unaltered. Increased GluN2A, synaptophysin, BDNF, but not MAP2, may suggest that neonatal BGOS feeding alters neurotransmission rather than synaptic architecture. Although the functional consequences of our findings require further investigation, the current study confirms that the manipulation of gut bacteria in early-life, has central effects that persist until at least young adulthood.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Suplementos Nutricionais , Hipocampo/metabolismo , Prebióticos/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptofisina/metabolismo , Administração Oral , Animais , Animais Recém-Nascidos , Western Blotting , Feminino , Proteína GAP-43/metabolismo , Hipocampo/crescimento & desenvolvimento , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Ratos Sprague-DawleyRESUMO
Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.
Assuntos
Depressão/metabolismo , Receptores de GABA-B/fisiologia , Anedonia , Animais , Comportamento Animal , Proliferação de Células , Corticosterona/metabolismo , Depressão/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Isoformas de Proteínas/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de Risco , Estresse Psicológico , NataçãoRESUMO
The influence of the gut microbiota on brain chemistry has been convincingly demonstrated in rodents. In the absence of gut bacteria, the central expression of brain derived neurotropic factor, (BDNF), and N-methyl-d-aspartate receptor (NMDAR) subunits are reduced, whereas, oral probiotics increase brain BDNF, and impart significant anxiolytic effects. We tested whether prebiotic compounds, which increase intrinsic enteric microbiota, also affected brain BDNF and NMDARs. In addition, we examined whether plasma from prebiotic treated rats released BDNF from human SH-SY5Y neuroblastoma cells, to provide an initial indication of mechanism of action. Rats were gavaged with fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS) or water for five weeks, prior to measurements of brain BDNF, NMDAR subunits and amino acids associated with glutamate neurotransmission (glutamate, glutamine, and serine and alanine enantiomers). Prebiotics increased hippocampal BDNF and NR1 subunit expression relative to controls. The intake of GOS also increased hippocampal NR2A subunits, and frontal cortex NR1 and d-serine. Prebiotics did not alter glutamate, glutamine, l-serine, l-alanine or d-alanine concentrations in the brain, though GOSfeeding raised plasma d-alanine. Elevated levels of plasma peptide YY (PYY) after GOS intake was observed. Plasma from GOS rats increased the release of BDNF from SH-SY5Y cells, but not in the presence of PYY antisera. The addition of synthetic PYY to SH-SY5Y cell cultures, also elevated BDNF secretion. We conclude that prebiotic-mediated proliferation of gut microbiota in rats, like probiotics, increases brain BDNF expression, possibly through the involvement of gut hormones. The effect of GOS on components of central NMDAR signalling was greater than FOS, and may reflect the proliferative potency of GOS on microbiota. Our data therefore, provide a sound basis to further investigate the utility of prebiotics in the maintenance of brain health and adjunctive treatment of neuropsychiatric disorders.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Prebióticos , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Animais , Bifidobacterium/isolamento & purificação , Peso Corporal , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Fezes/microbiologia , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Humanos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The neurotransmitter glutamate is increasingly being implicated as playing a role in the molecular pathology underlying depression. The group III family of metabotropic glutamate (mGlu) receptors (mGlu(4,) mGlu(7) and mGlu(8) receptors) remains the most poorly investigated of all glutamate receptors in this regard, despite early research efforts showing that they may be major players in stress-induced pathology, genetic vulnerability to the onset of depression and in the action of pharmacotherapies. To redress this deficit, we investigated whether the mRNA levels of the group III mGlu receptors display sensitivity to the preclinical stress models' chronic immobilisation stress (CIS) in BALB/c mice and chronic social defeat in BALB/c and C57BL/6j mice. We also investigated the potential of the mood stabiliser lithium to reverse any stress-induced alterations to expression levels of the group III mGlu receptors. Furthermore, we investigated if changes to hippocampal group III mGlu receptors are involved in the augmentation strategy of administering lithium in conjunction with the tricyclic antidepressant desipramine using BALB/c mice. Finally, we investigated whether differences in hippocampal group III mGlu receptors exist between the non-helpless NH/Rouen mouse line and the helpless H/Rouen line. We found no changes to hippocampal group III mGlu receptor expression in any of the stress models investigated, the H/Rouen mouse genetic model of depression or due to pharmacological treatment. This indicates that these receptors may not be involved in the manifestation of behavioural and physiological changes observed in these models and furthermore, may not contribute to the therapeutic mechanisms of the above mentioned pharmacotherapies.
Assuntos
Antidepressivos/farmacologia , Depressão/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/genética , Estresse Psicológico/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Desipramina/farmacologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Cloreto de Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , RNA Mensageiro/análise , RNA Mensageiro/genética , Restrição Física/psicologiaRESUMO
There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
Assuntos
Emoções/fisiologia , Lactobacillus/fisiologia , Receptores de GABA/genética , Nervo Vago/fisiologia , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Animais , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Corticosterona/sangue , DNA Bacteriano/genética , Depressão/fisiopatologia , Febre/sangue , Febre/microbiologia , Febre/fisiopatologia , Expressão Gênica , Interações Hospedeiro-Patógeno , Hibridização In Situ , Lactobacillus/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Atividade Motora/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-B/genética , Especificidade da Espécie , Vagotomia , Nervo Vago/cirurgiaRESUMO
This study investigated the key aspects of a successful integration experience into mental health nursing from the perspectives of new nurses working in a psychiatric institution. Analysis of 10 semistructured interviews revealed that the relational atmosphere in which new nurses find themselves is determinant of their satisfaction with their integration experience. Quality relational connections with patients constitute the primary motivation of new nurses in choosing a career in mental health. At the same time, quality relational connections between and among team members sustain such motivation. Conversely, a negative relational atmosphere sets the stage for new nurses to experience disillusionment and despair.
Assuntos
Satisfação no Emprego , Enfermagem Psiquiátrica , Hospitais Psiquiátricos , Humanos , Entrevistas como Assunto , Motivação , Relações Enfermeiro-Paciente , Equipe de Assistência ao Paciente , Reorganização de Recursos Humanos , Recursos HumanosRESUMO
Early-life stress can induce marked behavioral and physiological impairments in adulthood including cognitive deficits, depression, anxiety, and gastrointestinal dysfunction. Although robust rat models of early-life stress exist there are few established effective paradigms in the mouse. Genetic background and protocol parameters used are two critical variables in such model development. Thus we investigated the impact of two different early-life stress protocols in two commonly used inbred mouse strains. C57BL/6 and innately anxious BALB/c male mice were maternally deprived 3 h daily, either from postnatal day 1 to 14 (protocol 1) or 6 to 10 (protocol 2). Animals were assessed in adulthood for cognitive performance (spontaneous alternation behavior test), anxiety [open-field, light/dark box (L/DB), and elevated plus maze (EPM) tests], and depression-related behaviors (forced swim test) in addition to stress-sensitive physiological changes. Overall, the results showed that early-life stressed mice from both strains displayed good cognitive ability and no elevations in anxiety. However, paradoxical changes occurred in C57BL/6 mice as the longer protocol (protocol 1) decreased anxiety in the L/DB and increased exploration in the EPM. In BALB/c mice there were also limited effects of maternal separation with both separation protocols inducing reductions in stress-induced defecation and protocol 1 reducing the colon length. These data suggest that, independent of stress duration, mice from both strains were on the whole resilient to the maladaptive effects of early-life stress. Thus maternal separation models of brain-gut axis dysfunction should rely on either different stressor protocols or other strains of mice.
RESUMO
Stress can impair the immune, endocrine and nervous systems. Such perturbations can also affect brain-gut axis communication and lead to functional gastrointestinal disorders such as irritable bowel syndrome (IBS). IBS is a common yet poorly understood disorder which is often co-morbid with anxiety and depression. As there are few mouse models of IBS, this study aimed to investigate if a short and intense social stress which involved bouts of physical interaction could induce behavioural and physiological changes similar to those observed in IBS patients in the innately anxious BALB/c mice. Male BALB/c mice were exposed for 2h to an aggressive male intruder for acute (one-day) or chronic (six-day) stress. Behaviour was analyzed and weight monitored. Two hours post stress, trunk blood and tissues were collected. Plasma was analyzed for inflammatory cytokines and corticosterone and morphological damage to the colon was also assessed. Mice displayed either dominant or submissive status following repeated intruder exposure. Behavioural status correlated with an increase in corticosterone and pro-inflammatory cytokines in both acute and chronic submissive groups. Mice from both status groups had body weight loss coupled with mild damage to the colon. Together these data show that short-term social interaction stress exposure was able to induce behavioural and physiological impairments similar to that observed in patients with dysregulated brain-gut axis function. Moreover, these data demonstrate that social stress-based mouse models may be appropriate for interrogating the mechanisms underlying such disorders.
Assuntos
Colo/patologia , Dominação-Subordinação , Síndrome do Intestino Irritável/etiologia , Estresse Psicológico/complicações , Adaptação Fisiológica , Análise de Variância , Animais , Corticosterona/sangue , Citocinas/sangue , Modelos Animais de Doenças , Síndrome do Intestino Irritável/patologia , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Comportamento Social , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologiaRESUMO
The neurokinin 3 (NK3) receptor is a novel target under investigation for improvement of symptoms of schizophrenia, because of its ability to modulate dopaminergic signaling. To further understanding of the function of this receptor, sensitivity to dopaminergic stimuli and levels of dopaminergic receptors and tyrosine hydroxylase in NK3 receptor knockout mice were studied. Knockout of the receptor was confirmed by lack of NK3 protein and lack of electrophysiological responsivity of presumed dopaminergic neurons to senktide. NK3 receptor knockout mice showed mild hyperlocomotion and deficits on the rotarod. NK3 receptor knockout mice did not show significant differences in sensitivity to locomotor effects of acute amphetamine (0.3, 1, and 3 mg/kg subcutaneously) or significant alterations in sensitization to locomotor effects of amphetamine, but did show nonsignificant hyperreactivity to 1 mg/kg amphetamine and a nonsignificantly increased propensity to develop sensitization. A small decrease in D1 receptor binding was seen in the dorsal striatum and olfactory tubercle, and a small decrease of in tyrosine hydroxylase in the olfactory tubercle, but no change was seen in D2 receptor binding. Together, these results support a role for the NK3 receptor in reactivity to dopaminergic stimuli, but the lack of robust changes indicates that the sensitivity to dopamine may be activity-dependent or benign in nature.