Genetic and brain-epigenetics in a behavioural disorder model in chicken
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ABSTRACT: DNA-methylation changes in the brain and fixation of alleles between chicken lineages due to the selection on two extremes of a maladaptive behaviour
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. This SuperSeries is composed of the following subset Series:; GSE14902: The relationship between brain mRNA levels and behaviour among inbred Lewis rats: Experiment 1; GSE14903: The relationship between brain mRNA levels and behaviour among inbred Lewis rats: Experiment 2 Experiment Overall Design: Refer to individual Series
Project description:Sporadic heterozygous mutations in SYNGAP1 affect social and emotional behaviour that are often observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape of SYNGAP1 mutation-mediated intellectual disability is unexplored. Here, we have surprisingly found that the p300/CBP specific acetylation marks of histones are significantly repressed in the adolescent hippocampus of Syngap1+/- mouse. To establish the causal relationship of Syngap1+/- phenotype and the altered histone acetylation signature we have treated 2-4 months old Syngap1+/- mouse with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored deficits in spine density, synaptic function, and social preferences of Syngap1+/- mouse that is very closely comparable to wild type littermates. The hippocampal RNA-Seq analysis of the treated mice revealed that the expression of many critical genes related to the ID/ASD reversed due to the treatment of the specific small molecule activator. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification (s).
Project description:Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring.
Project description:The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focussed on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice locally lacking STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the immune system, serotonergic neurotransmission and psychopathology.
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. Experiment Overall Design: Ten rats with varying behavioural phenotypes were analyzed. 4 behaviour tests: SF, locomotion, ASR, and PPI.
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. Keywords: Phenotype-Association Study
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. Keywords: Phenotype-Association Study
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. Experiment Overall Design: Nine rats with varying behavioural phenotypes were analyzed. Three behavioural tests: SF, locomotion, and ASR.
Project description:Behaviour is derived from complex molecular interactions within the brain, in response to specific environmental stimuli. In some rare cases, the direct causes of behaviour have been attributed to the interactions of a single or small group of gene transcripts and proteins. We conducted two experiments with the hope of defining some of the molecular interactors for four separate behaviours: sugar feeding, locomotor activity in a novel field, and acoustic startle reflex, and prepulse inhibition of the acoustic startle reflex, which have been linked to prefrontal cortex dopaminergic function or as predictors of sensorimotor gating in diseases such as schizophrenia. Rats with high and low response phenotypes were selected to determine the differences between these two extremes of behaviour. From our analyses, transcripts of Homer1, a neuronal scaffolding protein which interacts with group1 metabotropic glutamate receptors, were found to be significantly correlated with array data in both experiments, and with behaviour data across three separate tests in the second experiment, indicating that this gene's transcripts and probably downstream protein interactions have a significant correlation with behaviour phenotype in the inbred Lewis rat. Future areas of pursuit for this data should involve modification of the expression of Homer1 in an isolated fashion to determine a pharmacological threshold for differences in behaviour. This SuperSeries is composed of the SubSeries listed below.