A Drosophila model for the role of epigenetics in brain function and development

A genetic study in Drosophila gives important insights into the epigenetic control of gene expression implicated in a human mental retardation syndrome

Collective unconscious: How gut microbes shape human behavior

peer-reviewedThe human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately 1 kg of bacteria in the average adult, approximately the weight of the human brain. The evolutionary formation of a complex gut microbiota in mammals has played an important role in enabling brain development and perhaps sophisticated social interaction. Genes within the human gut microbiota, termed the microbiome, significantly outnumber human genes in the body, and are capable of producing a myriad of neuroactive compounds. Gut microbes are part of the unconscious system regulating behavior. Recent investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. In the absence of microbes, underlying neurochemistry is profoundly altered. Studies of gut microbes may play an important role in advancing understanding of disorders of cognitive functioning and social interaction, such as autism

Probiotic modulation of the microbiota-gut-brain axis and behaviour in zebrafish

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

Probiotic modulation of the microbiota-gut-brain axis and behaviour in zebrafish

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

Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice

Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation, such as those found in autism spectrum disorders (ASDs)

The microbiome regulates amygdala-dependent fear recall

The amygdala is a key brain region that is critically involved in the processing and expression of anxiety and fear-related signals. In parallel, a growing number of preclinical and human studies have implicated the microbiome-gut-brain in regulating anxiety and stress-related responses. However, the role of the microbiome in fear-related behaviours is unclear. To this end we investigated the importance of the host microbiome on amygdala-dependent behavioural readouts using the cued fear conditioning paradigm. We also assessed changes in neuronal transcription and post-transcriptional regulation in the amygdala of naive and stimulated germfree (GF) mice, using a genome-wide transcriptome profiling approach. Our results reveal that GF mice display reduced freezing during the cued memory retention test. Moreover, we demonstrate that under baseline conditions, GF mice display altered transcriptional profile with a marked increase in immediate-early genes (for example, Fos, Egr2, Fosb, Arc) as well as genes implicated in neural activity, synaptic transmission and nervous system development. We also found a predicted interaction between mRNA and specific microRNAs that are differentially regulated in GF mice. Interestingly, colonized GF mice (ex-GF) were behaviourally comparable to conventionally raised (CON) mice. Together, our data demonstrates a unique transcriptional response in GF animals, likely because of already elevated levels of immediate-early gene expression and the potentially underlying neuronal hyperactivity that in turn primes the amygdala for a different transcriptional response. Thus, we demonstrate for what is to our knowledge the first time that the presence of the host microbiome is crucial for the appropriate behavioural response during amygdala-dependent memory retention

The orphan nuclear receptor TLX regulates hippocampal transcriptome changes induced by IL-1β

TLX is an orphan nuclear receptor highly expressed within neural progenitor cells (NPCs) in the hippocampus where is regulates proliferation. Inflammation has been shown to have negative effects on hippocampal function as well as on NPC proliferation. Specifically, the pro-inflammatory cytokine IL-1β has been shown to suppress NPC proliferation as well as TLX expression in the hippocampus. However, it is unknown whether TLX itself is involved in regulating the inflammatory response in the hippocampus. To explore the role of TLX in inflammation, we assessed changes in the transcriptional landscape of the hippocampus of TLX knockout mice (TLX-/-) compared to wildtype (WT) littermate controls with and without intrahippocampal injection of IL-1β using a whole transcriptome RNA sequencing approach. We demonstrated that there is an increase in the transcription of genes involved in the promotion of inflammation and regulation of cell chemotaxis (Tnf, Il1b, Cxcr1, Cxcr2, Tlr4) and a decrease in the expression of genes relating to synaptic signalling (Lypd1, Syt4, Cplx2) in cannulated TLX-/- mice compared to WT controls. We demonstrate that mice lacking in TLX share a similar increase in 176 genes involved in regulating inflammation (e.g. Cxcl1, Tnf, Il1b) as WT mice injected with IL-1β into the hippocampus. Moreover, TLX-/- mice injected with IL-1β display a blunted transcriptional profile compared to WT mice injected with IL-1β. Thus, TLX-/- mice, which already have an exaggerated inflammatory profile after cannulation surgery, are primed to respond differently to an inflammatory stimulus such as IL-1β. Together, these results demonstrate that TLX regulates hippocampal inflammatory transcriptome response to brain injury (in this case cannulation surgery) and cytokine stimulation

KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.Beca Ramón y CajalGAIN- Agencia Gallega de Innovació

Regulation of prefrontal cortex myelination by the microbiota

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

Host microbiota regulates central nervous system serotonin receptor 2C editing in rodents

Microbial colonization of the gastrointestinal tract plays a crucial role in the development of enteric and central nervous system functionality. The serotonergic system has been heavily implicated in microbiota–gut–brain axis signaling, particularly in proof-of-principle studies in germ-free (GF) animals. One aspect of the serotonergic system that has been left unexplored in relation to the microbiota is the unique ability of the serotonin receptor 2C (5-HT2C) to undergo post-transcriptional editing, which has been implicated in decreased receptor functionality. We investigated whether GF mice, with absent microbiota from birth, have altered 5-HT2C receptor expression and editing in the brain, and if colonization of the microbiota is able to restore editing patterns. Next, we investigated whether microbiota depletion later in life using a chronic antibiotic treatment could affect 5-HT2C receptor editing patterns in rats. We found that GF mice have an increased prevalence of the edited 5-HT2C receptor isoforms in the amygdala, hypothalamus, prefrontal cortex, and striatum, which was partially normalized upon colonization post-weaning. However, no alterations were observed in the hypothalamus after microbiota depletion using an antibiotic treatment in adult rats. This suggests that alterations in the microbiome during development, but not later in life, could influence 5-HT2C receptor editing patterns. Overall, these results demonstrate that the microbiota affects 5-HT2C receptor editing in the brain and may inform novel therapeutic strategies in conditions in which 5-HT2C receptor editing is altered, such as depression