Biology subjects

Getselter, D.

Publications and source records attributed to Getselter, D..

6 recordsLinked to original sources

bioRxiv2024

CHD8 adulthood microglial knockout induces behavioral, morphological, and transcriptional changes in a sex-dependent manner

AbstractMutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional transgenic mouse models, we determined that adulthood deletion of CHD8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockout had more subtle effects on behavior, mainly on depression-like behavior, and induced subtle changes in gene transcription related to the Wnt/Beta-Catenin pathway. These changes were also only present in male neuron knockout mice. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males.

neuroscience↗

bioRxiv2024

Forebrain neuronal SMC3 regulates body weight and metabolic health partially through regulation of hypothalamic Melanocortin 4 receptor

SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Excitatory conditional neuron-specific SMC3 knockout (cKO) mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus displayed dysregulated neuronal morphology and associated transcriptional abnormalities in RNA-seq analysis across various cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level, a pivotal regulator of appetite and metabolism. Correspondingly, ChIP-seq analysis revealed genome-wide alterations in the binding dynamics of SMC3 of the cKO animals, including Mc4r associated regions. Notably, a significant correlation emerged between multiple sites exhibiting a marked decrease in binding and downregulated genes. The administration of Setmelanotide, an MC4r agonist, to cKO group resulted in a notable reduction in both weight and food consumption in these mice. Therefore, we have identified specific and reversable metabolic parameters that are regulated by neuronal Smc3 in adulthood.

neuroscience↗

bioRxiv2023

CTCF regulates anxiety and depression like behavior and maintenance of neuronal identity in the adult mouse brain

CCCTC-binding factor (CTCF) is a chromatin binding factor that binds to DNA sequence specific sites and, together with cohesin complex, establishes chromatin loops and regulates gene expression. CTCF was previously implicated as a major contributor in neural development. Genetic aberrations in CTCF are associated with intellectual disability, aggression, attention deficit, and autistic behavior. Previous mice-model studies have identified a necessary role for CTCF during development of CaMKIIa expressing excitatory neurons in the ability of learning and memory. However, it is not clear if CTCF is only necessary for development in the brain, or also in maintenance of neuronal functions and behavior in the adulthood. In the current study, adulthood-specific knockout of CTCF in excitatory neurons induced an elevation in anxiety and depression related behavior and a decrease in seeking social novelty. Depression and apathy-like behavior was reversed by treatment with serotonin specific reuptake inhibitor sertraline. Golgi staining analysis reveals major regression of dendritic complexity in the hippocampus and prefrontal cortex. In parallel, there is increased DNA compaction and decreased global H3K9 acetylation. Single nuclei RNA sequencing confirms a retreat in neuronal subtype identity in excitatory neurons after knockout. Gene ontology analysis display upregulation of genes that related regulation of cell population, neuronal development and neuronal differentiation and migration. These findings determine that CTCF is required for a propriate function of the mature excitatory neurons, independent of roles during development. Significance StatementThe gene CTCF is an important regulator of gene expression. Mutations in CTCF have been identified in individuals with a range of neurodevelopmental disorders, including intellectual disability and autism. However, it is unknown if CTCF is important only for neuronal development, or plays functional roles in the brain during adulthood. The current study finds that CTCF deletion during adulthood in excitatory neurons induces a behavioral phenotype that that includes increase in anxiety and depression-like behavior and changes in social behavior. In addition, CTCF depletion in adulthood affects the morphology, identity and gene expression of these specific types of neurons. Therefore, CTCF is not only important in brain development, but also in maintenance of proper neuronal function and behavior during adulthood.

neuroscience↗

bioRxiv2023

Aggression: A gut reaction? The effects of gut microbiome on aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. In our investigation, we meticulously examined the behavioral patterns of four groups of mice - wild-type, germ-free (GF), mice treated with antibiotics, and recolonized GF mice - to gain mechanistic insights into the impact of the gut microbiome on aggression. We discovered a significant correlation between diminished microbiome and increased aggression. Importantly, this behavioral shift could be restored when a WT microbiota was reinstated. Microbiota manipulation also significantly altered brain function, particularly in aggression-associated genes, and urine metabolite profiles. Notably, our study extends beyond the murine model, shedding light on clinical implications of early-life antibiotic exposure. We found that fecal microbiome transplants from 1mo old infants prescribed antibiotics during their first days of life led to a marked increase in aggression in recipient mice. This research demonstrates that the microbiota modulates aggression and underscores its importance in the realm of behavioral science. One-Sentence SummaryThe antibiotic-altered gut microbiome is implicated in increased aggression. It also leads to altered brain function, particularly in genes linked to aggression, and urine metabolite profiles showing a multi-system response to microbiota disruption.

animal behavior and cognition↗

bioRxiv2023

Bacteroides is increased in an autism cohort and induces autism-relevant behavioral changes in mice in a sex-dependent manner

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition which is defined by decreased social communication and the presence of repetitive or stereotypic behaviors. Recent evidence has suggested that the gut-brain axis may be important in neurodevelopment in general and may play a role in ASD in particular. Here, we present a study of the gut microbiome in 96 individuals diagnosed with ASD in Israel, compared to 42 neurotypical individuals. We determined differences in alpha and beta diversity in the microbiome of individuals with ASD and demonstrated that the phylum Bacteroidetes and genus Bacteroides were the most significantly over-represented in individuals with ASD. To understand the possible functional significance of these changes, we treated newborn mice with Bacteroides fragilis at birth. B. fragilis-treated male mice displayed social behavior dysfunction, increased repetitive behaviors and gene expression dysregulation in the prefrontal cortex, while female mice did not display behavioral deficits. These findings suggest that overabundance of Bacteroides, particularly in early life, may have functional consequences for individuals with ASD.

neuroscience↗

bioRxiv2021

CHD8 regulates gut epithelial cell function and affects autism-related behaviours through the gut-brain axis

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.

neuroscience↗