Behavioral, Neurotransmitter and Transcriptomic Analyses in male and female Fmr1 Knockout Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275170 | GEO | 2024/08/26
REPOSITORIES: GEO
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Project description:The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is Fragile X syndrome (FXS), an NDD caused by the dysfunctional RNA binding protein FMRP. Here we demonstrate how the brain region-specific composition of post-synaptic density (PSD) contributes to FXS. The FXS mouse model shows, in the striatum, an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, that is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
2023-06-08 | PXD040331 | Pride
Project description:Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences for which there are currently no FDA approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes related to protein folding, mRNA processing, immune signaling, and neurotransmission in striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analysis. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion did not alter methamphetamine-seeking behavior following 21 days of abstinence, highlighting the complexity of drug-seeking behaviors. Taken together, these results suggest that methamphetamine induces both short and long-term changes in striatal microglia that contribute to altered drug-taking behavior and may be leveraged for preclinical development of methamphetamine cessation therapeutics.
2024-06-11 | GSE245951 | GEO
Project description:During the nest-founding phase of the bumble bee colony cycle, queens undergo striking changes in maternal care behavior. Early in the founding phase, prior to the emergence of workers in the nest, queens are reproductive and also provision and feed their offspring. However, later in the founding phase, queens cease feeding offspring and become specialized on reproduction. This transition is synchronized with the emergence of workers in the colony, who assume the task of feeding their siblings. Using a social manipulation experiment, we tested the hypothesis that workers socially regulate the transition from feeding brood to specialization on reproduction in nest-founding bumble bee queens. Consistent with this hypothesis, we found that early-stage queens with workers prematurely added to their nests reduce their brood-feeding behavior and increase egg-laying, and likewise, late-stage queens increase their brood-feeding behavior and decrease egg-laying when workers are removed from their nests. Further, brood-feeding and egg-laying behavior were negatively correlated in these queens. We used an Agilent brain EST-based microarray to explore a second hypothesis, that workers alter brain gene expression in nest-founding queens. We found evidence that brain gene expression in nest-founding queens is altered by the presence of workers, with the effect much stronger in late-stage founding queens. Additionally, expression levels of some genes were correlated with quantitative differences in brood-feeding and egg-laying behavior. This study provides new insights into how the transition from feeding brood to specialization on reproduction in bumble bee queens is regulated during the nest initiation phase of the colony cycle.
2014-06-21 | E-MTAB-1855 | biostudies-arrayexpress
Project description:Propranolol is a beta-adrenergic receptor antagonist (β-blocker) that has been detected in United States wastewater effluents at concentrations ranging from 0.026 to 1.90 µg/l. In mammals, there is evidence that β-blockers can cause sexual dysfunction, and alter serotonergic pathways which may impact reproductive behavior but little is known about the effects on fish behavior. The present study tested the effects of propranolol on fecundity and on reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal concentrations of 0, 0.1, 1, 10 µg/l for 21 days. Measured concentrations (±SD) of propranolol were 0.05±0.02, 0.88±0.34 and 4.11±1.19 µg/l. There were no statistically significant differences in fecundity, fertilization rate, hatchability and time to hatch. Propranolol exposure was not associated with a change in nest rubbing behavior, time spent in the nest or approaching the females. There was a significant difference in the number of visits to the nest with males receiving low and medium propranolol treatments. The microarray analysis showed that there were 335 genes up-regulated and 400 genes down-regulated in the brain after exposure to the highest dose of propranolol. Among those genes, myoglobin and calsequestrin transcripts (fold change=10.84 and 5.49, respectively) were highly up-regulated. Ontological analyses indicated changes in genes involved in calcium ion transport, transcription, proteolysis and apoptosis/anti-apoptosis. The results showed that exposure to propranolol at concentrations as high as 4.11 µg/l did not significantly impact reproductive behavior or spawning abilities of fathead minnow but did alter the regulation of genes within the brain of fish. Effects of propanolol exposure were investigated in the brain of adult male fathead minnow exposed to 10 µg/L of propanolol or a solvent control solution (0.01% ethanol). For each treatment, the brain of four different fish were analyzed.
2012-05-31 | E-GEOD-34947 | biostudies-arrayexpress
Project description:Social behaviors are essential for survival and reproduction and vary strongly among individuals, species, and heritable brain diseases. The molecular and cellular bases of this variation are poorly resolved, and discovering them is necessary to understand how neural circuit and behavioral functions—and dysfunctions—vary in social contexts. Here we integrate single nucleus RNA-sequencing (snRNA-seq) with comparative genomics and automated behavior analysis to investigate the neurobiology of castle-building, a recently-evolved social, spatial, goal-directed, and repetitive construction behavior in Lake Malawi cichlid fishes. We simultaneously control for and analyze two biological variables correlated with castle-building behavior: quivering, a courtship “dance” behavior, and relative gonadal mass. We find signatures of building-, quivering-, and gonadal-associated neuronal excitation, gene expression, and neurogenesis in distinct cell populations. Converging lines of evidence support the involvement of estrogen, TrkB, and CCK signaling systems, and specific pallial excitatory neuronal subpopulations, in castle-building behavior. We show additional evidence that castle-building has evolved in part through genomic divergence in a gene module that is selectively expressed in stem-like quiescent radial glial cells (RGCs) lining the ventricular zone of the pallium. This RGC subpopulation exhibits signatures of a building-associated departure from quiescence, which in turn is associated with neuronal rebalancing in the putative fish homologue of the hippocampus. Our work supports an unexpected role for glia and neurogenesis in the evolution of social behavior, and more broadly shows how snRNA-seq can be used to systematically profile the cellular bases of previously unstudied social behaviors in new species systems.
2023-06-14 | GSE217615 | GEO
Project description:Social behaviors are essential for survival and reproduction and vary strongly among individuals, species, and heritable brain diseases. The molecular and cellular bases of this variation are poorly resolved, and discovering them is necessary to understand how neural circuit and behavioral functions—and dysfunctions—vary in social contexts. Here we integrate single nucleus RNA-sequencing (snRNA-seq) with comparative genomics and automated behavior analysis to investigate the neurobiology of castle-building, a recently-evolved social, spatial, goal-directed, and repetitive construction behavior in Lake Malawi cichlid fishes. We simultaneously control for and analyze two biological variables correlated with castle-building behavior: quivering, a courtship “dance” behavior, and relative gonadal mass. We find signatures of building-, quivering-, and gonadal-associated neuronal excitation, gene expression, and neurogenesis in distinct cell populations. Converging lines of evidence support the involvement of estrogen, TrkB, and CCK signaling systems, and specific pallial excitatory neuronal subpopulations, in castle-building behavior. We show additional evidence that castle-building has evolved in part through genomic divergence in a gene module that is selectively expressed in stem-like quiescent radial glial cells (RGCs) lining the ventricular zone of the pallium. This RGC subpopulation exhibits signatures of a building-associated departure from quiescence, which in turn is associated with neuronal rebalancing in the putative fish homologue of the hippocampus. Our work supports an unexpected role for glia and neurogenesis in the evolution of social behavior, and more broadly shows how snRNA-seq can be used to systematically profile the cellular bases of previously unstudied social behaviors in new species systems.
2023-06-12 | GSE211477 | GEO
Project description:Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein-protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.
2023-06-30 | GSE224521 | GEO
Project description:Most behaviors are associated with heritable genetic variation. Genetic mapping has revealed genomic regions or, in a few cases, specific genes explaining part of this variation. However, understanding how genetic divergence shapes behavioral evolution remains unclear. Here we analyze the evolution of an innate extended phenotype: bower building among male cichlid fish of Lake Malawi, which build bowers of two types, pits and castles. F1 hybrids of pit-digging and castle-building species perform sequential construction of first pit and then castle bowers. Analysis of brain gene expression in these hybrids showed that genes near behavior-associated variants display behavior-dependent allele-specific expression with preferential expression of the pit-species allele during pit digging, and of the castle-species allele during castle building. These genes are highly enriched for functions and pathways involved in neurodevelopment and neural plasticity. Our results suggest that natural behaviors can be associated with complex genetic architectures that alter behavior via cis-regulatory differences whose effects on gene expression are specific to the behavior itself.
2017-06-01 | GSE97490 | GEO
Project description:Propranolol is a beta-adrenergic receptor antagonist (β-blocker) that has been detected in United States wastewater effluents at concentrations ranging from 0.026 to 1.90 µg/l. In mammals, there is evidence that β-blockers can cause sexual dysfunction, and alter serotonergic pathways which may impact reproductive behavior but little is known about the effects on fish behavior. The present study tested the effects of propranolol on fecundity and on reproductive behavior of the fathead minnow, Pimephales promelas, a fish that exhibits male parental care. Sexually mature fathead minnows were housed at a ratio of one male and two females per tank and exposed to nominal concentrations of 0, 0.1, 1, 10 µg/l for 21 days. Measured concentrations (±SD) of propranolol were 0.05±0.02, 0.88±0.34 and 4.11±1.19 µg/l. There were no statistically significant differences in fecundity, fertilization rate, hatchability and time to hatch. Propranolol exposure was not associated with a change in nest rubbing behavior, time spent in the nest or approaching the females. There was a significant difference in the number of visits to the nest with males receiving low and medium propranolol treatments. The microarray analysis showed that there were 335 genes up-regulated and 400 genes down-regulated in the brain after exposure to the highest dose of propranolol. Among those genes, myoglobin and calsequestrin transcripts (fold change=10.84 and 5.49, respectively) were highly up-regulated. Ontological analyses indicated changes in genes involved in calcium ion transport, transcription, proteolysis and apoptosis/anti-apoptosis. The results showed that exposure to propranolol at concentrations as high as 4.11 µg/l did not significantly impact reproductive behavior or spawning abilities of fathead minnow but did alter the regulation of genes within the brain of fish.
2012-06-01 | GSE34947 | GEO
Project description:SMC3 is a chromatin binding factor that plays central roles in genome organization and in proper neurodevelopment. Mutations in SMC3 gene (SMC3) induce neurodevelopmental and behavioral phenotypes in humans, including changes in anxiety behavior and self-injury. However, it is not clear what are the exact roles of SMC3 in behavior in adulthood or if its effects are only developmental. Using an adulthood forebrain excitatory neuron specific Smc3 knockout mouse model, the current study determined specific sex-dependent effects of SMC3 ablation during the adulthood. Behavioral tests identified anxiolytic effects of Smc3 knockout in females and anxiogenic effects in males four weeks after initiation of adulthood knockout. The prefrontal cortex, a regulator of anxiety behavior, also displayed sex-dependent effects in dendritic complexity. Transcriptional analysis revealed differential effects of Smc3 knockout in males and females, including changes in anxiety-related genes and relevant transcriptional pathways. While anxiety behavior was sex-specific, both males and females developed self-injury behavior at approximately ten weeks after induction of knockout. The current study demonstrates that neuronal SMC3 regulates anxiety during the adulthood in a sex-specific manner.
2024-09-01 | GSE270835 | GEO